Advertisement

Diagnostic Applications of Nuclear Medicine: Multiple Myeloma

  • Martina Sollini
  • Sara Galimberti
  • Roberto Boni
  • Paola Anna ErbaEmail author
Living reference work entry

Latest version View entry history

Abstract

Multiple myeloma represents about 1.8% of all cancers and 10% of all hematologic malignancies.

Multiple myeloma (MM) is the most common primary bone cancer. The clonal proliferation of malignant plasma cells in the bone marrow may result both in local growth and in systemic effects due to the overproduction of a monoclonal protein (M-protein). Plasma cell proliferation is linked to a variety of clinical presentations of the disease, ranging from simple monoclonal gammopathy of undetermined significance (MGUS) to smoldering myeloma (SMM) to full-blown “malignant” MM. MM differs from MGUS and SMM by the presence of the end-organ damage associated with a complex syndrome named CRAB. However, in the updated version of the criteria for the diagnosis of plasma cell proliferative disorders established by the International Myeloma Working Group (IMWG), more specific criteria have been established to define MM, MGUS, and SMM. Excess bone marrow plasmacells, M-protein, osteolytic bone lesions, renal disease, and immunodeficiency constitute the pathophysiologic bases of the clinical manifestations of MM. Severe bone pain, pathologic fractures, spinal cord compression, and hypercalcemia are caused by lytic bone lesions. The course of MM is highly variable, and the clinical behavior is remarkably heterogeneous. Many studies have identified prognostic factors capable of predicting this heterogeneity in survival (serum β2-microglobulin, albumin, C-reactive protein, and lactate dehydrogenase). The standard workup of MM is based on a number of laboratory tests that are utilized for risk stratification. The International Staging System (ISS) is a powerful and reproducible three-stage classification in which the ISS3 class is associated with the poorest outcome. Imaging studies demonstrate the extent and severity of bone involvement (intramedullary/extramedullary, site and number of lesions) at baseline, including disease-related complications, such as pathologic fractures; they also serve to assess response to treatment and provide follow-up surveillance. The ISS introduced over 25 years ago is mainly based on serum β2-microglobulin and albumin levels, without any reference to the presence of bone lesions or to the methodology employed for their evaluation. Although the ISS serves as a prognostic indicator rather than as an accurate scoring system, it adequately estimates tumor burden and risk stratification, allowing differentiation of MGUS and SMM from MM. In 1975 Durie and Salmon introduced a clinical staging system based on the presence of bone lesions to grade the severity of the disease. While the original Durie and Salmon system was essentially based on the use of planar x-ray for evaluating bones, a newer version, the PLUS system was released in 2005 to improve the accuracy of staging with advanced imaging modalities such as [18F]FDG-PET/CT, and MRI.

Keywords

Multiple myeloma Bone tumor Multimodality imgaging Hematological malignancy 

Glossary

[18F]FDG

2-Deoxy-2-[18F]fluoro-d-glucose

68Ga-DOTATOC

68Ga-DOTA-octreotide

99mTc-HMPAO

99mTc-Hexamethylpropyleneamine oxime

99mTc-MDP

99mTc-Hydroxymethylene diphosphonate

99mTc(V)-DMSA

99mTc-Labeled pentavalent dimercaptosuccinic acid

ABCB 1

Member 1 of the adenosine triphosphate binding cassette superfamily B, also known as multidrug resistance protein 1

ASH

American Society of Hematology

ASCT

Autologous stem-cell bone marrow transplantation

BM

Bone marrow

CR

Complete response

CRAB

Hypercalcemia (C), renal failure (R), anemia (A), and bone lesions (B)

CT

X-ray computed tomography

DCE

Dynamic contrast-enhanced sequences

DEXA

Dual-energy X-ray absorptiometry

DKK1

Dickkopf 1, an inhibitor of osteoblast precursor cells

DMSA

Dimercaptosuccinic acid

DOTA

1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid

DWI

Diffusion-weighted imaging

ECOG

Eastern Cooperative Oncology Group

FDA

United States Food and Drug Administration

FISH

Fluorescent in situ hybridization

FLC

Free light chain

HDT

High-dose therapy

IMWG

International Myeloma Working Group

Ig

Immunoglobulin

Igh

Immunoglobulin heavy chain

IL

Interleukin

IMPeTUs

Italian Myeloma criteria for PET USe

ISS

International Staging System

LC

Laterocervical

LDCT

low-dose X-ray computed tomography

LDH

Lactate dehydrogenase

MDCT

Multidetector computed tomography

MDEs

Myeloma-defining events

MDR

Multidrug resistance

MGUS

Monoclonal gammopathy of undetermined significance

MIP-1α

Macrophage inflammatory protein 1-alpha

MIP

Maximum intensity projection

MM

Multiple myeloma

MR

Minor response

MRI

Magnetic resonance imaging

n-CR

No complete response

NOPR

National Oncologic PET Registry

OPG

Osteoprogeterin

OS

Overall survival

PAMP

Pathogen-associated myeloma cell proliferation

PCLI

Plasma cell-labeling index

PD

Progressive disease

PET

Positron emission tomography

PET/CT

Positron emission tomography/Computed tomography

PET/MRI

Positron emission tomography/Magnetic resonance imaging

PFS

Progression-free survival

Pgp

P-glycoprotein, also known as multidrug resistance protein 1, or ABCB 1 (member 1 of the adenosine triphosphate binding cassette superfamily B)

POEMS

Syndrome characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell proliferative disorder, and skin changes

PR

Partial response

PTHrP

Parathyroid hormone-related protein

RANK

Receptor activator of nuclear factor kappa B

SAP

Serum amyloid P

sCR

Stringent complete response

SD

Stable disease

SMM

Smoldering myeloma

SPECT

Single-photon emission computed tomography

SSTR

Somatostatin receptor

STIR

Short tau inversion recovery sequence, a modality of magnetic resonance imaging

SUVmax

Standardized uptake value at point of maximum

SUV

Standardized uptake value

Sv

Unit of ionizing radiation dose in the International System of Units based on the health effect of ionizing radiation on the human body

SWOG

Southwest Oncology Group

TLRs

Toll-like receptors

TNFalpha

Tumor necrosis factor alpha

TRANCE

Tumor necrosis factor-related activation induced cytokine

TTP

Time to progression

VDT-PACE

Intensive induction chemotherapy based on a combination of bortezomib, dexamethasone, thalidomide, plus a 4-day continuous infusion of cisplatin, adriamycin, cyclophosphamide, and etoposide

VDT

Chemotherapy based on bortezomib, thalidomide, and pegylated liposomal doxorubicin

VEGF

Vascular endothelial growth factor

VGPR

Very good partial response

VRD

Chemotherapy regimen based on the combination of Revlimid®, Velcade®, and dexamethasone

VRD

Bortezoib-lenalidomide-dexamethasone

WBCs

White blood cells

WBLD-CT

Whole-body low-dose computed tomography

WB-MRI

Whole-body magnetic resonance imaging

WB-MDCT

Whole-body multiple detector computed tomography

WBXR

Whole-body X-ray

Wnt

Wingless gene encoding for the proto-oncogene Int-1 homolog, also known as wingless-type MMTV integration site family

Overview of the Disease

Multiple myeloma represents about 1.8% of all cancers and about 10% of all hematologic malignancies. Multiple myeloma (MM) is the most common primary bone cancer. The number of new cases estimated in 2016 is more than 30,300 with over 12,650 deaths. Its incidence is higher in men (61%) and in african-americans; some categories of workers (i.e., farmers, workers in wood mills, paper mills, and furniture manufacturing plants) seem to be more prone to develop the disease. The peak of incidence occurs between 45 and 85 years of age, with a median of 69 years, and rarely patients are younger than 40 years (<2%) [1, 2].

Multiple myeloma was first described by Solly [3] in 1844. Solly described an inflammatory process that began with a “morbid action” of the blood vessels in which the “earthy matter of the bone is absorbed and thrown out by the kidneys in the urine.” In the early 1900s, Wright recognized plasma cells as the tumor cells present in MM [4].

The clonal proliferation of malignant plasma cells in the bone marrow (Fig. 1) may result both in local growth and in systemic effects due to the overproduction of a monoclonal protein (M protein), first described by Waldenstrom in 1961 as a narrow band of hypergammaglobulinemia on electrophoresis [5]. Most commonly, M protein is IgG (52%) or IgA (21%), rarely IgD or IgE. Biclonal plasma proteins can also be detected, such as IgG and IgA (33%) or IgG and IgM (24%); on the other hand, non-secretive (negative both serum and urine immunofixations) and light chain only subtypes have been described (1%) [6]. Almost all patients evolve from an asymptomatic premalignant stage termed monoclonal gammopathy of undetermined significance (MGUS); through the smoldering myeloma (SMM), to the “malignant” MM [1, 7].
Fig. 1

Plasma cells originate in bone marrow. Normal polyclonal plasma cells secrete different antibodies (blue, red, green). Atypical clonal plasma cells secrete only one type of immunoglobulin, with the same rearrangement of IgH

Historically, MM differs from MGUS and SMM by the presence of the end-organ damage associated with a complex syndrome named CRAB [8]: hypercalcemia (C), renal failure (R), anemia (A), and bone lesions (B). However, in the updated version of the criteria for the diagnosis of plasma cell proliferative disorders established by the International Myeloma Working Group (IMWG), more specific criteria have been established to define MM, MGUS, and SMM [8, 9] (Table 1).
Table 1

Criteria for the diagnosis of plasma cell proliferative disorders established by the International Myeloma Working Group [8, 9]

Disease

Diagnostic criteria

IMWG

Updated

Monoclonal gammopathy of undetermined significance ( MGUS)

All three criteria must be met:

Non-IgM MGUS

• Serum monoclonal protein <3 g/dL

• Serum monoclonal protein (non-IgM type) <30 g/L

• Clonal BM plasma cells <10%

• Clonal BM plasma cells <10%*

• Absence of end-organ damage attributable to the plasma cell proliferative disorder

• Absence of end-organ damage (CRAB) or amyloidosis attributable to the plasma cell proliferative disorder

IgM MGUS

• Serum IgM monoclonal protein <30 g/L

• BM lymphoplasmacytic infiltration <10%

• No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, hepatosplenomegaly, or other end-organ damage attributable to the underlying lymphoproliferative disorder

Light-chain MGUS

• Abnormal FLC ratio (<0.26 or >1.65)

• Increased level of the appropriately involved light chain (increased kFLC in patients with ratio >1.65 and increased λ FLC in patients with ratio <0.26)

• No immunoglobulin heavy chain expression on immunofixation

• Absence of end-organ damage (CRAB) or amyloidosis attributable to the plasma cell proliferative disorder clonal BM plasma cells <10%

 Urinary monoclonal protein <500 mg/24 h

Smoldering multiple myeloma (also referred to as asymptomatic multiple myeloma)

Both criteria must be met:

Both criteria must be met:

• Serum monoclonal protein (IgG or IgA) ≥3 g/dl and/or clonal BM plasma cells ≥10%

• Serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥ 500 mg per 24 h and/or clonal bone marrow plasma cells 10–60%

• Absence of end-organ damage attributable to a plasma cell proliferative disorder

• Absence of myeloma-defining events or amyloidosis

Multiple myeloma (MM)

All criteria must be met:

Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma (clonality should be established by showing k/λ-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence) and any one or more of the following myeloma-defining events:

• Clonal BM plasma cells ≥ 10% or biopsy-proven plasmacytoma

• Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically

 Hypercalcemia: serum calcium >11.5 mg/dL

• Evidence of end-organ damage attributable to the underlying plasma cell proliferative disorder, specifically:

 Renal insufficiency: serum creatinine >1.73 μmol/L (or >2 mg/dL) or estimated creatinine clearance <40 mL/min

 1. Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or > 2.75 mmol/L (>11 mg/dL)

 Anemia: normochromic, normocytic with a hemoglobin value of ≥2 g/dL below the lower limit of normal or a hemoglobin value <10 g/dL

 2. Renal insufficiency: creatinine clearance <40 mL per min† or serum creatinine >177 μmol/L (>2 mg/dL)

 Bone lesions: lytic lesions, severe osteopenia, or pathologic fractures

 3. Anemia: hemoglobin value of >20 g/L below the lower limit of normal or a hemoglobin value <100 g/L

 4. Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET/CT (if BM has <10% clonal plasma cells, >1 bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement)

• Any one or more of the following biomarkers of malignancy:

 1. Clonal BM plasma cell percentage ≥60% (clonality should be established by showing k/λ-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence; bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen)

 2. Involved: uninvolved serum free light-chain ratio ≥100 (values based on the serum Freelite assay; the involved free light chain must be ≥100 mg/L)

 3. >1 focal lesions on MRI studies (size ≥5 mm)

*Bone marrow can be deferred in patients with low-risk monoclonal gammopathy of undetermined significance (IgG type, monoclonal protein <15 g/L, normal free light-chain ratio) in whom there are no clinical features concerning for myeloma.

MGUS is distinguished in: (i) non-IgM MGUS (progression rate of 1%/year in MM, solitary plasmacytoma, or immunoglobulin-related amyloidosis), (ii) IgM-MGUS (progression rate of 1.5%/year in Waldenström macroglobulinemia or immunoglobulin-related amyloidosis), and (iii) light-chain MGUS (progression rate of 0.3%/year in light-chain MM or immunoglobulin light-chain amyloidosis).

Smoldering myeloma is defined as serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500 mg per 24 h and/or clonal bone marrow plasma cells 10–60% associated to the absence of myeloma-defining events or amyloidosis. On the other hand, MM is defined as clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma (clonality should be established by showing k/λ-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence; bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen) and any one or more of the following myeloma events defined as end-organ damage that can be attributed to the underlying plasma cell proliferative disorder (hypercalcemia, renal insufficiency, anemia, bone lesion).

The same revision stated that the patients with high-risk smoldering myeloma (free light-chain involved/uninvolved ratio >100, more than two focal lesions in the spine or pelvis after MRI evaluation, and more than 60% of clonal atypical plasma cells in the bone marrow, defined as “myeloma-defining events or MDEs) have to receive treatment, because of the very high probability (about 80%) of developing a CRAB sign in a short period [9].

A free light-chain ratio >100 has been described in about 15% of patients with smoldering myeloma; their risk of progression within 2 years was 64–72% [10, 11].

The micro-environment of the bone marrow appears to be crucial for the development, maintenance, and progression of the disease [12]. A proliferative trigger for plasma cells consequent to antigenic stimuli is responsible for plasma cell activation. Toll-like receptors (TLRs), pathogen-associated myeloma cell proliferation (PAMP), and CD126 are important key molecules in the process of plasma cells malignant transformation. Myeloma plasma cells are typically characterized by a very long life (with low thymidine-labeling index, 1–2%), while the other differentiation steps are maintained.

