Diagnosis and treatment of multiple myeloma and AL amyloidosis with focus on improvement of renal lesion
Multiple myeloma (MM) and AL amyloidosis are caused by the expansion of monoclonal plasma cells and secretion of dysproteinemia (Bence Jones protein and free light chain) and some patients require the hemodialysis. Myeloma kidney is mainly caused by the cast nephropathy of the distal tubuli, whereas, AL amyloid-protein is mainly deposited in glomeruli with massive fibrillar involvement. Therefore, almost MM patients presents a symptom of renal insufficiency, whereas, almost patients of AL amyloidosis present a nephrotic syndrome with severe hypoalbuminemia. These two diseases have some similar characteristics such as up-regulation of cyclin D1 gene by 11:14 chromosomal translocation. High-dose chemotherapy supported with autologous peripheral blood stem cells is effective for these two diseases. However, they are still difficult to be cured and require long-term disease control. In recent years, introduction of novel agents has changed their treatment strategies from the palliation therapy to the clinical cure.
KeywordsMultiple myeloma AL amyloidosis ASCT Renal insufficiency
Multiple myeloma (MM) is an incurable disease with high incidence rate in the elderly. Responsiveness to treatments varies largely among the patients due to high heterogeneity of MM. Decision of the treatment has been a difficult issue in MM. However, changes can be seen in its treatment strategies since good quality of response can be realistically obtained due to an introduction of novel drugs (bortezomib, lenalidomide, and thalidomide). This article reviews the latest trend and the future perspective of treatment for MM which has advanced remarkably in recent years.
MM and AL amyloidosis are similar diseases resulting from clonal proliferation and dysfunction of plasma cells, in which renal dysfunction due to deposition of immunoglobulin (M protein/amyloid) or other causes are frequently observed. Since exacerbation of renal function is closely associated with the prognosis of patients, maintenance or improvement of renal function by managing the underlying disease is required. In recent years, stratification of myeloma as high-risk and standard-risk by Mayo group has been introduced . Deletion of 17p by FISH, t (14:16), Cytogenetic hypodiploidy, and β2-microglobulin >5.5 and LDH level >upper limit of normal are high risk sign. T (4:14) and cytogenetic deletion 13 are considered as intermediate risk by the reasons of overcoming with new drugs. After that, IMWG stratification is also published; Standard-risk were Hyperdiploidy (45 % of MM mainly IgG type and aged patients), t(11;14)(q13;q32) CCND1↑, and t(6;14) CCND3↑. Intermediate-risk were t(4;14)(p16;q32) MMSET↑ and deletion 13 or hypodiploidy by conventional karyotyping. High-risk were 17p deletion, t(14;16)(q32;q23) C-MAF↑, and t(14;20)(q32;q11) MAFB↑.
We classified AL amyloidosis into four groups as follows; cardiac, renal, gastrointestinal and pulmonary amyloidosis, and the others according to the main organ with AL amyloid materials deposition. In this decade, novel agents (bortezomib, thalidomide and lenalidomide) have become available to treat multiple myeloma in Japan. In this article, we review the recent trend for the diagnosis and treatment strategies of multiple myeloma and AL amyloidosis by focusing on how to improve renal lesion.
Diagnosis and treatment of multiple myeloma
In 1962, Bergsagel et al.  reported that l-phenylalanine mustard (melphalan) could induce remissions in approximately one third of patients with MM. In 1967, Salmon et al.  reported that high doses of glucocorticoids could induce remissions in patients with refractory or relapsing MM. Combination therapy with melphalan and prednisolone in 1969 by Alexanian et al.  showed a better result than melphalan alone.
However, the response rate with alkylators and corticosteroids was only approximately 50 %, and CR was rare. Cure was never a goal of therapy as it was assumed unattainable. Instead, the goal was to control the disease as much as possible, providing the best quality of life to patients for the longest duration by judicious, intermittent use of the 2 available classes of active chemotherapeutic agents. Also in 1986, clinical studies evaluating HDT with single ASCT (McElwain) and double ASCT (Barlogie) were conducted. In 1996, the first randomized study showed benefits with HDT with ASCT versus standard chemotherapy. Berenson et al described an efficacy of bisphosphonate pamidronate in reducing skeletal events in patients with advanced MM.
