SOHO Supplement 2014
Asymptomatic Monoclonal Gammopathies Claire Bories,1 Sundar Jagannath2 Abstract Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) represent the earlier phases of plasma cell dyscrasias. Their definition is based on absence of end-organ damage with presence of a malignant clone that grows in the bone marrow. They share, as a common feature, the risk of progression to a symptomatic disease. MGUS progression risk is approximately 1% per year, and SMM has a risk of progression of 10% for the first 5 years which tapers off over time. The main purpose of identification of these earlier phases of the plasma cell dyscrasia was to identify patients who do not warrant treatment with chemotherapy, in whom the risk of treatment outweighs the benefit. Over the years, the definitions have not been modified to incorporate developments in imaging (magnetic resonance or positron emission and computed tomography), or genomics to identify patients at highest risk of progression within 2 years, where wait and watch might not be an appropriate option. In the absence of such definition, patients who have only a 50% chance of progression within 2 years are being offered therapy, which might also not be an optimal approach. In this review, we provide an overview of the definition, current prognostic factors, and risk stratifications in asymptomatic gammopathies, and discuss clinical trial outcomes in high-risk SMM. Clinical Lymphoma, Myeloma & Leukemia, Vol. 14, No. S3, S78-86 ª 2014 Elsevier Inc. All rights reserved. Keywords: MGUS, Prognosis, Risk stratification, Smoldering Myeloma, Treatment of high-risk smoldering myeloma
Introduction Asymptomatic gammopathies represent early stages of plasma cell (PC) dyscrasias, also named monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) or asymptomatic myeloma. The term MGUS was introduced at the end of the late 1970s by Kyle to denote a presence of a monoclonal protein in persons without evidence of multiple myeloma (MM), macrogloblinemia, amyloidosis, or other related PC or lymphoproliferative disorder.1 The term smoldering myeloma was introduced by Kyle and Greipp2 in 1980 to describe a group of patients with 10% PC in the bone marrow (BM) and a serum M-protein 3 g/dL who had an indolent course of disease and did not require treatment for 5 years after diagnosis. The same year, Alexanian3 coined the term indolent myeloma to describe patients with 15% of BM PC, < 3 lytic lesions, minimal monoclonal protein level depending on the type of immunoglobulin of 25 g/L for immunoglobulin (Ig)G and 10 g/L for IgA and a time to progression > 2 years. The current definition of smoldering 1
Service des Maladies du Sang, CHRU Lille, France Department of Hematology/Oncology, Mt Sinai Medical Center, New York, NY
2
Submitted: Feb 21, 2014; Accepted: May 19, 2014 Address for correspondence: Sundar Jagannath, MD, Mt Sinai Medical Center, Hematology/Oncology, 1 Gustave L. Levy Place, Box 1185, New York, New York 10029 E-mail contact: [email protected]
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or asymptomatic myeloma was determined by the International Myeloma Working Group (IMWG) consensus in 20034 that included 10% BM PC and/or serum M-protein 3 g/dL without end organ damage. The major objective was to use simple tests to identify patients who did not merit treatment where the risk of treatment outweighed the benefit. This definition was universally adopted for the simplicity and reproducibility. As we now know, MGUS consistently precedes MM.5 MGUS and SMM carry the potential of becoming symptomatic and progressing into the MM disease. Therefore risk stratification was developed to identify patients with greater risk for progression to symptomatic disease. During the past decade, dramatic progress has been made in disease assessment. Tumor cytogenetics, fluorescence in situ hybridization (FISH) analysis, flow cytometry, and genomic studies have shed better understanding of the biology of the disease and newer imaging techniques with higher resolution that can survey the skeleton such as magnetic resonance imaging (MRI) and positron emission tomography (PET)-computed tomography (CT) have allowed earlier detection of skeletal involvement. The advent of novel agents with lower toxicity and greater depth of response has also made treatment more attractive than conventional chemotherapy of the past. Recently, investigators from Spain have shown in a randomized trial that early treatment intervention of asymptomatic myeloma patients at high risk for progression not only delays disease progression but also improves survival. This has set the stage for a critical review of asymptomatic myeloma patients who are candidates for early intervention.