Primary translocations involving the immunoglobulin heavy chain locus on chromosome 14q32 are detectable in about 50% of MGUSs, while in symptomatic MM, several molecular abnormalities are present, such as Ras and/or TP53 and/or myc family mutations, p16 methylations, or secondary translocations [13]. High-matrix metalloproteinase-2 levels and enhanced neoangiogenesis are also detectable in MM with increased vascular density typical of active disease, thus suggesting a strong relationship between the progression of myeloma and neovascularisation [14].

Moreover, patients affected by smoldering myeloma but carrying t(4:14), 1q gain, or del(17p) showed a median time to progression (TTP) of 24 months and are considered as “at high risk.” Trisomies are associated to a TTP of 34 months, so defining a “intermediate risk” population, whereas other cytogenetic abnormalities and t(11;14) are considered as “at standard risk” (TTP 54 months) [15].

Excess bone marrow plasma cells, M protein, osteolytic bone lesions (present in >90% of patients), renal disease, and immunodeficiency [12] constitute the pathophysiologic bases of the clinical manifestations of MM. Severe bone pain, pathologic fractures (>70%), spinal cord compression (2–3%), and hypercalcemia (15%) are caused by lytic bone lesions (although spinal cord compression is sometimes caused by collapse of a vertebral body due to the disappearance of a lesion in response to therapy) [16].

Although bone lesions in MM can occur in any bone, lesions are found in the spine (49%), skull (35%), pelvis (34%), ribs (33%), and proximal portions of the arms and legs (22% and 13%, respectively) as well as in the mandible (10%). At diagnosis almost 10% of the patients present diffuse osteopenia or osteoporosis. MM bone disease involves more than 50% of a bone surface, and osteoblastic activity is drastically depressed or absent [17].

Transformed malignant plasma cells are responsible, both directly and indirectly, for local bone resorption, through activation of osteoclast activity and inhibition of the osteoblasts. In fact, myeloma cells secrete several osteoclast-activating factors (IL-1, IL-6, TNF-alpha) that stimulate the secretion of the so-called tumor necrosis factor-related activation induced cytokine (TRANCE); this compound interferes with osteoblast differentiation. Furthermore, IL-1, IL-6, and TNF-alpha stimulate the secretion of dickkopf 1 (DKK1), a potent inhibitor of osteoblast precursor cells. The myeloma cells frequently release also the parathyroid hormone-related protein (PTHrP). Figure 2 diagrammatically depicts some of those complex interactions.
Fig. 2

Schematic representation of interactions between MM cells and bone microenvironment (left panel) as compared to the physiological balance (right panel). Dickkopf 1, a potent inhibitor of osteoblast precursor cells (DKK1), over-inhibited in normal condition via wingless gene (Wnt), is activated by MM cells promoting osteoblasts activity and decreasing osteoprogeterin (OPG) circulating levels. Furthermore, cytokine (IL-1, IL-6, and MIP-1α) and RANK promoting osteoclasts tip the balance toward bone resorption resulting in the typical lytic bone appearance of MM lesions

The local proliferation of myeloma cells may lead to the appearance of a solid lesion that involves the soft tissue primarily arising outside the bone or extending from a preexistent bone lesion. In the absence of systemic spread (normal BM without evidence of clonal plasma cells, normal skeletal survey, and MRI/CT of spine and pelvis except for the primary solitary lesion), this situation is named solitary plasmacytoma [9, 18].

Excess protein produced by myeloma can increase the viscosity of plasma. Hyperviscosity is associated with impairment of the microcirculation, particularly in the eye and central nervous system causing visual impairment, dizziness, headache, and hearing loss. Rarely there is spontaneous bleeding [19] due to platelet dysfunction. Patients with myeloma are at increased risk of infection due to reduction of normal plasma cell function. Infections are potentially fatal complications that can occur during chemotherapy, at relapse or following bone marrow transplantation, and are most frequently caused by Streptococcus pneumoniae, Haemophilus influenzae, or Herpes zoster virus [20]. Other complications include myocardial ischemia or congestive heart failure due to deposition of light-chain protein (amyloid) in the myocardium causing dilated or restrictive cardiomyopathy, as well as a hypersensitivity syndrome and/or anemia [21].

Neuropathy in patients with myeloma is usually symmetric, distal sensory or sensory motor with axonal degeneration, often associated with amyloid deposits, or antibodies against peripheral myelinated fibers [22]. In 1% of the cases, myeloma occurs in a rare syndrome (POEMS syndrome) [12]: this syndrome is characterized by polyneuropathy, monoclonal plasma cell proliferative disorder (almost always λ) associated to one or more major criteria (sclerotic bone lesions, Castleman’s disease, or elevated levels of VEGF), and one or more minor criteria (organomegaly, extravascular volume overload, endocrinopathy, skin changes, papilledema thrombocytosis/polycythemia) [9].

Although the presence of lytic bone lesions is highly suggestive for MM, it is not by itself sufficient to establish the diagnosis. The minimum criteria for MM diagnosis are either the detection of at least 10% abnormal plasma cells in the bone marrow (after biopsy) or of M-protein levels >30 g/L in serum or >1 g excreted in the 24-h urine [8].

Initial investigation of a patient with suspected multiple myeloma should include family history (focus on first-degree relatives with the diagnosis of hematologic malignancies, especially lymphoma, chronic lymphocytic leukemia, and plasma cell dyscrasias), past medical history (focus on comorbid conditions, such as coronary artery disease, congestive heart failure, hypertension, renal disorders, liver disorders, and lung diseases), a complete blood count with differential, and a complete biochemistry (including liver function tests, renal function tests, electrolytes, calcium, and albumin) [23].

The clinical course of MM is highly variable, and the clinical behavior is remarkably heterogeneous. Many studies have identified prognostic factors capable of predicting this heterogeneity in survival (serum β2-microglobulin, albumin, C-reactive protein, and lactate dehydrogenase) [1].

The standard workup of MM is based on a number of laboratory tests that are utilized for risk stratification. The international staging system (ISS) is a powerful and reproducible three-stage classification (Table 2), in which ISS3 class is associated with the poorest outcome [8]. Such assessments include complete blood count, routine biochemistry and urine analysis, serum and urine protein electrophoresis (preferably on an aliquot of the 24-h collection), lactate dehydrogenase and β2-microglobulin levels, immunofixation of serum or urine sample for the detection of M component, nephelometry (for measuring the free light chains employed to monitor also patients with oligo- or nonsecretory myeloma), and cytogenetics or FISH analysis.
Table 2

Mayo risk stratification for high-risk myeloma (From Kyle et al. [8])

High-risk characteristic

Conventional cytogenetics

 Deletion of chromosome 13 (monosomy)

 Hypodiploidy

 Either hypodiploidy or deletion of chromosome 13

Fluorescent in situ hybridization (FISH)

 t(4;14)

 t(14:16)

 17p–

Plasma cell-labeling index (PCLI) studies: PCLI ≥3%

Cytogenetics includes conventional karyotyping and FISH for t(4;14), t(14;16), chromosome 17, and chromosome 1. Indeed, t(4;14), t(4:16), deletion(17p), and (1q) are mostly associated with a poorer outcome. It has recently been demonstrated that combining both t(4;14) and del(17p), along with the ISS stage, could significantly improve the prognostic assessment [24]. Gene-expression profiling may segregate patients with standard or high-risk disease, but this is not yet established in routine practice [1].

The fraction of plasma cells infiltrating the bone marrow is evaluated based on May-Grünwald Giemsa-stained smears. MM plasma cells typically stain positive for CD38, CD56, and CD138 and are usually negative for surface immunoglobulin and CD19. The number of plasma cells in the bone marrow is an important criterion for distinguishing MM from MGUS and from solitary plasmacytoma. MM is usually characterized by more than 10% plasma cells in the bone marrow, although, due to the heterogeneous distribution of plasma cells in the bone marrow, this fraction may vary substantially depending on the site of sample aspiration; this parameter is therefore not a consistent prognostic factor. Nevertheless, cytology of bone marrow aspirates remains the standard method for quantitating plasma cells infiltration. The bone marrow plasma cell labeling index (PCLI), a parameter of the DNA synthesis rate derived from in vitro incubation with tritiated thymidine, represents an additional predictor of survival [12]. This index is usually low at diagnosis (<1%) in MGUS and SMM, but it increases at relapse since it correlates with neoangiogenesis, therefore with active disease, as well as inversely with survival regardless of the tumor mass. However, 40% of patients with symptomatic MM have normal PCLI [25].

Imaging studies demonstrate the extent and severity of bone involvement (intramedullary/extramedullary, site, and number of lesions) at baseline, including disease-related complications, such as pathologic fractures; they also serve to assess response to treatment and provide follow-up surveillance [7]. The standard skeletal survey reveals punched-out lytic lesions, osteopenia, or fractures in approximately 80% of patients at the time of diagnosis. Due to the lack of the osteoblastic response, the bone scan is insensitive for the detection of many bone lesions in myeloma patients.

The clinical staging system for MM (international staging system, ISS, Table 3), introduced over 25 years ago, is mainly based on serum β2-microglobulin and albumin levels, without any reference to the presence of bone lesions nor to the methodology employed for their evaluation. Although the ISS serves as prognostic indicator rather than as an accurate scoring system, it has proven to adequately estimate tumor burden and risk stratification, also enabling to distinguish MGUS and SMM from MM [8]. The CRAB criteria are preferred to establish MM-related organ dysfunction [26]. In 1975 Durie and Salmon introduced a clinical staging system based on the presence of bone lesions to grade the severity of the disease: a normal bone structure or plasmacytoma characterized as stage 1 and advanced lytic bone lesions characterized as stage 3, while stage 2 corresponded to patients who did not fit either stage 1 or stage 3 features (see Table 4a) [27]. While the original Durie and Salmon system was essentially based on the use of planar X-ray for evaluating bones, a newer version, the PLUS system, was released in 2005 (see Table 4b) with the aim of improving the accuracy of staging by the use of advanced imaging modalities such as [18F]FDG-PET, [18F]FDG-PET/CT, and MRI (Table 4b) [28]. These techniques enable to evaluate the total number of bone lesions, to distinguish MGUS or SMM from active myeloma, as well as to better discriminate between stage II and III disease. Nevertheless, the original system based on conventional X-ray only is still employed in areas where access to advanced imaging modalities is limited.
Table 3

International staging system (ISS) for MM (From Kyle et al. [8])

Stage

Criteria

Stage I

Serum β2-microglobulin <3.5 mg/L and albumin ≥3.5 g/dL

Stage II

No stage I or III

There are two categories:

 Serum β2-microglobulin < 3.5 mg/L but serum albumin< 3.5 g/dL

 Serum β2-microglobulin ranging from 3.5 to <5.5 mg/L irrespective of the serum albumin level

Stage III

Serum β2-microglobulin ≥5.5 mg/L

Table 4

Overview of Durie and Salmon staging system (A) and the Durie and Salmon PLUS staging system (B) [26]

 

A: Durie/Salmon staging system

B: Durie and Salmon PLUS staging system

Disease

Criteria

Measured myeloma cell mass in whole body (myeloma cells in billions/m2)

Classification

MRI and/or [18F]FDG-PET

MGUS

Stage I (low cell mass)

600 billion

 

All negative

All of the following:

 Hemoglobin value >10 g/dL

 Serum calcium value normal or <10.5 mg/dL

 Normal bone structure (scale 0) or solitary bone plasmacytoma only at bone X-ray

 Low M-protein production rates:

  IgG value <5.0 g/dL

  IgA value <3.0 g/dL

  Urine light-chain M protein on electrophoresis <4 g/24 h

Smoldering or indolent myeloma

Stage II (intermediate cell mass)

600–1200 billion

Stage I A

Can have single plasmacytoma and/or limited disease on imaging

No Stage I or Stage III

MM

Stage III (high cell mass)

1200 billion

Stage I B

<5 focal lesions

One or more of the following:

 Hemoglobin value <8.5 g/dL

Mild diffuse disease

 Serum calcium value >12 mg/dL

 Advanced lytic bone lesions at bone X-ray (scale 3)

 High M-protein production rates

  IgG value >7.0 g/dL

Stage II A/B

5–20 focal lesions

Moderate diffuse disease

  IgA value >5.0 g/dL

  Urine light-chain M protein on electrophoresis >12 g/24 h

Stage III A/B

20 focal lesions

Severe diffuse disease

Sub classification (either A or B)

 A: relatively normal renal function (serum creatinine value) <2.0 mg/dL and no extramedullary disease

 B: abnormal renal function (serum creatinine value) ≥ 2.0 mg/dL and extramedullary disease

A detailed staging system is crucial, since MM has extremely heterogeneous outcomes, and treatment is strongly dependent on the disease onset. Based on the stage and risk factors, risk-adapted therapeutic strategies can therefore be defined. While MGUS does not require any treatment (except long-term observation), there is no evidence that early treatment of patients with SMM prolongs their survival. The diagnosis of active symptomatic MM requiring therapy is based on end-organ effects of the disease.

Despite all treatment options, MM is still considered an incurable disorder with a median survival of about 2–3 years in high-risk patients compared to 5–7 years with high-dose therapy followed by autologous stem-cell bone marrow transplantation (ASCT) in standard-risk patients. Cytogenetic and FISH studies reveal chromosome abnormalities of prognostic significance in 33% and in 90%, respectively, of the patients with MM [12]. Translocations such as t(4;14), t(14;16), or 17p– are associated with poor prognosis (median survival 25 months), as also is the presence of hypodiploidy 21 or the deletion of chromosome 13. The concomitant presence of monosomy and/or deletion of chromosome 13 and serum β2-microglobulin levels greater than 2.5 mg/L are linked to reduced survival. An elevated PCLI also confers a negative prognosis [8]. Potential future biomarkers for diagnosis of multiple myeloma are reported in Table 5 [9]. Table 6 reports the 5-year survival rate of MM patients accordingly to the stage of disease [29].
Table 5

Potential future biomarkers for diagnosis of multiple myeloma (From Rajkumar et al. [9])

 

2-year probability of progression

High level of circulating plasma cells

80%

Abnormal plasma cell immunophenotype ≥95% plus immunopairs

50%

Cytogenetics subtypes t(4;14), 1q amp, or del17p

65%

High bone marrow plasma cell proliferative rate (increase in serum monoclonal protein by ≥10% on each of two successive evaluations within a 6-month period)

50%

Unexplained decrease in creatinine clearance by ≥25% accompanied by a rise in urinary monoclonal protein or serum-free light-chain concentration

Unknown

Table 6

5-year survival rate of MM patients accordingly to the stage of disease (Modified from Rajkumar [29])

Stage

5-year survival rate

Stage I

82%

 ISS stage I (serum albumin > 3.5 g/dL, serum β2-microglobulin < 3.5 mg/L)

 No high-risk cytogenetics

 Normal LDH

Stage II

62%

 Neither stage I or III

Stage III

40%

 ISS stage III (serum β2-microglobulin > 5.5 mg/L)

 High-risk cytogenetics [t(4;14), t(14;16) or del(17p)] or elevated LDH

Evaluation of Disease Burden with Imaging Modalities

In addition to the previous discussion on the incorporation of additional biomarker-defined myeloma-defining events to the standard CRAB features, updates are also needed that take into account the substantial changes to laboratory testing and imaging (e.g., low-dose whole-body CT and [18F]FDG-PET/CT) used in the diagnosis of MM that have happened since the initial publication of the IMWG diagnostic criteria [9, 16, 30, 31]. Appropriate use of imaging techniques is essential both for determining the severity of bone involvement and for identifying and characterizing the skeletal complications. Imaging is also critical for detecting extramedullary foci, for diagnosing infection and other complications, and for evaluating progression of the disease. Recently, the European Myeloma Network provided recommendations for the management of the most common complications of MM [32].