Chemotherapy is indicated for patients with newly diagnosed symptomatic myeloma, although it is generally not recommended for patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering, or asymptomatic myeloma. Age, performance status, and neurologic and co morbid conditions are critical factors in the choice of initial therapy. Melphalan and prednisone combination can no longer be considered as a standard of care in patients who are 65 years of age or older. Our findings suggest that bortezomib plus melphalan-prednisone is the standard front-line treatment for patients with myeloma who are 65 years of age or older and cannot tolerate more aggressive treatment .
During the past decades, high-dose therapy with autologous stem-cell transplantation (HDT-SCT) has become the standard treatment option for patients with untreated multiple myeloma (MM) who are younger than 65 years of age; however, HDT-SCT is not usually recommended for older patients and patients with clinically significant co-morbidities.
A recent study has shown that long-term survival improved significantly in younger patients while only limited improvement was achieved in elderly patients. Improved treatment for such older patients ineligible for HDT-SCT was much-awaited.
Should we treat patients with myeloma with multidrug, multitransplant combinations to pursue the goal of potentially curing a subset of patients, recognizing that the balance of adverse events and effect on quality of life will be substantial? Or should we consider myeloma as a chronic incurable disease with a goal of disease control, using the least toxic regimens, emphasizing a balance between efficacy and quality of life, and reserving more aggressive therapy for later lines?
Induction therapy for newly diagnosed multiple myeloma (NDMM)
Bortezomib IV is an ubiquitin-proteasome inhibitor and indicated for the treatment of MM. Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. It is cytotoxic to a variety of cancer cell types in vitro and causes suppression in tumor growth in vivo in nonclinical tumor models, including MM. Specifically, bortezomib is effective in MM via its inhibition of nuclear factor-κB activation, its attenuation of interleukin-6-mediated cell growth, a direct apoptotic effect, and possibly antiangiogenic and other effects . Regarding the treatment of patients who are not eligible for transplantation, MPT and MPB have shown significantly better overall survival (OS) benefit than that of MP and are the recommended treatments [6, 9]. The proteasome inhibitor bortezomib has been approved in the USA in 2005 for the treatment of MM patients with a history of at least one prior therapy, based on results from the phase III APEX study which showed superiority of bortezomib over high-dose dexamethasone in patients with relapsed MM . The majority of treatment guidelines currently recommend incorporating HDT/SCT into initial therapy programs for patients who are 65 years of age or younger and to consider such a therapy for patients 60–70 years of age with good performance status and a lack of co morbid illnesses since HDT/SCT provides the highest chance of inducing a complete remission. However, even when patients achieve CR, the vast majority of patients will ultimately relapse. The standard frontline therapy for patients who are 65 years of age or older, and for patients who are not likely to proceed to HDT/SCT, consists of oral MP at doses similar to those used in this study. Combination therapies such as MP (at a dose of 0.25 mg/kg/day) are given orally at doses used for 4 consecutive days every 6 weeks, showed superior survival versus melphalan alone. With MP therapy, an OR rate of approximately 50 %, a CR rate of 2 to 5 % and a median time to response of 3–5 months have been historically reported .
Final results of the phase 3 VISTA trial
Recently 5 year OS follow up data has been published. The data indicates that OS in MPB with 60.1 months follow-up is significantly superior to that of MP. The OS of MP-B and MP were 56.4 months (13.3 months improvement) and 43.1 months respectively. This data is very much remarkable because the OS improvement was 13.3 months although even MPT could improve only 6.6 months in its meta analysis. As a result of this VISTA study, MPB became the standard treatment for untreated transplant in-eligible patients .
To evaluate safety, pharmacokinetics (PK) and efficacy of bortezomib combined with melphalan and prednisolone (MPB) therapy, we conducted a phase I/II study for untreated Japanese MM patients who were ineligible for hematopoietic stem cell transplant (HSCT). This was a dose-escalation study designed to determine the recommended dose (RD) of bortezomib in combination with melphalan and prednisolone by evaluation of the maximum tolerated dose based on dose-limiting toxicity (DLT) in the phase I portion, and to investigate the overall response rate (ORR; CR + PR) and safety of MPB therapy in the phase II portion. Particularly, a continuity of treatment cycles was historically compared with a global phase III study (VISTA trial), and the incidence of interstitial lung disease was assessed. This phase I/II study in Japan suggests that the RD of bortezomib in MPB therapy is 1.3 mg/m2 and the MPB therapy in newly diagnosed Japanese MM patients ineligible for HSCT is as effective as that shown in VISTA trial. Further investigation is necessary to confirm the appropriate administration schedule of this combination in Japanese patients .