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2014.05.004
Diagnosis Epidemiology Monoclonal Gammopathy of Undetermined Significance. Kyle et al6 reported a prevalence of 3.2% of MGUS in a population older than 50 years, with a male predominance (4% vs. 2.7%). This number increased with advanced age and was almost 4 times as high among persons 80 years of age or older. IgG monoclonal protein was mostly reported (68.9%), IgM accounted for 17.2%, IgA isotype was seen in 10.8%, and biclonal protein in 3.2%. The light chain was k in 62% of the patients and l in 37.9%. When considering the light chain MGUS, the prevalence changed to 4.2% in a population older than 50 years (light chain MGUS: 0.8%).7 Smoldering Multiple Myeloma. Since the criteria defining the SMM were established by the IMWG,4 studies report a median age of diagnosis between 60 and 70 years.8-10 SMM represents almost 8% of all diagnoses of MM and are predominantly IgG SMM (74%) or IgA (22.5%).8 At the time of presentation of SMM Spanish group noted, 28% had a previous diagnosis of MGUS.9 Current Criteria. Definitions of MGUS and SMM are given in Table 1.11 Three subgroups of MGUS have been described by Rajkumar et al, from the Mayo Clinic in 201011: non-IgM MGUS, IgM MGUS, and light chain MGUS. Smoldering multiple myeloma is a point of transition between MGUS and MM and must meet both criteria: a serum M-Protein (IgA or IgG) 30 g/L and/or BM clonal PC infiltration 10%, and absence of hyper Calcemia, Renal impairment, Anemia, Bone disease (CRAB) criteria. The point of transition between light chain MGUS and light chain MM is called idiopathic Bence Jones proteinuria and meet the following criteria: urinary monoclonal protein in urine protein electrophoresis 500 mg per 24 hours and/or clonal BM PC 10%, no immunoglobulin heavy-chain expression on immunofixation, and absence of endorgan damage. Cytogenetics. Few studies have described the chromosome abnormalities encountered in the precursor diseases of MM. The paucity of PC in the BM of patients, together with the low proliferative capacity of these cells are a barrier for establishing a conventional karyotype. FISH analysis might be an alternative to study the genetic background of PC dyscrasias. Chiecchio et al12 have reported cytogenetic finding in 189 MGUS patients, 127 SMM patients, and 400 patients with newly diagnosed MM using FISH analysis. Deletion 13, deletion of p53, IgH heavy chain locus translocation, and ploidy were studied in all groups of PC dyscrasias. Most of the patient had copy number changes or at least 1 chromosomal alteration for the region tested (89% in MGUS, 98% in SMM, and 99% in MM). A lower frequency of del13 was seen in the premalignant conditions than in MM. The incidence of 16q23 and TP53 deletion was also significantly progressively increased from MGUS to MM. Rearrangement involving the IgH heavy chain locus were detected with similar frequencies for t(6;14), t(11;14), and t(14;16). t(4;14) was rare in MGUS but presented the same incidence in SMM and MM. IgH
rearrangement involving 4p16, 6p21, 11q13, 16q23, and 20q11 were highly associated with a nonhyperdiploid karyotype in the 3 different groups. These results highlight that none of the chromosomal aberrations are exclusive to a single diagnostic group but rather consist of many overlapping oncogenic events from MGUS to MM.
Gene Expression Profiling Advances in molecular biology and genetics have demonstrated distinct genetic subtypes of the MM disease. Gene expression profiling (GEP) of purified CD138-positive (CD138þ) PC has been used to identify distinct molecular subgroups of MM and a highrisk group in myeloma validated by the IMWG in 2009.13 Because MGUS consistently precedes MM,5 genomic analysis of asymptomatic monoclonal gammopathies might be relevant in characterizing the molecular pathway associated with progression. However, GEP analysis might be a challenge in MGUS because it depends on the ability to isolate aberrant CD138þ clonal PC, which is low in MGUS by definition. Dhodapkar et al14 have shown, in a cohort of 126 patients from the SWOG intergroup who had available GEP data, that all major molecular subtypes of MM were detected in MGUS (n ¼ 39) and SMM (n ¼ 87) patients. Indeed, patients with SMM had a greater proportion of hyperdiploid subtype and a lower proportion of cyclin D2 subtype than patients with MGUS. In comparison with the MGUS cohort, the SMM cohort had a greater proportion of GEP signature of high-risk, according to the GEP-70 model.15
Prognosis Monoclonal Gammopathy of Undetermined Significance. Kyle et al16 reported a large series of 1384 patients with IgG, IgA, IgM, or biclonal MGUS. The cumulative probability of progression to MM, lymphoma, amyloidosis, Waldenström macroglobulinemia, chronic lymphocytic leukemia, or plasmacytoma was approximately 1% per year and this risk of progression remained the same after 25 years or more. Prognostic Factors. Risk factors for progression in the MGUS condition have been well described in the literature and include a broad spectrum of parameters. Isotype (IgA or IgM) and level of the monoclonal component,10,16-18 or the light chain-associated,10 BM PC infiltration,10,18 evolution of serum M-protein level,19 immunoparesis (diminution of the uninvolved immunoglobulins),10,18 presence of a Bence Jones proteinuria,10,18 DNA ploidy,10 proportion of abnormal BM PC within the BM PC compartment (aPC/BMPC) identified using flow cytometry10,19 have been the most described risk factors in MGUS. Although MRI or PET-CT is not recommended for evaluation in case of MGUS, investigators noted that detection of 2 or more focal lesions without lytic lesion predicted for earlier progression to MM.20 Of note, Dispenzieri et al7 have shown that risk of progression for light chain MGUS is not significantly different from the low-risk MGUS: 0.3% a year (vs. 0.6% for the other MGUS). However, light chain MGUS patients have increased incidence of renal impairment and they have to be worked up for light chain deposition disease or amyloidosis.