For staging purpose, the detection of osteolytic lesions is generally based on conventional planar X-ray (Fig. 3) which is currently considered to be the standard technique and is recommended for the detection of bone disease in the CRAB criteria that are used for the definition of myeloma-defining events [16, 31, 33]. Lytic lesions on plain X-rays are typically holes, punched-out lesions with absent reactive sclerosis of the surrounding bone, typically localized in the flat bones of the skull and pelvis. In the long bones, lesions may appear as endosteal scalloping, small lytic lesions (<1 cm), mottled areas of multiple small lesions, or large destructive lesions [34]. These lesions are the consequence of nodular replacement of marrow by plasma cells with destruction of the entire bone [35]. Conventional X-ray may also reveal diffuse osteoporosis, which is best recognized in the spine [36]. Radiological and clinical findings (presence of pain) are used in the scoring system (Table 7a) to predict the risk of fracture of long bones and to identify optimal treatment (Table 7b): patients with a high score benefit from internal fixation, whereas patients with a low score can be treated with radiotherapy alone. Asymptomatic patients with X-ray evidence of disease (at least one lytic lesion) have a high risk of progression, with a median time to progression of 8 months.
Fig. 3

X-ray appearance of lytic lesions in MM localized at the right humerus and vertebral bodies. Single lytic lesion (a) and two lytic lesions with osteoblastic reaction (b). Multiple lytic lesions of the dorsal spine (D6–D9) in patient treated with D10-L5 vertebroplasty (c anteroposterior view, d latero-lateral view)

Table 7

Scoring system for diagnosing impending pathological fractures (Adapted from Winterbottom et al. [20])

A

Variable

Score

1

2

3

Site

Upper limb

Lower limb

Peritrochanteric

Pain

Mild

Moderate

Functional

Lesion

Blastic

Mixed

Lytic

Size

<1/3 diameter

1/3–1/2 diameter

>2/3 diameter

B

 

Total score

Risk of impending fracture

Management

≤7

Low (5%)

Conservative (chemo-/radiotherapy)

8

Suggestive (15%)

Conservative or surgery (to be evaluated case by case)

≥9

Diagnostic (33%)

Prophylactic bone fixation

Whole-body skeletal survey, traditionally used in the Durie and Salmon staging system, is burdened with a relatively high rate of false negatives (30–70%), thus resulting in a significant underestimation of the severity of disease. In fact, conventional X-ray cannot always identify the presence of bone lesions, especially in the early stages of the disease, since lytic lesions become apparent when as much as 30–50% of the bone mineral density is lost. Furthermore, in plain X-rays some areas are not well visualized (i.e., lateral and anteroposterior views of the spine are needed for better visualizing of the vertebral bodies), and it is not possible to distinguish myeloma-related osteoporosis from osteoporosis due to other causes (i.e., steroid-induced or postmenopausal osteoporosis) [37]. Conventional X-ray examinations are also somewhat operator- and technology-dependent, thus increasing the risk of underdiagnosing lytic disease.

A major disadvantage of conventional X-ray is the relatively long imaging time and the necessity of maintaining different positions that not all patients (often elderly and suffering pain for previous pathological fractures) are able to maintain. The potential of low-dose whole-body radiographic system (Statscan, a radiographic system that records high quality films of the skeleton in a short time) for detecting focal myeloma lesions has been explored; preliminary results are very promising, but clinical experience with this technique (which was originally developed for trauma and emergency patients) is still limited.

However, novel techniques can detect more lytic lesions compared to conventional radiography [32]. Whole-body multidetector computed tomography (WBMD-CT) is more sensitive for the detection of lytic lesions in myeloma compared to conventional radiography (between 70% and 89% for MDCT, depending on stage of the disease), as it can detect more lesions with an extremely high resolution (very small lesions can be detected, even <5 mm) and better performance when evaluating areas that are critical for planar X-ray; it is very quick to perform (2 min or less), it is more accurate for diagnosis and helpful for planning radiotherapy or surgical interventions; furthermore, it can be employed in cases of suspected spinal cord compression when MRI is contraindicated [31, 32, 38, 39, 40, 41, 42]. However, specificity of MDCT for assessing certain skeletal changes often associated with myeloma, such as osteopenia, is low. To reduce the radiation burden, whole-body low-dose CT (WBLD-CT) may be used [20, 26]. Also whole-body LDCT was found to be superior to whole-body X-ray for the detection of osteolytic lesions (Table 8) [43].
Table 8

Comparison between whole-body LDCT and whole-body X-ray in the detection of osteolytic lesions in MM (Modified from Terpos et al. [43])

References

Study design

Patients, n

Reference test

Key findings

Gleeson et al. [47]

Prospective

39

WBXR, WB-MRI, BM biopsy

WBLD-CT > WBXR, higher detection rate comparable to WB-MRI

Kropil et al. [48]

Prospective

29

WBXR

WBLD-CT > WBXR, detection ratio for lytic lesion WBLD-CT/WBXR = 2.06 (7 for the skull, 2.07 for the thoracic cage, 4.6 for the spine, and 2.54 for the pelvis)

Princewill et al. [46]

Retrospective

51

WBXR

WBLD-CT > WBXR, detection ratio for lytic lesion WBLD-CT/WBXR = 3.9 (1.09 for the skull, 74 for the thoracic cage, 4.92 for the spine, 6.67 for the pelvis and the fat bones, and 2.31 for the long bone); 61% of cases upstaged with WBLD-CT

Wolf et al. [45]

Prospective

52

WBXR

WBLD-CT > WBXR, particularly in the axial skeleton; 63% of cases upstaged with WBLD-CT; 23% of cases negative at WBXR and positive at WBLD-CT

WBXR whole-body X-ray (conventional skeletal survey), WBLD-CT whole-body low-dose computed tomography

Since the administration of iodinated contrast agent is not required for evaluating the skeleton with CT, it is useful even in patients with Bence-Jones proteinuria, who are at risk of cast nephropathy and renal failure. However, actual bone destruction must occur for CT imaging to become positive, since focal tumor infiltration confined to the bone marrow remains undetectable. In fact, diffuse interstitial infiltration of the bone marrow is not invariably associated with trabecular/cortical bone destruction, so that the rate of false-negative CT scans is relatively high [44].

Whole-body LDCT advantages over whole-body X-ray include:
  1. 1.

    Superior diagnostic sensitivity for depiction of osteolytic lesions, especially in areas where the whole-body X-ray detection rate is low (i.e., pelvis and spine).

     
  2. 2.

    Superiority in estimating fracture risk and bone instability.

     
  3. 3.

    Duration of the examination, which is 5 min or less, an important issue for patients in extreme pain.

     
  4. 4.

    Production of higher-quality 3D high-resolution images for planning biopsies and therapeutic interventions.

     
  5. 5.

    Demonstration of unsuspected manifestations of myeloma or other disease, especially in the lungs and kidneys (33% in the study by Wolf et al. [45]) [38, 45, 46, 47, 48, 49, 50].

     

Major disadvantages of whole-body LDCT include lack of availability in several centers [9, 38], and lack of specificity for the differential diagnosis between malignant and osteoporotic fractures, despite improvements during recent years [51]. Furthermore, although exposure to radiation is much lower compared with standard CT, it continues to be higher than whole-body X-ray: mean dose of whole-body LDCT is approximately 3.6 and 2.8 mSv for females and males, respectively, compared with 1.2 mSv for whole-body X-ray [52]. Nevertheless, the higher diagnostic accuracy of whole-body LDCT and patient comfort, which is particularly important for older patients, renders the dose/quality ratio favorable for whole-body LDCT [43].

Figure 4 represents typical CT examples of lytic lesions of the spine and of a solitary plasmacytoma.
Fig. 4

Typical CT example of lytic lesions of the spine (a, sagittal view) and iliac bone (b and c in coronal and transaxial view, respectively) with the bone window. Panel on the bottom shows the transaxial (d) and sagittal (e) views of a posterior tract of right rib plasmacytoma

Similarly, positron emission tomography in combination with CT (PET/CT) is superior to conventional radiography in the detection of lytic disease, while whole-body magnetic resonance imaging (WB-MRI) accurately depicts the marrow involvement in MM patients.

MRI identifies bone marrow involvement, based on the loss of the fatty bone marrow component consequent to replacement by plasma cells. MRI has high sensitivity in distinguishing focal or diffuse infiltration of the bone (especially in the spine), as well as detecting destruction of the mineral bone. Myeloma lesions in the marrow appear typically hypointense in T1-weighted sequences and hyperintense in T2-weighted and STIR sequences (Fig. 5).
Fig. 5

STIR (a) and T2 (b) images of a lytic bone lesion of the left pubis. Hyperintense in T2-weighted and STIR sequences

Five MRI patterns of marrow involvement have been recognized in multiple myeloma:
  1. 1.

    A focal pattern that consists of localized areas of myeloma cell infiltration 5 mm or greater in diameter (in 30–50% of patients with advanced MM but also in high-risk smoldering myeloma).

     
  2. 2.

    A diffuse pattern, characterized by almost complete replacement of normal marrow by myeloma cells (in 25–40% of patients with MM).

     
  3. 3.

    A combined diffuse and focal pattern (in 10% of patients with MM).

     
  4. 4.

    A normal bone marrow pattern (in 15–25% of patients with MM).

     
  5. 5.

    A variegated or “salt and pepper” pattern, with innumerable small bone marrow focal lesions (in 1–5% of patients with MM) [16, 33, 43, 53].

     
MRI findings reflect pathophysiological processes such as iron overload, amyloid deposition, or reactive marrow hyperplasia. Patients with MM may exhibit normal MRI appearance when the tumor burden is low, while focal or diffuse bone marrow infiltration exhibit variable patterns. At diagnosis, bone marrow infiltration is detected by MRI in 29–50% of the patients with Durie-Salmon stage I disease and negative plain radiographs. Furthermore, MRI offers prognostic information, as the number of lesions detected correlates with response to treatment and with overall survival. Patients with advanced disease and normal MRI respond better to conventional chemotherapy and have better survival than patients with focal/diffuse bone marrow infiltration. Nevertheless, patients with positive MRI do not always require immediate treatment. In fact, in stage I, treatment is not indicated until symptoms appear. The detection of ≥10 spine lesions in patients with advanced stage is associated with an increased risk (6–11-fold) of fracture than patients with normal MRI or with less than ten lesions. MRI can distinguish osteoporotic from malignant fractures and is the technique of choice when cord compression is suspected MRI provides accurate information about the epidural space, the level and extension of cord or nerve root compression, and size of the lesion. The main disadvantage of MRI is long scan duration (about 45 min). Moreover, claustrophobic patients or patients with metallic implant/device cannot undergo the exam. The typical MRI protocol for evaluating MM patients does not include some skeletal segments (i.e., the sternum, clavicles, and ribs) and therefore may underestimate the disease burden. Whole-body MRI (WB-MRI, Fig. 6) may overcome those limitations; in fact WB-MRI is more sensitive than WB-MDCT for assessing bone marrow infiltration (both focal and diffuse) and is recommended immediately after the X-ray survey. It allows identifying lesions early in their course (before osteolysis occurs) as well as nonsecretory and macrofocal myeloma (especially in the spine and pelvis), which is characterized by lesions with low metabolism and activity.
Fig. 6

A 65-year-old patient with multiple myeloma. WB-MRI demonstrates multifocal osteolysis in the cranial vault, sternum, and ribs (a+b) and in the lower extremities (d). Diffuse infiltration of the lumbar spine and pelvis is shown by the homogeneous signal decrease in bone marrow and demonstrated emanated spinal involvement, particularly in the superior segment

MRI may also be improved with the use of dynamic contrast-enhanced sequences (DCE-MRI) that evaluate the bone marrow microcirculation caused by myeloma-induced angiogenesis. The DCE-MRI-derived “A” variable describes intensity of the signal (therefore angiogenesis) and is found to be significantly increased in MM patients, in whom it correlates with the presence of osteolytic lesions, with the degree of bone destruction and with the presence of local complications. The amplitude of “A” is a negative prognostic factor for event-free survival and for overall survival in MM [20, 26, 54, 55].

Diffusion-weighted imaging (DWI), which is based on contrast deriving mainly from differences in the diffusivity of water molecules in the tissue environment, is a novel and promising MRI technique. DWI-MRI uses the calculation of apparent diffusion coefficient values to better evaluate myeloma burden and MRI infiltration patterns [56, 57]. Apparent diffusion coefficient values are higher in patients with MM at diagnosis, compared with patients in remission 20 weeks after initiation of treatment [58]. DWI-MRI was found superior to whole-body X-ray for the detection of bone involvement in patients with relapsed/refractory MM in all areas of the skeleton except the skull, where both examinations had equal sensitivity [59]. In a small study, DWI-MRI was found more sensitive than [18F]FDG-PET/CT in detecting myeloma lesions (77% and 47%, respectively) in both newly diagnosed (n = 15) and pretreated (n = 9) MM patients [60]. In a recent study, 17 patients were evaluated using DWI-MRI, and [18F]FDG-PET/CT and imaging results were compared to bone marrow biopsy. In all studied regions whole-body DWI scores were higher than those produced by [18F]FDG-PET/CT. DWI-MRI was particularly accurate in diagnosing diffuse disease (37% of regions imaged on whole-body DWI scans compared with only 7% on [18F]FDG-PET/CT). Both techniques were equally sensitive in the detection of focal lesions [61].