Cyclophosphamide and thalidomide
Cyclophosphamide has been added to thalidomide and dexamethasone (CTD) with excellent response rates among newly diagnosed MM patients who received subsequent SCT, with higher response rates seen after SCT.
The combination in 3-weekly schedules of cyclophosphamide (50 mg PO or 300 mg/m2 PO weekly or 150 mg/m2 d1–5), thalidomide (200–800 mg daily, increasing doses or intermittent administration 400 mg d1–5 and d14–18) and dexamethasone (40 mg per day for 4 days) (CTD) results in an ORR of around 60 %, a median TTP of 10–12 months and a 2-years PFS of 57 % [21, 22, 23].
Comprehensive reviews on the use of thalidomide have been published and include efficacy and safety in relapsed MM. The rationale for using thalidomide was based on its antiangiogenic properties because, in MM, increased microvessel density has been inversely correlated to survival. However, thalidomide has multiple modes of action, including immunomodulatory effects. This initial experience generated a great enthusiasm, and a large number of phase II trials were rapidly conducted. A systematic review of such 42 trials on >1600 patients confirm that the response rate is 29 % with an estimated 1-year overall survival (OS) of 60 %. The well-known teratogenicity of thalidomide is not a major concern in patients with MM because of patients age, but justifies careful informing of patients and programs to avoid drug exposure in women with childbearing potential. The major toxicities of thalidomide are fatigue, somnolence, constipation, and mostly peripheral neuropathy, which are related to the daily dosage and to treatment duration. The overall incidence of peripheral neuropathy is 30 % but may be higher if treatment is prolonged for >1 year. Because this complication may be disabling and sometimes irreversible, patients should decrease the dose or stop the treatment if significant numbness occurs.
After induction treatment, two to four cycles of combination therapies is followed by the maintenance therapy, which is continuous therapy with a single agent, with reasonable balance between maximum benefits and minimum toxicities  until the time of disease progression.
Maintenance therapy for multiple myeloma
Post-transplant consolidation/maintenance with novel agents can become an important step forward. Thus, it has recently been reported that post-transplant consolidation with thalidomide, lenalidomide or bortezomib increases the CR rate. In this regard, it has been shown that post-ASCT consolidation with VTD can induce long-lasting molecular remission [25, 26]. Thalidomide maintenance prolonged the OS in two transplant series .
The response rate to treatment with single-agent thalidomide in patients with relapsed and/or refractory MM is between 30 and 40 % .The response rate increases from 50 to 65 % when thalidomide is combined with dexamethasone with or without cytotoxic agents.
The cure-versus-control debate is hot. Indeed, CR is a surrogate marker for improved OS. However, for the majorities of MM patients, the disease control approach (Maintenance therapy) involves targeting very good partial response (VGPR) rather than CR as a goal. This is a pilot study of the prospective, sequential registered trial of the significance of BD maintenance therapy for long-term survival with good QoL.
Recently, lenalidomide maintenance therapy improved median progression-free survival (41 vs. 23 months with placebo; hazard ratio, 0.50; P < 0.001) .
Therapy for relapsed or refractory multiple myeloma (RRMM)
Progressive disease is defined as follows: (1) Above 25 % elevation of M-protein, (2) hypercalcemia: corrected serum calcium >11.5 mg/dL, (3) the absolute increase of free light chain (FLC) must be >10 mg/dL, (4) definite development of new bone lesions or soft tissue plasmacytomas, (5) decrease in hemoglobin of >2 g/dL, (6) rise in serum creatinine by 2 mg/dL or more, (7) increase of BM myeloma cell above 10 %.
Analysis of second primary malignancies (SPM)
Another important issue in MM is risk of developing SPMs due to living longer from diagnosis. Population studies show MM patients have increased risk of specific SPMs following initial diagnosis, notably acute myeloid leukemia (AML). Some MM therapeutic agents are particularly associated with elevated risk of SPMs. Melphalan is associated with increased risk of secondary acute leukemia. There were imbalances in SPM incidence, including myeloid and lymphoid leukemias, with post-transplant lenalidomide maintenance therapy and with MP-lenalidomide. Persistent significant OS benefit with VMP versus MP; 13.3-months increase in median, and MPT versus MP increase 6.6 months .
