Multiple Myeloma and Plasmacytoma

Chapter

Abstract

This chapter will discuss radiation therapy for multiple myeloma and solitary plasmacytoma.

Keywords

Multiple myeloma Plasmacytoma 

Pearls

  • Plasma cell tumors are derived from terminally differentiated B cells that produce and often secrete monoclonal immunoglobulins.

  • Incidence is low overall, ~1–2% of US cancers diagnosed yearly (~30 k) are plasma cell tumors. More than 90% of these are multiple myeloma (MM); ~2–10% are solitary plasmacytoma (SP).

  • MM incidence is higher in African-Americans than Caucasians (~2:1). Median age at diagnosis 65 years.

  • SP is more common in men than women (4:1). Median age at diagnosis 50–55 years.

  • Etiology is unknown, may involve occupational exposures, RT, solvents.

  • MM as opposed to SP is generally incurable.

  • 20% of patients are asymptomatic at diagnosis.

  • MM may manifest as bone pain, neurologic symptoms, pathologic fracture, cord compression, anemia, hypercalcemia, renal insufficiency, or infection.

  • Osseous SP occurs most frequently in the vertebral column.

  • ~80% of extraosseous SP occurs in upper aerodigestive tract. Common presenting signs include epistaxis, nasal discharge, or nasal obstruction (Creach IJROBP 2009).

  • 50–80% of patients with osseous SP progress to MM in a bimodal fashion, either 2–3 years or 6–9 years after presentation. Factors that correlate with conversion are lesion size ≥5 cm, age >40 years old, presence of an M spike, spinal location, or persistence of an M-protein >1 year after RT.

  • 10–40% of patients with extraosseous SP progress to MM at 10 years.

  • MM diagnosis requires bone marrow biopsy ≥10% plasma cells + end organ damage, hypercalcemia, renal insufficiency, anemia, or bone lesions, clonal bone marrow plasma cells ≥60%, abnormal serum FLC ratio ≥ 100 (involved kappa) or <0.1 (involved lambda), >1 focal lesion on MRI >5 mm. Immunoperoxidase staining detects either kappa or lambda light chains, but not both, in the cytoplasm of bone marrow plasma cells and cytogenetics detects recurrent alteration in ~60% of patients (Rajkumar Lancet Onc 2014).

  • Solitary plasmacytoma: need confirmatory tissue biopsy of single lesion; normal BM biopsy (<10% plasma cells), negative skeletal survey, and no signs or symptoms of systemic disease.

  • Smoldering myeloma (asymptomatic myeloma): serum M-protein ≥3 g/dL or Bence-Jones protein ≥500 mg/24 h and/or BM clonal plasma cells 10–60%, and no myeloma defining events. Risk of progression to symptomatic MM 10%/year (Kyle et al. NEJM 1980).

  • MGUS is defined as clonal plasma cell content <10% in BM, serum M-protein ≤3 g/dL, and no myeloma defining events. Risk of transformation to serious B cell disorder 1%/year.

Workup

  • H&P.

  • CBC and differential with examination of peripheral smear, chemistries, LFTs, albumin, calcium.

  • SPEP with immunofixation and quantitation of immunoglobulins, Twenty-four-hr UPEP and immunofixation. 24-hour urine for Bence-Jones proteins.

  • Serum viscosity if M-protein concentration >5 g/dL.

  • Beta-2 microglobulin, LDH, and C-reactive protein reflect tumor burden.

  • Unilateral bone marrow aspirate and biopsy.

  • Bone marrow immunohistochemistry and flow cytometry.

  • Skeletal survey. Bone scan often noncontributory since purely osteolytic lesions have low isotope uptake, compared to osteoblastic lesions that typically have more uptake. MRI or PET is indicated if no abnormality found on plain radiograph in a symptomatic area (Terpos et al. JCO 2013).

  • Gene expression profiling is increasingly used for prognostic classification and to check for minimal residual disease.

  • Cytogenetic/karyotype for hyper/hypodiploidy. Hyperdiploidy has better prognosis.

  • FISH [del 13, del 17, t(4;14), t(11;14), t(14;16)].

  • Consider MRI total spine for suspected vertebral compression.