Bone scintigraphy with 99mTc-labeled disphosphonate is not useful for diagnosis nor for staging of MM, as the detection of bone lesions is about 35–60% [20, 54] (Fig. 7), with sensitivities generally lower than that of conventional X-rays. In a comparison of the X-ray skeletal survey versus bone scintigraphy [62], increased uptake of the radiopharmaceutical in radiographically abnormal regions occurred in only 44% of the cases, while normal uptake was seen in 48%, and reduced uptake in 8% of the cases. Lesions that are well defined on the bone scan are the result of complications in MM, mainly osteoblastic response to a compression fracture of a vertebral body or pelvic insufficiency fracture, soft-tissue calcifications within a plasmacytoma [63], or tumor-associated amyloidosis [64]. This pattern is consistent with the prevalent loss of bone mass not associated with osteoblastic activation, which is typical of the myeloma bone lesions. Thus, in MM, bone scintigraphy is generally nearly normal, or it may demonstrate areas with decreased radiopharmaceutical accumulation or the typical osteoporotic pattern (see example in Fig. 8a). On the other hand, bone scintigraphy may be helpful for evaluating some specific skeletal segments such as the sternum and ribs that can hardly be explored with plain X-rays (Fig. 8b).
Fig. 7

Bone scintigraphy (a) and [18F]FDG-PET/CT (b) in a patient with MM IgG. Bone scintigraphy missed lesions in a left rib and in the left sacrum

Fig. 8

(a) Typical pattern of mild and diffuse 99mTc-MDP uptake in a patients with MM. (b) Atypical appearance of multiple myeloma at bone scan: multiple lesions are evident as in the area of radiopharmaceutical uptake at the skull, left clavicula, humeri, ribs, spine, left iliac bone, and left femur

Nuclear medicine imaging with nonspecific oncotropic radiopharmaceuticals, such as 67Ga-citrate, 99mTc(V)-DMSA, 201Tl-chloride, 99mTc-Sestamibi, or [18F]FDG have all met greater success in imaging MM than typical bone-scanning agents. 67Ga-citrate localizes in areas of active tumor either through primary localization within the tumor cells or because of the presence of mononuclear cell and lymphocytic infiltrates observed along with the plasma cells and characterizing the tumor-induced secondary “inflammatory response.” Whether these mechanisms act singly or in combination remains unknown [65, 66, 67]. 67Ga-citrate is rarely used for tumor detection in MM because increased uptake may be observed in some abnormal soft-tissue sites and in solitary myelomas of bone [62, 68, 69, 70], although with variable degrees. Furthermore, the use of 67Ga is hampered by certain disadvantages versus 99mTc-Sestamibi or [18F]FDG imaging, such as multiday scanning and low resolution. When infection is suspected in MM patients, 67Ga-citrate may be used if 99mTc-HMPAO/111In-oxine-labeled autologous WBCs are not available. 99mTc(V)-DMSA has been reported to accumulate in plasmacytoma, irrespective of the presence of amyloidosis [71, 72].

201Tl-chloride has been used for the detection of MM, based on uptake mediated by either increased metabolic demand of the tumor or secondary inflammatory response induced in the marrow [73]. In a study comparing 201Tl-chloride and 99mTc-labeled bone-seeking agents in patients with MM, 201Tl-chloride was shown to be a promising agent for detecting disease [74]; however, in the clinical routine based on single-photon radiopharmaceuticals for characterizing MM patients, this agent is currently replaced by 99mTc-Sestamibi, which shows similar localization properties, associated, however, with images of higher quality and lower cost.

99mTc-Sestamibi accumulates in cells with high metabolic requirements and can therefore be employed to assess in a semiquantitative manner the degree of bone marrow infiltration by plasma cells; this technique is both highly sensitive (92%) and specific (96%). The patterns of 99mTc-Sestamibi uptake typical of MM can be described as normal (N), focal (F), diffuse (D), and mixed (F+D). Another semiquantitative score (similar to that originally described by Pace et al. [75]) is based on extension (E) and intensity (I) of 99mTc-Sestamibi uptake, as follows (Fig. 9):
Fig. 9

99mTc-Sestamibi scintigraphy demonstrating different degree on bone marrow involvement: focal (a, b, d) and diffuse (c) or I3E3 (ad)

  • E0 = no evidence of bone marrow uptake

  • E1 = uptake confined to the spine and pelvis

  • E2 = uptake in the spine, pelvis and ribs, or in the proximal humeral and femoral epiphyses

  • E3 = uptake in the spine, pelvis, ribs, and in distal humeral and femoral epiphyses

  • I0 = no evidence of bone marrow uptake

  • I1 = bone marrow uptake < uptake in the myocardium

  • I2 = bone marrow uptake = uptake in the myocardium

  • I3 = bone marrow uptake > uptake in the myocardium

The degree of radiopharmaceutical uptake correlates well with the degree of plasma cell infiltration, with the amount of a monoclonal component, with the clinical status and with stage of the disease. In some studies good correlation was also found between 99mTc-Sestamibi uptake and other parameters of disease activity, such as the serum levels of lactate dehydrogenase, C-reactive protein, and β2-microglobulin. Diffuse moderate or intense 99mTc-Sestamibi uptake, or focal uptake, correlates with poor prognosis. However, 99mTc-Sestamibi imaging is less sensitive than MRI (50.5% vs. 100%) [76] for evaluating focal lesions localized in the spine (especially in patients with early disease stage), because scintigraphic assessment of such segment is hampered by the high physiologic uptake in the liver and bowel. SPECT imaging has been shown to overcome the relatively poor spatial resolution of planar 99mTc-Sestamibi scintigraphy. It is important to emphasize that the 99mTc-Sestamibi scan is always negative in case of MGUS, while false negative results have been described in case of overexpression of P-glycoprotein, associated with multidrug-resistant myeloma [20, 26, 75, 77, 78].

Agool et al. [79] have more recently proposed the use of somatostatin receptor (SSTR) imaging as an alternative method to visualize malignant plasma cells. In fact, in vitro studies have demonstrated that MM cell lines express functional SSTR2, SSTR3, and SSTR5, the latter being the most represented. Additionally, in vitro growth of myeloma cells can be inhibited by somatostatin and octreotide. Preliminary data in patients with relapsing MM indicate that SSTR imaging is very sensitive, demonstrating abnormal accumulation in 82% of patients compared to a 33% detection rate with whole-body X-ray. Partial or total normalization of the scintigraphic pattern has also been observed in patients responding to treatment. The expression of SSTR could be related to aggressiveness of the disease. However, the limitation represented by poor spatial resolution of planar images (used in this trial) can be overcome either by employing SPECT/CT or by using PET/CT with a positron emitting SSTR analogue (i.e., 68Ga-DOTATOC).

Scintigraphy with the serum amyloid P (SAP) labeled with either 99mTc or 123I has been proposed to confirm the diagnosis [20, 54, 80] and to quantify the extent of the deposits of light-chain (AL) amyloidosis.

[18F]FDG is today the standard for radionuclide imaging in patients with MM, because it identifies early bone marrow infiltration in patients with apparent solitary plasmacytoma and demonstrates the extent of extramedullary involvement. [18F]FDG-PET shows both high sensitivity (86%) and high specificity (92%) [81], with the additional advantage of distinguishing between metabolically active disease ([18F]FDG positive) and clinical conditions characterized by very low burden, such as MGUS or smoldering disease ([18F]FDG negative). Active transformed plasma cells are extremely glucose avid; therefore, [18F]FDG-PET shows focal or diffuse pattern of uptake reflecting the distribution of bone marrow disease. While patients with MGUS generally have a negative [18F]FDG-PET scan (although diffuse low-grade bone marrow uptake can occasionally be observed), the appearance of [18F]FDG focal uptake in a patient with MGUS indicates transformation into an active myeloma. Identification of extramedullary disease on a [18F]FDG-PET scan performed at diagnosis correlates with poor prognosis (see Figs. 10 and 11 for different representative patterns of [18F]FDG uptake in patients with plasmacytoma and MM, respectively). An early clinical investigation on the performance of [18F]FDG-PET in MM (66 patients followed serially) showed the capability of the technique to identify patients with high-risk disease and to monitor patients either in nonsecretory myeloma or in complete remission without measurable M component [82]. Such initial observations were subsequently confirmed by other studies, also demonstrating that [18F]FDG-PET could lead to upstaging of the disease in 31–37.5% of patients (depending on the series) and to changes in treatment management in up to 56% of the cases [83]. These results stimulated larger studies with [18F]FDG-PET in patients with myeloma [84, 85]. Data derived from The National Oncologic PET Registry (NOPR), a large prospective program aiming at recording changes of the intended clinical management of cancer patients on the basis of the [18F]FDG-PET/CT findings, have further confirmed this trend. The registry has so far included over 1300 myeloma patients (13.1% scan/incidence in 2007), showing a definite impact on management in about 52% of patients when the scan was requested for staging purpose, 46% in case of restaging, and 51% in presence of suspected recurrence.
Fig. 10

The typical representative patterns of [18F]FDG uptake in patients with solitary plasmacytoma. MIP images (a) and the relative transaxial sections on fused images (b), CT (c) and PET (d), demonstrating an intense area of radiopharmaceutical uptake corresponding to a large lesion developing from the posterior trait of the right rib. No additional lesions are present in any other bone segments

Fig. 11

Different patterns of [18F]FDG uptake in patients with MM. Panel (a) diffuse and moderate [18F]FDG uptake in bone (as intense as the liver uptake) with focal area of major accumulation corresponding to multiple bone sites of active myeloma. Top right MIP images, coronal view (CT with bone window, PET, and fused images) on top left, and transaxial view showing humeral, scapular, spine, and rib involvement on the bottom (CT with mediastinal window, PET, and fused images). Panel (b) diffuse and intense [18F]FDG uptake in bone (more intense than the liver) with focal area of major accumulation corresponding to multiple bone and soft-tissue site disease. Top right MIP images, coronal view (CT with bone window, PET, and fused images) on top left, and transaxial view showing humeral, spine, sternum, and rib involvement with a judge lesion of the lateral right rib involving the chest wall (CT with mediastinal window, PET, and fused images). Of notice, [18F]FDG reproduces the pattern of homogeneous and diffuse uptake along the humeri and femora which is typical of 99mTc-Sestamibi in advanced myeloma with better spatial resolution

In MM the 2.5 threshold for the standardized uptake value (SUV, often considered as the cutoff for other forms of cancer) may not be applicable. In fact, many lesions <10 mm (that are obvious on MRI or using dedicated CT) cannot be detected on the [18F]FDG scan using this threshold if one does not take into account the recovery coefficient, whereby SUV decreases along with decreasing lesion size. Figure 12 shows an example of faint pathological [18F]FDG uptake (SUVmax under the 2.5 threshold) in a bone lesion and a concomitant larger bone lesion characterized by higher uptake. Therefore, the complementary imaging information provided by the CT component of a [18F]FDG-PET/CT examination is very effective, even if CT is performed in most cases in the low-dose mode (Fig. 13). With all these considerations in mind when interpreting [18F]FDG-PET/CT scans, this imaging modality has reported in this study to be more sensitive than both plain X-ray (89.2% vs. 47.4%) and CT alone (89.2% vs. 70.4%) [86]. In addition to demonstrating persistent or recurrent osseous disease, [18F]FDG-PET/CT is more sensitive than other imaging modalities for localizing extramedullary sites of disease, thus revealing additional lesions in almost 30% of the patients who had been diagnosed with solitary plasmacytoma by MRI [87, 88]; this results in upstaging extent of the disease and has therefore a relevant impact on the choice of therapeutic strategies [89, 90, 91]. However, sensitivity of [18F]FDG-PET for assessing diffuse disease in the spine and pelvis remains almost half than that of MRI [78].
Fig. 12

Example in the same patient of MM lesions characterized by different patterns of [18F]FDG uptake with a SUVmax of 2.2 in the right clavicle (a) and SUVmax of 4 in the right ileum (b)

Fig. 13

Example of the complementary of PET and CT images in a patient with MM

Thus, while [18F]FDG-PET/CT performs better than either 99mTc-Sestamibi scintigraphy or MRI in detecting focal bone and bone marrow lesions, MRI remains the method of choice for evaluating diffuse bone marrow infiltration in the spine, considering that diffusely increased nonspecific [18F]FDG uptake is frequently observed in the bone marrow of young people or in patients with anemia [78, 83, 92]. [18F]FDG-PET/CT should be preferred for an accurate initial staging of patients with MM (Fig. 14), while MRI is to be preferred when assessing the degree of bone marrow infiltration by plasma cells in the early phase of the disease. By combining MRI of the spine/pelvis and whole-body PET/CT, the ability to detect sites of active MM, both medullary and extramedullary, can be as high as 92%. Although rarely, active disease demonstrated by bone marrow assessment may be missed by both [18F]FDG-PET/CT and MRI (false-negative cases); however, when [18F]FDG-PET/CT and MRI are concordantly positive, no false-positive results are generally observed, thus yielding specificity and positive predictive values close to 100%. This consideration is of value in aiding clinicians to either continue with or change chemotherapy regimens on the basis of persistently positive findings on imaging studies. The low negative predictive values of [18F]FDG-PET/CT (50%) and MRI (59%) and also of the combination of the two (64%) suggest that negative results should always be considered with caution and correlated to other markers of disease activity [93].
Fig. 14

Staging in a patient with MM IgG k (stage IIIA, ISS1). MIP and axial images show [18F]FDG uptake in the pelvis and right femora

The prognostic significance of [18F]FDG-PET/CT is not yet well established. Bartel et al. [94] evaluated the prognostic value of [18F]FDG-PET/CT in patients with newly diagnosed MM. By applying tertile-derived cut-points, several imaging parameters affected overall survival and event-free survival adversely, in particular, the presence of extramedullary disease and the number of lytic lesions detected by metastatic bone survey and the number of focal sites of [18F]FDG uptake. Abnormal MRI findings and high SUV of focal [18F]FDG uptake were associated with shorter event-free survival, while having borderline effects on overall survival. The number of lesions detected by PET/CT was the parameter most closely correlated with other prognostic variables, such as β2-microglobulin, lactate dehydrogenase, and C-reactive protein and gene expression profiling-derived indices: positive correlation with high risk and two proliferation parameters and inverse correlation with low bone disease subgroup. The PET/CT findings also maintained an independent adverse prognostic value, if combined with positive cytogenetic abnormalities and elevated lactate dehydrogenase levels. [18F]FDG-PET/CT identified 30% of patients who had poorer prognosis despite having low-risk disease as defined by gene expression profiling analysis. Based on logistic regression analysis, the PET findings were independently positively correlated to both MRI and metastatic bone survey. Among the non-imaging parameters, the results of PET correlated positively with C-reactive protein and negatively with gene array-defined low bone disease.

[18F]FDG-PET also offers the advantage of identifying superimposed infection. On the other hand, such high sensitivity can increase the false positive results when the scan is performed within a short interval after radiotherapy or surgery; it is therefore recommended to perform the scan at least 4 weeks after a surgical procedure or 2–3 months after completion of radiotherapy [83, 95].