Secondary malignancies and lenalidomide: by summarizing the data to-date, the incidence of all/invasive SPM is significantly increased in Lenalidomide arms, driven by hematologic SPM (P < 0.001). B-ALL, Hodgkin lymphoma is reported in post high-dose melphalan and ASCT setting. Sensitivity analysis (including SPM as an event) demonstrates negligible PFS differences. The overall benefit–risk profile of lenalidomide in NDMM remains positive [31, 32]. Risk Factors for Secondary Malignancies Treatment with lenalidomide may be treatment duration >24 months, male, age >55 years, ISS stage III, previous DCEP (role of concomittant or previous exposure to alkylators?) induction by univariate and multivariate analysis in IFM 2005.
In Japanese SPM Report by JRCMC, retrospective analysis for 325 MM patients from 1998 to 2010 (13 years) showed t-MDS/AML developed 17 (5.2 %) patients. Median time to onset: 52 months in t-AML and months in t-MDS. All the patients with t-AML died in a short time, suspected to be treated with Melphalan, and no patients had been given Lenalidomide. We have to select chemo regimen taking into account the risk of t-MDS/AML .
Renal dysfunction in multiple myeloma
Improvement of renal function and treatment strategy for multiple myeloma
Lenalidomide is an anti-myeloma drug possessing dual functions of antitumor effect and immunomodulating activity. Because lenalidomide is urinary excreted, its blood concentration increases in patients with renal dysfunction which leads to high incidence risk of adverse reactions . However, lenalidomide itself has no renal toxicity and clinical studies showed improvement of renal function in the patients treated with lenalidomide. Lenalidomide can be administrated by proper adjustment of its dose corresponding to renal function according to the package description . In fact, it is reported that adjusted dosing of lenalidomide to patients with renal dysfunction resulted with similar anti-myeloma efficacy to those with normal renal function [39, 40], and recovery of renal function was also observed . Similar to bortezomib, cases that withdrew from dialysis are reported . Stratified analysis of lenalidomide/dexamethasone therapy by age showed similar efficacy and tolerability in elderly (over 65 years of age) to those of youth . Hence this therapy is considered to be useful especially for elderly patients with renal dysfunction if the dose is properly adjusted corresponding to the renal function. Thalidomide does not require dose control depending on renal dysfunction, but it has not been reported in large studies that thalidomide is effective on the improvement of renal function. In any case, early diagnosis and timing of initiation of treatment are important. In addition, full understanding of efficacy and safety profiles of novel agents and using them in combination with existing drugs appropriate for individual patients are the basis of treatment strategy.
Diagnosis of AL amyloidosis and renal dysfunction
Renal dysfunction in AL amyloidosis is frequently caused by glomerular injury due to deposit of amyloid and observes high albuminuria and nephrotic syndrome. Its progression leads to kidney failure, and in many cases requires dialysis.
Therapy of AL amyloidosis
As mentioned above, the therapy and treatment strategy of MM and AL amyloidosis have largely changed in these recent years. At same time, it is becoming more important to control the disease in a long-term fashion, maintaining QoL of patient because it is still difficult to cure the disease. The increase in the number of treatment options means that personalized medicine which selects a treatment corresponding to the systemic condition of the patient, and the purpose of the treatment will be more important. It is important to treat MM as chronic disease by taking into full consideration efficacy and safety of novel drugs and by effectively combining them with existing drugs. Also we should consider how we could help patients through the treatment to live long actively in the society.
MM and AL amyloidosis are caused by functional abnormality of monoclonal plasma cells, and high-dose chemotherapy supported with autologous peripheral blood stem cells is effective to these diseases. However, they are still difficult to be cured and require long-term disease control. In recent years, introduction of novel agents has changed their treatment strategies.
Better understanding of the biology of the amyloidogenic plasma cell clone and the molecular mechanisms underlying the light chain misfolding, tissue targeting and toxicity will define disease-related prognostic criteria. Risk-adapted therapeutic strategies may be required.
However, it is important to take these diseases as chronic diseases. For this purpose, early diagnosis and timing of initiation of treatments is important. Moreover, understanding of characteristics of novel agents and using them in combination with existing drugs appropriately for individual patient is critical. In addition, collaboration with renal medicine is essential to avoid introduction of dialysis. Also we should consider how we could help patients by treatment to live long actively in the society.
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