  • Consider CT (avoid contrast if renal dysfunction) if painful weight-bearing areas.

  • Consider PET/CT scan for suspicion of plasmacytoma of bone.

Table 38.1

Durie-Salmon myeloma staging system*

Stage

Criteria

Measured myeloma cell mass (cells × 10 12 /m 2 )

I

All of the following:

1. Hemoglobin value >10 g/100 mL

2. Serum calcium value normal (≤12 mg/100 mL)

3. Bone X-ray, normal bone structure, or solitary bone plasmacytoma only

4. Low M-component production rates

 IgG value <5 g/100 mL

 IgA value <3 g/100 mL

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

<0.6 (low)

II

Fitting neither stage I nor stage III

0.6–1.20 (intermediate)

III

One or more of the following:

1. Hemoglobin value <8.5 g/100 mL

2. Serum calcium value >12 mg/100 mL

3. Advanced lytic bone lesions

4. High M-component production rates

 IgG value >7 g/100 mL

 IgA value >5 g/100 mL

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

>1.20 (high)

Subclassification

A: Relatively normal renal function (serum creatinine value <2.0 mg/100 mL).

B: Abnormal renal function (serum creatinine value ≥2.0 mg/100 mL).

*From Durie et al. (1975). Copyright 1975 American Cancer Society. This material is reproduced with permission of John Wiley and Sons

Table 38.2

Revised International Staging System (R-ISS)*

Stage

Criteria

5-yr OS (median survival)

I

Serum β2-microglobulin <3.5 mg/L

Serum albumin ≥3.5 g/dL

No high-risk chromosomal abnormalities

Serum LDH < upper limit of normal

82% (>87 mos)

II

Neither stage I nor stage III

62% (87 mos)

III

Serum β2-microglobulin ≥5.5 mg/L

High-risk chromosomal abnormalities**

Or serum LDH > upper limit of normal

40% (56 mos)

*Data from: Palumbo et al. (2015)

**High-risk chromosomal abnormalities = del (17p), t(4;14), t(14;16)

Table 38.3

Treatment recommendations

Stage

Recommended treatment

I or systemic smoldering

Observe or treat with systemic therapy

SP – osseous

Involved field RT (≥30 Gy). LC ~90%, MS ~10 year, ~70% progress to MM. Whole body MRI to look for additional sites of disease

SP – extraosseous

Involved field RT (≥45 Gy) alone, surgery alone, or surgery + RT. LC >90%, MS >10 years, ~30% progress to MM

II or III

Chemo consists of a two- or three-agent combination of either alkylators, proteasome inhibitors, immunomodulatory agents (e.g., lenalidomide/pomalidomide + prednisone/dexamethasone + bortezomib/carfilzomib), histone deacetylase inhibitors, or newer monoclonal antibodies + bisphosphonate for bone disease

Consider high-dose therapy followed by autologous stem-cell transplant. Allogeneic transplant in context of clinical trial

Consider RT for palliation of local bone pain, prevention of pathologic fractures, or relief of spinal cord compression

New MM with cord compression and significant end organ damage – start steroids and bortezomib with RT to spine (hold lenalidomide until after RT)

Consider surgical consultation for impending fracture or spinal cord involvement

Studies

Solitary Plasmacytoma (SP)

  • Frassica (IJROBP 1989): Mayo experience of 46 patients treated for solitary plasmacytoma of bone. Local control 100% for dose >45 Gy with median f/u 7.5 years.

  • Alexiou (Cancer 1999): Review article of 400+ publications with total 869 patients with extraosseous SP treated with RT alone, surgery alone, or combined surgery + RT. In upper aerodigestive (UAD) tract tumors, combined treatment resulted in higher OS; however, in non-UAD located tumors, there was no survival difference between treatment arms. Low risk of lymph node involvement (7.6% in UAD, 2.6% in non-UAD areas).

  • Hu (Oncology 2000): Review article of SP literature, including total 338 patients with SP. Patients with osseous SP have LC rate 88–100%, rate of progression to MM 50–80% at 10 years, 10-year OS 45–70%. Patients with extraosseous SP have LC 80–100%, rate of progression to MM 10–40% at 10 years, 10-year OS 40–90%.