Limitations of [18F]FDG-PET/CT include the lack of sensitivity for detecting diffuse bone marrow involvement (in this case MRI remains the gold standard) and low-density plasmacyte infiltration. Moreover, physiological [18F]FDG uptake in the brain reduces the sensitivity for small skull lesions [96]. One of the major limitations of [18F]FDG-PET/CT lies in the lack of standardized interpretation criteria and the controversies regarding the use of SUVmax to define its positivity. Recently, an Italian panel of experts introduced novel criteria (IMPeTUs) [97] for the interpretation of PET/CT images in MM. The final version of the criteria (Table 9) includes the description, using 5-point scales, of metabolic state of the bone marrow, number and site of focal PET-positive lesions with or without osteolytic characteristics, presence and site of extramedullary disease, presence of paramedullary disease, and presence of fractures. The visual degree of uptake is defined for bone marrow, the target lesion (i.e., the hottest area), and extramedullary lesions according to the schema proposed in the Deauville criteria for the evaluation of lymphoma patients. The IMPeTUs criteria must be validated in prospective studies to evaluate their clinical value.
Table 9

The IMPeTUs criteria for the interpretation of PET/CT images in MM (Modified from Nanni et al. [97])

Lesion type

Site

Number of lesion (x)

Grading

Diffuse

Bone marrowa

 

Deauville 5-point scaleb

Focal

Skull

x = 1 (no lesions)

Deauville 5-point scaleb

Spine

x = 2 (1–3 lesions)

Extraspinal (all the rest)

x = 3 (4–10 lesions)

x = 4 (>10 lesions)

Lytic

x = 1 (no lesions)

x = 2 (1–3 lesions)

x = 3 (4–10 lesions)

x = 4 (>10 lesions)

Fracture

At least one at CT

Paramedullaryc

At least one

Extramedullary

Nodal (n = 7)/extranodal (n = 5)d,

At least one

Deauville 5-point scaleb

aAppended if increased uptake in limbs and ribs

bDeauville 5-point scale

 1 = No uptake at all

 2 ≤ Mediastinal blood pool uptake (SUVmax)

 3 > Mediastinal blood pool uptake, ≤ liver uptake

 4 > Liver uptake more than 10%

 5 > Liver uptake (twice)

cBone lesion involving surrounding soft tissues with bone cortical interruption

dNodal disease (N) plus site: laterocervical (LC), supraclavicular (SC), mediastinal (M), axillary (Ax), retroperitoneal (Rp), mesentery (Mes), inguinal (In); extranodal disease (EN) plus site: liver (Li), muscle (Mus), spleen (Spl), skin (Sk), other (Oth)

The diagnostic potential of non-[18F]FDG positron-emitting radiopharmaceuticals has been investigated in patients with MM. In particular, radiolabled choline (a precursor of phospholipid synthesis whose uptake is increased in proliferating cells) has been compared to [18F]FDG [98, 99]. Authors suggest that the superior sensitivity of radiolabeled choline-PET/CT over [18F]FDG-PET/CT for detecting bone lesions is due to the high phospholipid metabolic rate of myelomatous cells, as these compounds are involved in the modulation of intracellular growth signal transduction pathways. The main clinical disadvantage in the use of radiolabeled choline is its high physiological liver uptake that may prevent the detection of hepatic lesions.

Results of in vitro experiments showing that the radiolabeled amino acid [11C]methionine is incorporated into immunoglobulins produced by the malignant plasma cells have prompted a clinical study performed with [11C]methionine-PET/CT in MM patients by Dankerl et al. [100]. Consistently with the underlying hypothesis, osteolytic lesions exhibited a high uptake of [11C]methionine, similar to that of [18F]FDG. Furthermore, newly diagnosed osteolytic lesions in untreated patients were strongly [11C]methionine positive, while recurring osteolytic lesions were [11C]methionine negative. Although the series evaluated in this study was relatively small, the substantial mismatch between the number of lesions identified by [11C]methionine-PET and those identified by CT represented an important added value of metabolic imaging for early detection of lesions not yet obvious as macroscopic bone changes; these findings would therefore provide an accurate estimate of tumor burden, particularly for clinically silent and unexpected localizations. Very recently, Lapa et al. [101] performed a head-to-head comparison of [11C]Methionine and [18F]FDG-PET/CT scans in 43 patients referred for staging or restaging of MM.

PET/CT with 3′-18F-fluoro-3′-deoxy-L-thymidine (18F-FLT, whose uptake mirrors DNA synthesis via thymidine kinase-1) has been proposed to distinguish hematological malignancies from other clinical conditions causing pancytopenia. Although the exact mechanism of 18F-FLT uptake in bone marrow remains unclear, several studies suggest that it is linked to the cycling activity of hematopoietic cells, thus reflecting the state of the entire bone marrow compartment [26]. Bone marrow uptake of 18F-FLT is intense in patients with myelodysplasia and myeloproliferative disorders, while it is lower-to-absent in patients with MM, myelofibrosis, or aplastic anemia. Patients with MM may present variable degrees of 18F-FLT uptake in response to bone marrow expansion into the peripheral bones.

Extensive skeletal involvement has also been incidentally detected during PET with [11C]Acetate [102]. It is not entirely clear why myelomatous lesions would exhibit such high uptake of [11C]Acetate, although this observation is consistent with a much earlier in vitro study with plasma cells obtained from patients with MM, showing enhanced uptake of acetate as a substrate for the Krebs cycle [103]. On the other hand, it is well known that malignant cells (including MM cells) typically have increased glycolysis versus their normal counterparts, as also confirmed by a correspondingly increased [18F]FDG consumption; since the Krebs cycle (whose metabolic substrate is acetate) constitutes a component of overall glycolysis, it is not surprising that uptake of both [18F]FDG and [11C]Acetate occurs in MM.

Although there are some issues that need to be clarified when using sensitive techniques such as WBLD-CT, PET/CT, or MRI (e.g., what the difference is between an MM patient with 4 lytic lesions detected by conventional radiography and another patient with 14 lytic lesions detected by WBLD-CT), data so far support the use of WBLD-CT as standard procedure for the diagnosis of lytic disease in patients with MM (grade 1A) as pointed out by the “European Myeloma Network Guidelines for the Management of Multiple Myeloma-related Complications” [32] (Fig. 15).
Fig. 15

Algorithm for imaging in multiple myeloma (Modified fromTerpos et al. [32])

Positive lesions in WBLD-CT are considered those with a diameter of 5 mm or more. Conventional radiography can also be used if WBLD-CT is not available. In asymptomatic patients with no lytic disease in WBLD-CT, MRI and [18F]FDG PET/CT are not recommended. In the presence of more than 1 focal lesion, the patients are characterized as having symptomatic disease that needs therapy (grade 1A) [32].

However, in the “Revised International Myeloma Working Group diagnostic criteria for multiple myeloma and smoldering multiple myeloma,” the detection of one or more osteolytic lesions on skeletal radiography, CT, or [18F]FDG-PET/CT has been reported. Therefore, the IMWG recommends either [18F]FDG-PET/CT, low-dose whole-body CT, or MRI of the whole-body or spine in all patients with suspected smoldering multiple myeloma. Increased [18F]FDG uptake alone is not adequate for the diagnosis of MM; evidence of underlying osteolytic bone destruction is needed on the CT portion of the examination.

Assessing Response to Treatment

Although there are several studies evaluating the role of imaging at diagnosis, there are limited data for the value of imaging during treatment and follow-up of patients with myeloma [43]. Many criteria can be employed to assess response to therapy in MM patients, including those set by the European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry/American Bone Marrow Transplant Registry, by the Chronic Leukemia-Myeloma Task Force, by the Southwest Oncology Group (SWOG), and by the Eastern Cooperative Oncology Group (ECOG). In 2006, the International Myeloma Working group (IMWG) recognized the importance of standardizing such criteria and elaborated the so-called uniform response criteria (Table 10). While adopting the classical categories of Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD), the system introduced the new category of “positive response of additional clinical significance” following treatment. Although the IMWG response criteria deleted the category “minor response” (considered to be somewhat vague and therefore unreliable), more recently this category has been reintroduced by the ASH-FDA in patients with relapsed refractory myeloma, while specific criteria for progression have been defined for SMM (Table 11) [8].
Table 10

International Myeloma Working Group uniform response criteria for MM (From Kyle et al. [8])

Category

Criteria

Complete response (CR)

Negative immunofixation of serum and urine and disappearance of any soft-tissue plasmacytomas and <5% plasma cells in bone marrow

Patients with only measurable disease by serum FLC levels: CR is defined as normal FLC ratio (0.26–1.65) in addition to CR criteria listed above

Stringent complete response (sCR)

Negative immunofixation of serum and urine and disappearance of any soft-tissue plasmacytomas and <5% plasma cells in bone marrow and normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence

Very good partial response (VGPR)

Serum and urine M protein detectable by immunofixation but not on electrophoresis or ≥90% or greater reduction in serum M protein plus urine M protein <100 mg/24 h

Note: Patients with only measurable disease by serum FLC levels, VGPR is defined as a >90% decrease in the difference between involved and uninvolved FLC levels

Partial response (PR)

≥50% reduction of serum M protein and reduction in 24 h urinary M protein by ≥90% or to <200 mg/24 h and ≥50% reduction in the size of soft-tissue plasmacytomas if present at baseline

Note: If the serum and urine M protein are unmeasurable, ≥50% decrease in the difference between involved and uninvolved FLC levels

If serum and urine M protein and serum FLC are unmeasurable, ≥50% reduction in bone marrow plasma cells, provided baseline percentage was ≥30%

Stable disease (SD)

Not meeting criteria for CR, VGPR, PR, or PD

Progressive disease (PD)

>25% from lowest response value in any one or more of the following:

 Serum M protein (absolute increase must be ≥0.5 g/100 mL)a

 Urine M protein (absolute increase must be ≥200 mg/24 h)

 Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved

  FLC levels (absolute increase must be >10 mg/L)

Bone marrow plasma cell percentage (absolute% must be ≥10%)

 Definite development of new bone lesions/soft-tissue plasmacytomas or definite increase in size of existing bone lesions/soft-tissue plasmacytomas

 Development of hypercalcemia (corrected serum calcium >11.5 mg/100 mL) ascribable solely to the plasma cell proliferative disorder

All response categories (CR, sCR, VGPR, and PR) require two consecutive assessments made at any time before the institution of any new therapy; complete PR and SD categories also require no known evidence of progressive or new bone lesions if radiographic studies were performed. Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments need not be confirmed

aFor PD serum M protein increases of ≥1 gm/100 mL are sufficient to define relapse if starting M protein is ≥5 gm/100 mL

Table 11

Additional response criteria for specific disease stages. International Myeloma Working Group uniform response criteria for MM (From Kyle et al. [8])

Category

Criteria

Relapsed MM

At least one prior regimen and not meeting criteria for relapsed and refractory MM

Relapsed and refractory MM

Relapse of disease while on salvage therapy or progression within 60 days of most recent therapy

Minor response (MR) in patients with relapsed refractory MM

≥25% but <49% reduction of serum M protein and reduction in 24 h urine M protein by 50–89%, which still exceeds 200 mg/24 h and reduction in size (25–49%) of any soft-tissue plasmacytoma and no increase in size/number of lytic bone lesions (development of compression fracture does not exclude response)

Progression to active MM in patients with smoldering MM

Evidence of PD based on the IMWG criteria (Table 9) and any one or more of the following:

 Development of new lesion (soft-tissue plasmacytoma/bone lesions)

 Hypercalcemia (>11 mg/100 mL)

 Decrease in hemoglobin of ≥2 g/100 mL

 Serum creatinine level ≥2 mg/100 mL

Although changes in BM infiltration are not employed as a guiding criterion for assessing response to treatment, finding <5% plasma cells is one of the requisites for complete remission. Furthermore, in patients without measurable disease, it is possible to monitor the disease by the serum-free, light-chain assay. Irrespective of the specific system employed to classify response to treatment, the main pitfall of these systems is represented by the method used to assess bone marrow and bone lesions. In fact, plain radiography is of limited value for evaluating the response to treatment; in particular, even if the appearance of new bone lesions clearly indicates disease progression, lytic bone lesions rarely show radiologic signs of recovery. Furthermore, new compression vertebral fractures may occur either in case of disease progression or in case of bone loss or in case of reduction of the tumor mass that supports the bone cortex [3, 8, 26, 78]. MDCT is not generally used for assessing response to treatment, since osteolytic lesions rarely recover. In selected cases, mainly those characterized by significant soft-tissue component (i.e., plasmacytoma), response to therapy can instead be demonstrated by reduction in tumor size as assessed with CT. Moreover, CT may be of value in patients with persistent unexplained symptoms despite therapy or with risk of impending fracture or when no clinico-biochemical response to treatment is observed. The disappearance of any MRI-detectable bone marrow lesion typically represents complete response, while a partial response to therapy is associated with changes of the MRI pattern from diffuse to focal/variegate or with the reduction of the signal on the T2-weighted spin echo images. Nevertheless, MRI has limited value for the early assessment of response to treatment, since complete resolution of bone marrow lesions may take as long as 9–12 months from the completion of the therapy. DCE-MRI is superior to standard MRI for this purpose; in particular, favorable response is indicated by the disappearance of gadolinium enhancement or by the absence of contrast-induced enhancement in a follow-up study as compared to the baseline scan. DCE-MRI derives parameters correlated with microvascular density in the bone marrow both before and after therapy [104, 105]. However, the real added value of this technique seems to lie in the possibility to predict which patients might benefit from therapy with anti-angiogenetic drugs, i.e., bevacizumab (a monoclonal antibody that inhibits VEGF). Nevertheless, this approach has not yet gained a definite role in the evaluation of the course of the disease and of activity of the myeloma lesions. Preliminary reports suggest that DWI-MRI may be used for the better definition of response to therapy, but this has to be confirmed in larger studies and in comparison with [18F]FDG-PET/CT results [50, 57]. The combination of DWI and DCE-MRI produced a score with a high agreement (76%) with the IMWG criteria of response in 27 patients with myeloma under treatment [106]; however, more data are needed to evaluate such score in larger studies [43].

Given the heterogeneous nature of the disease and inconsistent response to treatment, along with the relatively small number of published studies in this field, MRI currently has a limited role in response assessment. In general, MRI findings of response to therapy (CR or PR) include resolution or decrease of the extent of focal lesions or diffuse patterns in conventional chemotherapy or novel anti-myeloma agents [107, 108, 109]. In a small study with 33 patients who underwent an ASCT, MRI resulted in high specificity and accuracy (86% and 79%, respectively) but only 64% sensitivity for the detection of remission because of false-positive results of nonviable lesions [109]. Thus, for better evaluation of remission, functional imaging techniques (e.g., PET/CT or possibly DWI-MRI) seem to be more appropriate. Nonetheless, in a retrospective study which compared MRI and [18F]FDG-PET/CT in 210 patients with MM, MRI achieved better results than PET/CT for the detection of myeloma at diagnosis and at progression, while PET/CT detected findings of response to anti-myeloma therapy earlier than MRI [110].

Regarding patients with smoldering multiple myeloma with a negative MRI study at diagnosis, the timing of follow-up with MRI and the significance of any findings on these studies have not yet been established. Merz et al. [111] evaluated the role of repeated MRI in 63 patients with smoldering multiple myeloma. The second examination was performed 3–6 months after the first. Approximately one-half of the patients showed progression on MRI, while 40% developed symptomatic disease, according to CRAB criteria.

Other studies [78, 112] have found a close correlation between the results of 99mTc-Sestamibi scintigraphy (i.e., disappearance of any area of uptake) and the conventional criteria used for defining clinical response to therapy (i.e., measurement of the M-protein component). Overall, these findings support the hypothesis that bone marrow uptake is an indicator of myeloma activity in the bone marrow, even in the absence of focal areas of increased uptake. This procedure has shown high specificity (86%) in patients in CR, whereas sensitivity was 45% in presence of PR; these findings emphasize the high performance of 99mTc-Sestamibi scintigraphy for identifying absent disease, whereas its sensitivity is lower for the definition of residual disease when response is not complete. Multivariate analysis also showed that the sensitivity of 99mTc-Sestamibi scintigraphy was low in the presence of bone marrow infiltration <30%.

The prognostic value of 99mTc-Sestamibi imaging for predicting recurrence of the disease has been extensively investigated by Pace et al. [75]. In a group of patients evaluated both at baseline and after chemotherapy, they demonstrated a significant association between pretreatment scintigraphic pattern and clinical status at follow-up. In particular, none of the patients responding to therapy had a posttreatment 99mTc-Sestamibi scan showing focal uptake or diffuse uptake with a summed score higher than 2; by contrast, the nonresponders showed either diffuse bone marrow uptake or areas of focal uptake with summed score higher than 2. A negative baseline 99mTc-Sestamibi imaging showed high prognostic value for clinico-biochemical remission, and multivariate analysis demonstrated the added value of the 99mTc-Sestamibi uptake pattern with respect to known prognostic variables, such as C-reactive protein. Furthermore, 99mTc-Sestamibi imaging patterns at follow-up were significantly associated with the clinical status evaluated after chemotherapy.

In an independent study, a semiquantitative parameter of 99mTc-Sestamibi washout derived from dual point scintigraphic acquisitions as the counts/pixel at early imaging (10 min) minus counts/pixel at delayed imaging (60 min) divided by counts/pixel at 10 min (corrected for decay) has been also employed to distinguish patients responding to treatment from nonresponders. A fast clearance of 99mTc-Sestamibi from the bone marrow of patients with MM is associated with poor response to subsequent chemotherapy.

Moreover, 99mTc-Sestamibi washout reflects the degree of expression of the P-glycoprotein (Pgp), a transmembrane protein encoded by the ABCB1 gene that mediates the outward transport of many cytotoxic compounds including a variety of anticancer agents and confers tumor cells the capability to escape the lethal effect of many cytotoxic compounds, thus causing multidrug resistance (MDR). Overexpression of Pgp in resistant-cultured tumor cells causes a reduced net uptake of 99mTc-Sestamibi as a consequence of an enhanced Pgp-dependent outward transport of the tracer [113]. Thus, since overexpression of Pgp is one of the primary mechanisms of MDR in MM as well as in other malignancies [114, 115], it can be hypothesized that the 99mTc-Sestamibi washout rate could serve to predict response to chemotherapy in MM patients.

However, all these studies have included small groups of patients, and none of them evaluated the impact of 99mTc-Sestamibi scintigraphy on progression-free survival and overall survival.

In case of effective response to therapy, [18F]FDG uptake declines rapidly (within hours). The persistence of a positive [18F]FDG-PET has high prognostic value, as it correlates with early recurrence. Furthermore, [18F]FDG-PET/CT represents the most sensitive imaging technique to evaluate response of the bone lesions to treatment, particularly for distinguishing treated bone marrow lesions from viable neoplastic tissues [8, 26, 92] (Figs. 16 and 17).
Fig. 16

Treatment response evaluation assessed by [18F]FDG-PET/CT in a patient with MM IgG K (stage IIIb, ISS2). Baseline MIP (a) shows many areas of [18F]FDG uptake disappeared (b) after chemotherapy (VelDexMyo regimen)

Fig. 17

[18F]FDG-PET/CT of the same patient shown in Fig. 16 after recurrence

[18F]FDG-PET/CT has been employed in patients with newly diagnosed MM as part of the “Total Therapy 3” study, characterized by four distinct phases of induction therapy (two cycles of VDT-PACE with peripheral blood stem cell collection after the first cycle + tandem transplantation with melphalan 200 mg/m2, consolidation with two cycles of dose-reduced VDT-PACE, and maintenance therapy for 3 years, with monthly cycles of VTD for the first year and thalidomide plus dexamethasone in years 2 and 3) [94]. The exam was performed at baseline (together with metastatic bone survey and MRI) and within 10 days from starting the first induction cycle of VDT-PACE. The follow-up studies included annual metastatic bone survey, while MRI scans were performed before each of two transplantations, before consolidation and maintenance phases, and semiannually thereafter. All imaging studies were also repeated at relapse, defined by M-protein and bone marrow criteria and by any of the imaging procedures. Similarly as in the case of other malignancies such as lymphoma, disappearance of [18F]FDG uptake before transplantation proved to be an independent favorable prognostic factor, thus demonstrating the importance of complete suppression of tumor metabolism in myeloma. Using the [18F]FDG-PET/CT criteria (absence of [18F]FDG focal uptake in bone segments and extramedullary disease), the authors were able to define CR status in 92% at 18 months, which became obvious earlier than the median onset of clinical n-CR (87%) and CR status (56%) by 4 and 12 months, respectively. The cumulative proportion of patients qualifying for MRI-defined CR was 29% at 18 months and reached 59% at 48 months. In patients without focal lesions, MRI-defined CR (hypointensity on STIR images) was reached in 62% at 18 months, similar to 56% of the patients attaining clinical CR status. While very early [18F]FDG-PET/CT changes (at 10 days) did not affect outcome, complete [18F]FDG suppression and extramedullary disease before transplantation conferred superior overall and event-free survival; in fact, 30 months after the first autotransplantation, 92% and 89% of the patients were alive and event-free compared with 71% and 63% among those with less than 100% disappearance of [18F]FDG uptake. Complete [18F]FDG suppression before the first transplantation correlated with superior outcomes in both low-risk and high-risk gene array-defined risk groups, reaching statistical significance for overall survival in low-risk and for event-free survival in high-risk myeloma. Normalization of the PET findings before transplantation was associated with improved outcomes, whereas gene array-defined high-risk designation conferred poor overall and event-free survival. In the absence of molecular genetic data, the favorable implications of pre-transplantation [18F]FDG suppression were canceled by elevated serum levels of lactate dehydrogenase and β2-microglobulin. Clinical CR or n-CR status before transplantation did not impact post-transplantation survival outcomes. The prognosis of high-risk patients not achieving complete [18F]FDG suppression was especially poor.

More recently, 700 patients with symptomatic MM eligible for high-dose therapy (HDT) have been randomized to receive either eight cycles of bortezomib-lenalidomide-dexamethasone followed by 1-year maintenance with lenalidomide or three cycles of VRD followed by high-dose therapy and autologous transplantation then VRD consolidation and 1-year lenalidomide maintenance (the IFM-DFCI 2009 study). Spine and pelvis MRI and whole-body PET-CT at diagnosis, after three cycles of VRD, and prior to maintenance were performed. At diagnosis, MRI was positive in 94.7% of patients and PET/CT 91%. Following three cycles, MRI remained positive in 93% and PET/CT in 55% of patients. Normalization of MRI after 3 months of induction therapy was not predictive neither for progression-free survival nor for overall survival, whereas normalization of PET/CT was associated with a significant improvement in PFS but not OS. Prior to maintenance, MRI remained positive in 83%, and PET/CT in 21% of the patients. Normalization of MRI before maintenance was not predictive for survivals, whereas normalization of PET/CT was associated with a prolonged PFS and OS, thus suggesting that PET/CT should be incorporated in the follow-up of MM patients who undergo to high-dose treatment [116].

Quantitative data on kinetics and distribution patterns of [18F]FDG obtained from dynamic PET/CT in 40 patients with MM correlated significantly with percentage of bone marrow infiltration by plasma cells [117]. Furthermore, PET/CT efficiently detected extramedullary disease in patients both at diagnosis and at relapse [118]. PET/CT was tested for better definition of CR in 282 MM patients. The examination was performed at diagnosis and every 12–18 months afterward. At diagnosis, 42% of patients with MM had more than three focal lesions (SUVmax >4.2 in 50% of cases). After treatment, PET/CT was negative for 70% of patients, while 53% of patients achieved CR according to IMWG criteria. Approximately 30% of patients at CR had a positive PET/CT. A negative PET/CT was an independent predictor for prolonged PFS and OS in patients with CR. In addition, for patients with CR, median PFS was 50 months for patients with a positive PET/CT and 90 months for patients with negative PET/CT [119].

In smoldering multiple myeloma, 16% of patients with normal whole-body X-ray had positive PET/CT results [120]. The median time to progression (TTP) for patients with positive PET/CT was shorter than patients with negative PET/CT (1.1 years vs. 4.5 year), while the probability of progression at 2 years for patients with positive PET/CT results was 58% [121]. The largest study in the field involved 188 patients with smoldering myeloma: [18F]FDG-PET/CT was positive in 39% of patients. The probability of progression to symptomatic MM within 2 years was 75% for patients with positive PET/CT under observation and 30% for patients with negative PET/CT. This probability was higher if hypermetabolic activity was combined with underlying osteolysis (2-year progression rate of 87%). The median TTP was 21 months compared with 60 months for patients with positive PET/CT and those with negative PET/CT, respectively [122].

PET/CT has also a role in nonsecretory or oligosecretory myeloma for the detection of active lesions in the body [123] (Fig. 18). In this setting it may be useful also to monitoring treatment response.
Fig. 18

Different pattern of [18F]FDG-PET/CT in a patient with oligosecretory/nonsecretory MM. Images show an area of focal [18F]FDG uptake in L3 (a) while no uptake in the pelvis (b)

PET/MRI represents a novel imaging modality with attractive potential clinical applications. In MM, there is only one prospective study comparing PET/MRI with PET/CT in 30 patients with MM with both techniques performed sequentially. There was high correlation between the two techniques, regarding the number of active lesions and the degree of uptake (SUV) [43, 124].

DEXA Scanning

The World Health Organization has identified dual-energy X-ray absorptiometry (DEXA) as the gold standard for measuring the severity of osteoporosis, for defining the risk of fractures, and for assessing changes in bone mineral density over time. This method is fast, noninvasive, and implies a low radiation burden to patients (between 0.001 and 0.01 mSv). However, bone mineral density can be affected by pathological conditions, such as vertebral collapse and spinal osteophytes that are often concomitant in patients with MM. At present, DEXA scanning cannot distinguish benign osteoporosis from osteoporosis induced by MM. Furthermore, the reduction in bone mineral density in patients with MM usually is not diffuse but is rather confined to the hematopoietically active portions of the skeleton; consequently, bone densitometry studies are not still sufficient to determine the presence of MM bone disease [9].