  • Ozsahin (IJROBP 2006): Rare Cancer Network study of 258 patients with SP. No dose response relationship for doses >30 Gy.

  • Sasaki (IJROBP 2012) Japanese retrospective review of extramedullary SP of head and neck. With RT, LC rates at 5 and 10 yrs were 95% and 87%, respectively. Surgery followed by radiation was a prognostic factor for better OS than RT alone.

Multiple Myeloma (MM)

  • Catell (IJROBP 1998): Twenty-seven patients with MM affecting long bones received radiation to symptomatic lesion, plus a margin of 1–2 cm with no attempt to treat entire shaft. Only four patients developed progressive disease in the same bone, but outside the previously irradiated field.

  • IFM 9502 (Blood 2002): 282 patients with MM undergoing conditioning regimens before autologous stem-cell transplantation randomized to high-dose melphalan vs. TBI (8 Gy in 4 fx) + lower dose melphalan. TBI arm had greater hematologic toxicity, higher toxic death rate, and decreased 45-month OS (45.5% vs. 66%).

  • Kuiper (Blood 2015): Multi-institutional data set of 4750 patients examined gene expression profiling in combination with ISS for prognosis, with EMC92-ISS demonstrating 4 risk group classification with respective median survival of 24, 47, 61, and 96 months.

  • Lee (Radiat Oncol J 2016): review of 51 MM bony lesions palliated with RT, dose 12–40 Gy (median 21 Gy) with 97.7% response in symptoms (pain or neurologic compromise). 13% had in-field recurrence, with successful re-irradiation in 66.7% of recurrences. Lesion size did not affect duration of in-field control.

Radiation Techniques

Simulation and Field Design

  • SP: Involved field RT including involved portion of bone +2–3 cm margin. Use CT/MRI to delineate tumor extent, especially paravertebral extension. FDG-PET may help assess response after RT (Kim et al. 2008).

  • MM: Main indication is for palliation. For symptomatic bony lesions, consider including entire bone, but may limit long bone/pelvis fields to decrease dose to bone marrow. If treating vertebral column, include involved vertebrae +1–2 vertebrae above and below. Consider balloon kyphoplasty or vertebroplasty for painful spinal compression fractures (Hirsch et al. Pain Physician 2011).

  • Use limited involved fields to limit the impact of irradiation on stem-cell harvest or impact on potential future treatments.

Dose Prescriptions

  • SP: 30–50 Gy over 3–5 weeks, 2 Gy/fx.

  • MM is radiosensitive, so lower doses can be given compared with standard palliative RT doses for bony mets from solid tumors.

  • MM: low-dose RT (10–30 Gy) in 1.5–2 Gy fractions vs. 8 Gy × 1 can be used as palliative treatment for uncontrolled pain, for impending pathologic fracture, or impending cord compression. May increase dose to 30–36 Gy for cord compression, bulky soft tissue component, and incomplete palliation.

Dose Limitations

  • Limit total marrow dose

  • Spinal cord <45 Gy at 1.8 Gy/fx

Complications

  • Normal tissue toxicity within RT field

  • Myelosuppression

  • MM: hypercalcemia, anemia, renal insufficiency, infection, skeletal lesions

Follow-Up

  • Systemic myeloma: Most patients continued on maintenance therapy. Quantitative immunoglobulins + M-protein every 3 months. Follow CBC, serum BUN, Cr, Ca, serum FLC bone survey annually or for symptoms. MRI/PET CT as clinically indicated. Bone marrow biopsy to assess response, minimal residual disease.

  • Smoldering multiple myeloma: Quantitative immunoglobulins + M-protein every 3 months. CBC, serum BUN, Cr, Ca every 3–4 months, skeletal survey annually.

  • SP osseous/extraosseous: M-protein every 3 months × 1 year, then annually. Bone survey, PET CT/MRI every 6 months × 1 year, then as clinically indicated.

Notes

Acknowledgments

We thank Thomas T. Bui, MD; Kavita Mishra, MD, MPH; and Mack Roach III, MD, for their work on the prior edition of this chapter.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Radiation Oncology, University of California San FranciscoSan FranciscoUSA

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