References

  1. 1.
    Moreau P, San Miguel J, Ludwig H, Schouten H, Mohty M, Dimopoulos M, et al. Multiple myeloma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24:vi133–7.Google Scholar
  2. 2.
    Surveillance Research Program, National Cancer Institute. Cancer Stat Fact Sheets [Internet]. Cancer Stat Surveill Res Program Natl Cancer Inst; 2016. Available from: http://seer.cancer.gov/statfacts.
  3. 3.
    Solly S. Remarks on the pathology of mollities ossium; with cases. Med Chir Trans. 1844;27:435–98.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Wright JH. A case of multiple myeloma. J Boston Soc Med Sci. 1900;4:195–204.5.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Waldenstrom J. Studies on conditions associated with disturbed gamma globulin formation (gammopathies). Harvey Lect. 1961;56:211–31.Google Scholar
  6. 6.
    Pruzanski W, Ogryzlo M. Abnormal proteinuria in malignant diseases. Adv Clin Chem. 1970;13:1970.Google Scholar
  7. 7.
    Mulligan ME, Badros AZ. PET/CT and MR imaging in myeloma. Skeletal Radiol. 2007;36:5–16.PubMedCrossRefGoogle Scholar
  8. 8.
    Kyle RA, Rajkumar V. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009;23:3–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. International myeloma working group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538–48.PubMedCrossRefGoogle Scholar
  10. 10.
    Larsen JT, Kumar SK, Dispenzieri A, Kyle RA, Katzmann JA, Rajkumar SV. Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. Leukemia. 2013;27:941–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Waxman AJ, Mick R, Garfall AL, Cohen A, Vogl DT, Stadtmauer EA, et al. Classifying ultra-high risk smoldering myeloma. Leukemia. 2014;29:751–3.PubMedCrossRefGoogle Scholar
  12. 12.
    Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC. Multiple myeloma. Lancet. 2009;374:324–39.PubMedCrossRefGoogle Scholar
  13. 13.
    Rajkumar SV. Multiple myeloma. Curr Probl Cancer. 2009;33:7–64.PubMedCrossRefGoogle Scholar
  14. 14.
    Ribatti D, Vacca A, Nico B, Quondamatteo F, Ria R, Minischetti M, et al. Bone marrow angiogenesis and mast cell density increase simultaneously with progression of human multiple myeloma. Br J Cancer. 1999;79:451–5.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Rajkumar S, Gupta V, Fonseca R, Dispenzieri A, Gonsalves W, Larson D, et al. Impact of primary molecular cytogenetic abnormalities and risk of progression in smoldering multiple myeloma. Leukemia. 2013;27:1738–44.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Dimopoulos M, Terpos E, Comenzo RL, Tosi P, Beksac M, Sezer O, et al. International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple myeloma. Leukemia Nat Pub Group. 2009;23:1545–56.CrossRefGoogle Scholar
  17. 17.
    Roodman GD. Skeletal imaging and management of bone disease. Hematol Am Soc Hematol Educ Program. 2008;1:313–9.Google Scholar
  18. 18.
    Delorme S, Baur-Melnyk A. Imaging in multiple myeloma. Eur J Radiol. 2009;70:401–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Lindsley H, Teller D, Noonan B, Peterson M, Mannik M. Hyperviscosity syndrome in multiple myeloma. A reversible, concentration- dependent aggregation of the myeloma protein. Am J Med. 1973;54:682–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Winterbottom AP, Shaw AS. Imaging patients with myeloma. Clin Radiol. 2009;64:1–11.PubMedCrossRefGoogle Scholar
  21. 21.
    McBride W, Jackman Jr JD, Gammon RS, Willerson JT. High-output cardiac failure in patients with multiple myeloma. N Engl J Med. 1988;319:1651–3.PubMedCrossRefGoogle Scholar
  22. 22.
    Latov N, Sherman WH, Nemni R, Galassi G, Shyong JS, Penn AS, et al. Plasma-cell dyscrasia and peripheral neuropathy with a monoclonal antibody to peripheral-nerve myelin. N Engl J Med. 1980;303:618–21.PubMedCrossRefGoogle Scholar
  23. 23.
    Dimopoulos M, Kyle R, Fermand JP, Rajkumar SV, San Miguel J, Chanan-Khan A, et al. Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. Blood. 2011;117:4701–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Avet-Loiseau H, Durie B, Cavo M, Attal M, Gutierrez N, Haessler J, et al. Combining fluorescent in situ hybridization data with ISS staging improves risk assessment in myeloma: an International Myeloma Working Group collaborative project. Leukemia. 2013;27282:711–7.CrossRefGoogle Scholar
  25. 25.
    Greipp PR. Prognosis in myeloma. Mayo Clin Proc. 1994;69:895–902.PubMedCrossRefGoogle Scholar
  26. 26.
    Lütje S, Rooy JWJ, Croockewit S, Koedam E, Oyen WJG, Raymakers RA. Role of radiography, MRI and FDG-PET/CT in diagnosing, staging and therapeutical evaluation of patients with multiple myeloma. Ann Hematol. 2009;88:1161–8.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975;36:842–54.PubMedCrossRefGoogle Scholar
  28. 28.
    Durie BGM. The role of anatomic and functional staging in myeloma: description of Durie/Salmon plus staging system. Eur J Cancer. 2006;42:1539–43.PubMedCrossRefGoogle Scholar
  29. 29.
    Rajkumar SV. Updated diagnostic criteria and staging system for multiple. ASCO Educ B. 2016;35:418–23.Google Scholar
  30. 30.
    Hillengass J, Landgren O. Challenges and opportunities of novel imaging techniques in monoclonal plasma cell disorders: imaging “early myeloma”. Leuk Lymphoma. 2013;54:1355–63.PubMedCrossRefGoogle Scholar
  31. 31.
    Regelink JC, Minnema MC, Terpos E, Kamphuis MH, Raijmakers PG, Pieters-van den Bos IC, et al. Comparison of modern and conventional imaging techniques in establishing multiple myeloma-related bone disease: a systematic review. Br J Haematol. 2013;162:50–61.PubMedCrossRefGoogle Scholar
  32. 32.
    Terpos E, Kleber M, Engelhardt M, Zweegman S, Gay F, Kastritis E, et al. European myeloma network guidelines for the management of multiple myeloma-related complications. Haematologica. 2015;100:1254–66.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Terpos E, Moulopoulos LA, Dimopoulos MA. Advances in imaging and the management of myeloma bone disease. J Clin Oncol. 2011;29:1907–15.PubMedCrossRefGoogle Scholar
  34. 34.
    Ågren B, Björkstrand B, Rudberg U, Aspelin PBL. Radiography and bone scintigraphy in bone marrow transplant multiple myeloma patients. Acta Radiol. 1997;38:144–50.PubMedCrossRefGoogle Scholar
  35. 35.
    Kapadia SB. Multiple myeloma: a clinicopathologic study of 62 consecutively autopsied cases. Medicine (Baltimore). 1980;59:380–92.CrossRefGoogle Scholar
  36. 36.
    Chassang M, Grimaud A, Cucchi JM, Novellas S, Amoretti N, Chevallier P, et al. Can low-dose computed tomographic scan of the spine replace conventional radiography? An evaluation based on imaging myelomas, bone metastases, and fractures from osteoporosis. Clin Imaging. 2007;31:225–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Collins CD. Multiple myeloma. Cancer Imaging. 2004;4:S47–53.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Pianko MJ, Terpos E, Roodman GD, Divgi CR, Zweegman S, Hillengass J, et al. Whole-body low-dose computed tomography and advanced imaging techniques for multiple myeloma bone disease. Clin Cancer Res. 2014;20:5888–97.PubMedCrossRefGoogle Scholar
  39. 39.
    Mahnken AH, Wildberger JE, Gehbauer G, Schmitz-Rode T, Blaum M, Fabry U, et al. Multidetector CT of the spine in multiple myeloma: comparison with MR imaging and radiography. AJR Am J Roentgenol. 2002;178:1429–36.PubMedCrossRefGoogle Scholar
  40. 40.
    Huda W, Vance A. Patient radiation doses from adult and pediatric CT. Am J Roentgenol. 2007;188:540–6.CrossRefGoogle Scholar
  41. 41.
    Weininger M, Lauterbach B, Knop S, Pabst T, Kenn W, Hahn D, et al. Whole-body MRI of multiple myeloma: comparison of different MRI sequences in assessment of different growth patterns. Eur J Radiol. 2009;69:339–45.PubMedCrossRefGoogle Scholar
  42. 42.
    Ghanem N, Lohrmann C, Engelhardt M, Pache G, Uhl M, Saueressig U, et al. Whole-body MRI in the detection of bone marrow infiltration in patients with plasma cell neoplasms in comparison to the radiological skeletal survey. Eur Radiol. 2006;16:1005–14.PubMedCrossRefGoogle Scholar
  43. 43.
    Terpos E, Dimopoulos MA, Moulopoulos LA. The role of imaging in the treatment of patients with multiple myeloma in 2016. Am Soc Clin Oncol Educ Book. 2016;35:e407–17.PubMedCrossRefGoogle Scholar
  44. 44.
    Baur-Melnyk A, Buhmann S, Becker C, Schoenberg SO, Lang N, Bartl R, et al. Whole-body MRI versus whole-body MDCT for staging of multiple myeloma. AJR Am J Roentgenol. 2008;190:1097–104.PubMedCrossRefGoogle Scholar
  45. 45.
    Wolf MB, Murray F, Kilk K, Hillengass J, Delorme S, Heiss C, et al. Sensitivity of whole-body CT and MRI versus projection radiography in the detection of osteolyses in patients with monoclonal plasma cell disease. Eur J Radiol. 2014;83:1222–30.PubMedCrossRefGoogle Scholar
  46. 46.
    Princewill K, Kyere S, Awan O, Mulligan M. Multiple myeloma lesion detection with whole body CT versus radiographic skeletal survey. Cancer Invest. 2013;31:206–11.PubMedCrossRefGoogle Scholar
  47. 47.
    Gleeson TG, Moriarty J, Shortt CP, Gleeson JP, Fitzpatrick P, Byrne B, et al. Accuracy of whole-body low-dose multidetector CT (WBLDCT) versus skeletal survey in the detection of myelomatous lesions, and correlation of disease distribution with whole-body MRI (WBMRI). Skeletal Radiol. 2009;38:225–36.PubMedCrossRefGoogle Scholar
  48. 48.
    Kröpil P, Fenk R, Fritz LB, Blondin D, Kobbe G, Mödder U, et al. Comparison of whole-body 64-slice multidetector computed tomography and conventional radiography in staging of multiple myeloma. Eur Radiol. 2008;18:51–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Ippolito D, Besostri V, Bonaffini PA, Rossini F, Di Lelio A, Sironi S. Diagnostic value of whole-body low-dose computed tomography (WBLDCT) in bone lesions detection in patients with multiple myeloma (MM). Eur J Radiol. 2013;82:2322–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Horger M, Claussen CD, Bross-Bach U, Vonthein R, Trabold T, Heuschmid M, et al. Whole-body low-dose multidetector row-CT in the diagnosis of multiple myeloma: an alternative to conventional radiography. Eur J Radiol. 2005;54:289–97.PubMedCrossRefGoogle Scholar
  51. 51.
    Cretti F, Perugini G. Patient dose evaluation for the whole-body low-dose multidetector CT (WBLDMDCT) skeleton study in multiple myeloma (MM). Radiol Medica. 2016;121:93–105.CrossRefGoogle Scholar
  52. 52.
    Borggrefe J, Giravent S, Campbell G, Thomsen F, Chang D, Franke M, et al. Association of osteolytic lesions, bone mineral loss and trabecular sclerosis with prevalent vertebral fractures in patients with multiple myeloma. Eur J Radiol. 2015;84:2269–74.PubMedCrossRefGoogle Scholar
  53. 53.
    Dimopoulos MA, Hillengass J, Usmani S, Zamagni E, Lentzsch S, Davies FE, et al. Role of magnetic resonance imaging in the management of patients with multiple myeloma: a consensus statement. J Clin Oncol. 2015;33:657–64.PubMedCrossRefGoogle Scholar
  54. 54.
    D’Sa S, Abildgaard N, Tighe J, Shaw P, Hall-Craggs M. Guidelines for the use of imaging in the management of myeloma. Br J Haematol. 2007;137:49–63.PubMedCrossRefGoogle Scholar
  55. 55.
    Merz M, Moehler TM, Ritsch J, Bäuerle T, Zechmann CM, Wagner B, et al. Prognostic significance of increased bone marrow microcirculation in newly diagnosed multiple myeloma: results of a prospective DCE-MRI study. Eur Radiol. 2016;26:1404–11.PubMedCrossRefGoogle Scholar
  56. 56.
    Nonomura Y, Yasumoto M, Yoshimura R, Haraguchi K, Ito S, Akashi T, et al. Relationship between bone marrow cellularity and apparent diffusion coefficient. J Magn Reson Imaging. 2001;13:757–60.PubMedCrossRefGoogle Scholar
  57. 57.
    Terpos E, Koutoulidis V, Fontara S, Zagouri F, Christoulas D, Koureas A, et al. Diffusion-weighted imaging improves accuracy in the diagnosis of MRI patterns of marrow involvement in newly diagnosed myeloma: results of a prospective study in 99 patients. Blood. 2015;126:4178.Google Scholar
  58. 58.
    Messiou C, Giles S, Collins DJ, West S, Davies FE, Morgan GJ, et al. Assessing response of myeloma bone disease with diffusion-weighted MRI. Br J Radiol. 2012;85:2–3.CrossRefGoogle Scholar
  59. 59.
    Giles SL, Desouza NM, Collins DJ, Morgan VA, West S, Davies FE, et al. Assessing myeloma bone disease with whole-body diffusion-weighted imaging: comparison with x-ray skeletal survey by region and relationship with laboratory estimates of disease burden. Clin Radiol. 2015;70:614–21.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Sachpekidis C, Mosebach J, Freitag MT, Wilhelm T, Mai EK, Haberkorn U, et al. Application of 18F-FDG PET and diffusion weighted imaging (DWI) in multiple myeloma : comparison of functional imaging modalities. Am J Nucl Med Mol Imaging. 2015;5:479–92.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Pawlyn C, Fowkes L, Otero S, Jones J, Boyd K, Davies F, et al. Whole-body diffusion-weighted MRI: a new gold standard for assessing disease burden in patients with multiple myeloma? Leukemia. 2016;30:1446–8.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Hubner KF, Andrews GA, Hayes RL, Poggenburg Jr JK, Solomon A. The use of rare-earth radionuclides and other bone-seekers in the evaluation of bone lesions in patients with multiple myeloma or solitary plasmacytoma. Radiology. 1977;125:171–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Shuke N, Okizaki A, Yamamoto W, Usui K, Aburano T. Accumulation of Tc-99m HMDP in extramedullary plasmacytoma of the stomach. Clin Nucl Med. 2001;26:354–5.PubMedCrossRefGoogle Scholar
  64. 64.
    VanAntwerp JD, O’Mara RE, Pitt MJ, Walsh S. Technetium-99m-diphosphonate accumulation in amyloid. J Nucl Med. 1975;16:238–40.PubMedGoogle Scholar
  65. 65.
    Kanoh T, Ohno T, Uchino H, Yamamoto I, Torizuka K. Avid uptake of gallium-67 in multiple myeloma. An additional indicator of the aggressive phase. Clin Nucl Med. 1987;12:482–4.PubMedCrossRefGoogle Scholar
  66. 66.
    Roach PJ, Arthur CK. Comparison of thallium-201 and gallium-67 scintigraphy in soft tissue and bone marrow multiple myeloma: a case report. Australas Radiol. 1997;41:67–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Lin W, Wang S. Ga-67 scan findings in bone marrow involvement with plasmablastic myeloma and corresponding Tc-99m MIBI images. Clin Nucl Med. 2001;26:963.PubMedCrossRefGoogle Scholar
  68. 68.
    Posch T, Olson S. Marked soft tissue uptake of bone tracer in a patient with amyloidosis and multiple myeloma. Clin Nucl Med. 1992;17:909.PubMedCrossRefGoogle Scholar
  69. 69.
    Bekerman C, Hoffer PB, Bitran JD. The role of gallium-67 in the clinical evaluation of cancer. Semin Nucl Med. 1984;14:296–323.PubMedCrossRefGoogle Scholar
  70. 70.
    Waxman AD, Siemsen JK, Levine AM, Holdorf D, Suzuki R, Singer FR, et al. Radiographic and radionuclide imaging in multiple myeloma: the role of gallium scintigraphy: concise communication. J Nucl Med. 1981;22:232–6.PubMedGoogle Scholar
  71. 71.
    Ohnishi T, Noguchi S, Murakami N, Tajiri J, Morita M, Tamaru M, et al. Pentavalent technetium-99m-DMSA uptake in a patient having multiple myeloma without amyloidosis. J Nucl Med. 1991;32:1785–7.PubMedGoogle Scholar
  72. 72.
    Ohta H, Endo K, Kanoh T, Konishi J, Kotoura H. Technetium-99m (V) DMSA uptake in amyloidosis. J Nucl Med. 1989;30:2049–52.PubMedGoogle Scholar
  73. 73.
    Ishibashi M, Nonoshita M, Uchida M, Kojima K, Tomita N, Matsumoto S, et al. Bone marrow uptake of thallium-201 before and after therapy in multiple. J Nucl Med. 1998;39:473–5.PubMedGoogle Scholar
  74. 74.
    Watanabe N, Shimizu M, Kageyama M, Tanimura K, Kinuya S, Shuke N, et al. Multiple myeloma evaluated with 201Tl scintigraphy compared with bone. J Nucl Med. 1999;40:1138–42.PubMedGoogle Scholar
  75. 75.
    Pace L, Catalano L, Pinto A, De Renzo A, Di Gennaro F, Califano C, et al. Different patterns of technetium-99m sestamibi uptake in multiple myeloma. Eur J Nucl Med. 1998;25:714–20.PubMedCrossRefGoogle Scholar
  76. 76.
    Mirzaei S, Filipits M, Keck A, Bergmayer W, Knoll P, Koehn H, et al. Comparison of Technetium-99m-MIBI imaging with MRI for detection of spine involvement in patients with multiple myeloma. BMC Nucl Med. 2003;3:2.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Kalaga RV, Kudagi V, Heller GV. Role of Tc-99m sestamibi myocardial perfusion imaging in identifying multiple myeloma. J Nucl Cardiol. 2009;16:835–7.PubMedCrossRefGoogle Scholar
  78. 78.
    Fonti R, Salvatore B, Quarantelli M, Sirignano C, Segreto S, Petruzziello F, et al. 18F-FDG PET/CT, 99mTc-MIBI, and MRI in evaluation of patients with multiple myeloma. J Nucl Med. 2008;49:195–200.PubMedCrossRefGoogle Scholar
  79. 79.
    Agool A, Slart RHJA, Dierckx RAJO, Kluin PM, Visser L, Jager PL, et al. Somatostatin receptor scintigraphy might be useful for detecting skeleton abnormalities in patients with multiple myeloma and plasmacytoma. Eur J Nucl Med Mol Imaging. 2010;37:124–30.PubMedCrossRefGoogle Scholar
  80. 80.
    Hazenberg BPC, van Rijswijk MH, Piers DA, Lub-de Hooge MN, Vellenga E, Haagsma EB, et al. Diagnostic performance of 123I-labeled serum amyloid P component scintigraphy in patients with amyloidosis. Am J Med. 2006;119(355):e15–24.Google Scholar
  81. 81.
    Bredella MA, Steinbach L, Caputo G, Segall G, Hawkins R. Value of FDG PET in the assessment of patients with multiple myeloma. AJR Am J Roentol. 2005;184:1199–204.CrossRefGoogle Scholar
  82. 82.
    Durie BG, Waxman AD, D’agnolo A, Williams C. Whole-body 18F-FDG PET identifies high-risk myeloma. J Nucl Med. 2002;43:1457–63.PubMedGoogle Scholar
  83. 83.
    Breyer RJ, Mulligan ME, Smith SE, Line BR, Badros AZ. Comparison of imaging with FDG PET/CT with other imaging modalities in myeloma. Skeletal Radiol. 2006;35:632–40.PubMedCrossRefGoogle Scholar
  84. 84.
    Hillner BE, Siegel BA, Liu D, Shields AF, Gareen IF, Hanna L, et al. Impact of positron emission tomography/computed tomography and positron emission tomography (PET) alone on expected management of patients with cancer: initial results from the National Oncologic PET registry. J Clin Oncol. 2008;26:2155–61.PubMedCrossRefGoogle Scholar
  85. 85.
    Larson SM. Practice-based evidence of the beneficial impact of positron emission tomography in clinical oncology. J Clin Oncol. 2008;26:2083–4.PubMedCrossRefGoogle Scholar
  86. 86.
    Chae M, Lee T, Park G, Yu J, Pai M, Kang H, et al. Comparing 18F-FDG-PET/CT with other imaging modalities for detecting involving bone of multiple myeloma. J Nucl Med. 2007;48:351P.Google Scholar
  87. 87.
    Even-Sapir E, Mishani E, Flusser G, Metser U. 18F-Fluoride positron emission tomography and positron emission tomography/computed tomography. Semin Nucl Med. 2007;37:462–9.PubMedCrossRefGoogle Scholar
  88. 88.
    Schirrmeister H, Buck AK, Bergmann L, Reske SN, Bommer M. Positron emission tomography (PET) for staging of solitary plasmacytoma. Cancer Biother Radiopharm. 2003;18:841–5.PubMedCrossRefGoogle Scholar
  89. 89.
    Nanni C, Rubello D, Zamagni E, Castellucci P, Ambrosini V, Montini G, et al. 18F-FDG PET/CT in myeloma with presumed solitary plasmocytoma of bone. In Vivo (Brooklyn). 2008;22:513–7.Google Scholar
  90. 90.
    Salaun PY, Gastinne T, Frampas E, Bodet-Milin C, Moreau P, Bodéré-Kraeber F. FDG-positron-emission tomography for staging and therapeutic assessment in patients with plasmacytoma. Haematologica. 2008;93:1269–71.PubMedCrossRefGoogle Scholar
  91. 91.
    Cook GJR, Wegner EA, Fogelman I. Pitfalls and artifacts in 18FDG PET and PET/CT oncologic imaging. Semin Nucl Med. 2004;34:122–33.PubMedCrossRefGoogle Scholar
  92. 92.
    Nanni C, Zamagni E, Farsad M, Castellucci P, Tosi P, Cangini D, et al. Role of 18F-FDG PET/CT in the assessment of bone involvement in newly diagnosed multiple myeloma: preliminary results. Eur J Nucl Med Mol Imaging. 2006;33:525–31.PubMedCrossRefGoogle Scholar
  93. 93.
    Hur J, Yoon C-S, Ryu YH, Yun MJ, Suh J-S. Comparative study of fluorodeoxyglucose positron emission tomography and magnetic resonance imaging for the detection of spinal bone marrow infiltration in untreated patients with multiple myeloma. Acta Radiol. 2008;49:427–35.PubMedCrossRefGoogle Scholar
  94. 94.
    Bartel TB, Haessler J, Brown TLY, Shaughnessy JD, Van Rhee F, Anaissie E, et al. F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma. Blood. 2009;114:2068–76.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Gorospe L, Raman S, Echeveste J, Avril N, Herrero Y, Herna NS. Whole-body PET/CT: spectrum of physiological variants, artifacts and interpretative pitfalls in cancer patients. Nucl Med Commun. 2005;26:671–87.PubMedCrossRefGoogle Scholar
  96. 96.
    Mesguich C, Fardanesh R, Tanenbaum L, Chari A, Jagannath S, Kostakoglu L. State of the art imaging of multiple myeloma: comparative review of FDG PET/CT imaging in various clinical settings. Eur J Radiol. 2014;83:2203–23.PubMedCrossRefGoogle Scholar
  97. 97.
    Nanni C, Zamagni E, Versari A, Chauvie S, Bianchi A, Rensi M, et al. Image interpretation criteria for FDG PET/CT in multiple myeloma: a new proposal from an Italian expert panel. IMPeTUs (Italian Myeloma criteria for PET USe). Eur J Nucl Med Mol Imaging. 2016;43:414–21.PubMedCrossRefGoogle Scholar
  98. 98.
    Nanni C, Zamagni E, Cavo M, Rubello D, Tacchetti P, Pettinato C, et al. 11C-choline vs. 18F-FDG PET/CT in assessing bone involvement in patients with multiple myeloma. World J Surg Oncol. 2007;5:68.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Cassou-Mounat T, Balogova S, Nataf V, Calzada M, Huchet V, Kerrou K, et al. 18F-fluorocholine versus 18F-fluorodeoxyglucose for PET/CT imaging in patients with suspected relapsing or progressive multiple myeloma: a pilot study. Eur J Nucl Med Mol Imaging. 2016;43(11):1995–2004. doi:10.1007/s00259-016-3392-7.Google Scholar
  100. 100.
    Dankerl A, Liebisch P, Glatting G, Friesen C, Blumstein NM, Kocot D, et al. Multiple myeloma: molecular imaging with 11C-Methionine PET/CT—initial experience 1. Radiology. 2007;242:498–508.PubMedCrossRefGoogle Scholar
  101. 101.
    Lapa C, Knop S, Schreder M, Rudelius M, Knott M, Jörg G, et al. 11C-Methionine-PET in multiple myeloma: correlation with clinical parameters and bone marrow involvement. Theranostics. 2016;6:254–61.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Lee SM, Kim TS, Lee JW, Kwon HW, Kim YI1, Kang SH, et al. Incidental finding of an 11C-acetate PET-positive multiple myeloma. Ann Nucl Med. 2010;24:41–4.PubMedCrossRefGoogle Scholar
  103. 103.
    Stjernholm RL. Carbohydrate metabolism in leukocytes. VII. Metabolism of glucose, acetate, and propionate by human plasma cells. J Bacteriol. 1967;93:1657–61.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Huang SY, Bin CB, Lu HY, Lin HH, Wei SY, Hsu SC, et al. Correlation among DCE-MRI measurements of bone marrow angiogenesis, microvessel density, and extramedullary disease in patients with multiple myeloma. Am J Hematol. 2012;87:837–9.PubMedCrossRefGoogle Scholar
  105. 105.
    Merz M, Ritsch J, Kunz C, Wagner B, Sauer S, Hose D, et al. Dynamic contrast-enhanced magnetic resonance imaging for assessment of antiangiogenic treatment effects in multiple myeloma. Clin Cancer Res. 2015;21:106–12.PubMedCrossRefGoogle Scholar
  106. 106.
    Dutoit JC, Claus E, Offner F, Noens L, Delanghe J, Verstraete KL. Combined evaluation of conventional MRI, dynamic contrast-enhanced MRI and diffusion weighted imaging for response evaluation of patients with multiple myeloma. Eur J Radiol. 2016;85:373–82.PubMedCrossRefGoogle Scholar
  107. 107.
    Moulopoulos LA, Dimopoulos MA, Alexanian R, Leeds NE, Libshitz HI. Multiple myeloma: MR patterns of response to treatment. Radiology. 1994;193:441–6.PubMedCrossRefGoogle Scholar
  108. 108.
    Hillengass J, Ayyaz S, Kilk K, Weber M-A, Hielscher T, Shah R, et al. Changes in magnetic resonance imaging before and after autologous stem cell transplantation correlate with response and survival in multiple myeloma. Haematologica. 2012;97:1757–60.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Bannas P, Hentschel HB, Bley TA, Treszl A, Eulenburg C, Derlin T, et al. Diagnostic performance of whole-body MRI for the detection of persistent or relapsing disease in multiple myeloma after stem cell transplantation. Eur Radiol. 2012;22:2007–12.PubMedCrossRefGoogle Scholar
  110. 110.
    Spinnato P, Bazzocchi A, Brioli A, Nanni C, Zamagni E, Albisinni U, et al. Contrast enhanced MRI and 18F-FDG PET-CT in the assessment of multiple myeloma: a comparison of results in different phases of the disease. Eur J Radiol. 2012;81:4013–8.PubMedCrossRefGoogle Scholar
  111. 111.
    Merz M, Hielscher T, Wagner B, Sauer S, Shah S, Ms R, et al. Predictive value of longitudinal whole-body magnetic resonance imaging in patients with smoldering multiple myeloma. Leukemia. 2014;28:1902–8.PubMedCrossRefGoogle Scholar
  112. 112.
    Fallahi D, Beiki D, Mousavi SA, Gholamrezanezhad A, Eftekhari M, Fard-Esfahani A, Alimoghaddam K, et al. 99mTc-MIBI whole body scintigraphy and P-glycoprotein for the prediction of multiple drug resistance in multiple myeloma patients. Hell J Nucl Med. 2009;12:255–9.PubMedGoogle Scholar
  113. 113.
    Piwnica-Worms D, Chiu ML, Budding M, Kronauge JF, Kramer RA, Croop JM. Functional imaging of multidrug-resistant P-glycoprotein with an organotechnetium complex. Cancer Res. 1993;53:977–84.PubMedGoogle Scholar
  114. 114.
    Mongkonsritragoon W, Kimlinger T, Ahmann G, Greipp P. Is multidrug resistance (P-glycoprotein) an intrinsic characteristic of plasma cells in patients with monoclonal gammopathy of undetermined significance plasmacytoma, multiple myeloma and amyloidosis? Leuk Lymphoma. 1998;29:577–84.PubMedCrossRefGoogle Scholar
  115. 115.
    Patriarca F, Melli C, Damiani D, Michieli M, Michelutti A, Cavo M, et al. Plasma cell P170 expression and response to treatment in multiple myeloma. Haematologica. 1996;81:232–7.PubMedGoogle Scholar
  116. 116.
    Moreau P, Attal M, Karlin L, Garderet L, Facon T, Benboubker L, et al. Prospective evaluation of MRI and PET-CT at diagnosis and before maintenance therapy in symptomatic patients with multiple myeloma included in the IFM/DFCI 2009 trial. Blood. 2015;126:92–5599 (abstract 395).CrossRefGoogle Scholar
  117. 117.
    Sachpekidis C, Mai EK, Goldschmidt H, Hillengass J, Hose D, Pan L, et al. 18F-FDG dynamic PET/CT in patients with multiple myeloma. Clin Nucl Med. 2015;40:e300–7.PubMedCrossRefGoogle Scholar
  118. 118.
    Tirumani SH, Sakellis C, Jacene H, Shinagare AB, Munshi NC, Ramaiya NH, et al. Role of FDG-PET/CT in extramedullary multiple myeloma: correlation of FDG-PET/CT findings with clinical outcome. Clin Nucl Med. 2016;41:e7–13.PubMedCrossRefGoogle Scholar
  119. 119.
    Zamagni E, Nanni C, Mancuso K, Tacchetti P, Pezzi A, Pantani L, et al. PET/CT improves the definition of complete response and allows to detect otherwise unidentifiable skeletal progression in multiple myeloma. Clin Cancer Res. 2015;21:4384–90.PubMedCrossRefGoogle Scholar
  120. 120.
    Zamagni E, Nanni C, Patriarca F, Englaro E, Castellucci P, Geatti O, et al. A prospective comparison of 18F-fluorodeoxyglucose positron emission tomography-computed tomography, magnetic resonance imaging and whole-body planar radiographs in the assessment of bone disease in newly diagnosed multiple myeloma. Haematologica. 2007;92:50–5.PubMedCrossRefGoogle Scholar
  121. 121.
    Zamagni E, Nanni C, Gay F, Pezzi A, Patriarca F, Bellò M, et al. 18F-FDG PET/CT focal, but not osteolytic, lesions predict the progression of smoldering myeloma to active disease. Leukemia. 2016;30:417–22.PubMedCrossRefGoogle Scholar
  122. 122.
    Siontis B, Kumar S, Dispenzieri A, Drake MT, Lacy MQ, Buadi F, et al. Positron emission tomography-computed tomography in the diagnostic evaluation of smoldering multiple myeloma: identification of patients needing therapy. Blood Cancer J. 2015;5:e364.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Lonial S, Jl K. Non-secretory myeloma : a clinician’s guide. Oncology. 2013;27:924–30.PubMedGoogle Scholar
  124. 124.
    Sachpekidis C, Hillengass J, Goldschmidt H, Mosebach J, Pan L, Pet F. Comparison of 18F-FDG PET/CT and PET/MRI in patients with multiple myeloma. Am J Nucl Med Mol Imaging. 2015;5:469–78.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Martina Sollini
    • 1
  • Sara Galimberti
    • 2
  • Roberto Boni
    • 3
  • Paola Anna Erba
    • 3
    Email author
  1. 1.Department of Biomedical SciencesHumanitas UniversityRozzanoItaly
  2. 2.Hematology UnitUniversity of PisaPisaItaly
  3. 3.Regional Center of Nuclear Medicine, Department of Translational Research and New Technology in MedicineUniversity of PisaPisaItaly

Personalised recommendations