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Type of Monoclonal Gammopathy
Premalignancy With a Low Risk of Progression (1%-2% Per Year)
Premalignancy With a High Risk of Progression (10% Per Year)
IgG and IgA (Non-IgM) Monoclonal Gammopathiesa
Non-IgM MGUS All 3 criteria must be met: Serum monoclonal protein 70% in the first 2 years.
Current Management of Asymptomatic Monoclonal Gammopathies Initial Work-Up and Management The more recent guidelines for managing asymptomatic gammopathies have been described by IMWG in 2010 and took
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Asymptomatic Monoclonal Gammopathies into account the risk stratification of the asymptomatic PC dyscrasias.
Monoclonal Gammopathy of Undetermined Significance The IMWG recommends a complete history and physical examination with emphasis on symptoms evoking MM or amyloidosis be done. The first evaluation includes a complete blood count, serum calcium and creatinine values, and a quantitative test for urine protein, with an electrophoresis and immunofixation performed if proteinuria is found.33 The recommendations then differ according to the risk defined by the Mayo Clinic.17 Patients diagnosed incidentally with a monoclonal gammopathy and noted to be low-risk with nothing to suggest MM or amyloidosis would be monitored 6 months after diagnosis and if stable every 1-2 years with serum protein electrophoresis. A BM biopsy and a skeletal survey would be optional for those patients. Patients with intermediate- and high-risk MGUS should undergo a BM examination with conventional cytogenetics and FISH, and if available, PC labeling index and a search for circulating PC in the peripheral blood using flow cytometry. All of the evaluations should be repeated within 6 months and then annually.33
Smoldering Multiple Myeloma Complete evaluation including serum protein electrophoresis, complete blood count, measurement of calcium and creatinine values, 24-hour urine collection for electrophoresis, and immunofixation should be performed at diagnosis and 2 to 3 months after to confirm the SMM. BM biopsy should be performed to establish the diagnosis of SMM. An MRI scan of the spine and pelvis is also recommended.33 For the first year, all patients with smoldering myeloma should be monitored at 3-month intervals; then low-risk patients can be monitored every 6 to 12 months; intermediate risk patients should be monitored every 3 to 6 months; and high-risk patients should be monitored at 3-month intervals. For high-risk patients with an increasing paraprotein level, annual BM and skeletal imaging using MRI or PET-CT is recommended. Close monitoring is mandatory in high-risk smoldering myeloma to facilitate early intervention before end organ damage.
Treatment
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Current IMWG recommendations33 for the management of asymptomatic gammopathies is the so called “watch and wait” until symptomatic disease. However, clinical trials have been conducted in asymptomatic patients to delay the progression to a symptomatic disease. The recent drugs used in MM therapies have fewer side effects than the conventional chemotherapies, and can be taken into consideration to delay the time of occurrence of a symptomatic disease; however, treating asymptomatic PC disorders could lead to drug resistance or clonal selection of a more aggressive disease. Treatments that have primarily been tried in smoldering myeloma include alkylating agents such as melphalan,34-36 immunomodulating drugs such as thalidomide,37-41 and more recently
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lenalidomide,42 bisphosphonates (zoledronic acid),37,43 pamidronate,39,44,45 interleukin 1 receptor antagonist,46 and curcumin.47 In Table 2, outcomes are summarized.2,3,34-47 Melphalan. In the 1980s and 1990s, 3 trials reported the effect of the combination of melphalan and prednisone in Durie and Salmon stage 1 myeloma disease. No advantage in overall survival was seen in the treated patients versus the nontreated and moreover, deferring treatment was found to be a reasonable alternative because no advantage was seen when initiating the treatment at diagnosis versus at progression in terms of overall survival. Bisphosphonates. Bisphosphonates have entered clinical practice as a useful adjunct for the treatment of symptomatic MM, providing, in controlled trials, a reduction of skeletal-related events (SRE). Therefore, some trials investigated their potential antitumoral effects and their potential ability to reduce bone turnover in SMM patients. The trial of Musto and colleagues43 reported in 163 SMM patients the effect of zoledronic acid given once a month as an infusion of 4 mg during 1 year versus observation. No difference in terms of progression was seen between the 2 groups. Many patients (44.4%) had disease progression with an mTTP of 67 months in the bisphosphonate group versus 45.1% of the patient with an mTTP of 59 months in the observational group. However, SREs were less frequent in the treated group compared with the observational group (55.5% vs. 78.3%). Similar conclusions were made by D’Arena et al45 in a comparison of the effect of pamidronate versus observation in 177 patients with SMM. Those results were counterbalanced by the adverse events reported, such as osteonecrosis of the jaw, hypocalcemia or fever. Thalidomide. The effects of thalidomide used alone or in combination with bisphosphonate in SMM have been reported. Witzig et al37 presented a phase III trial comparing the use of thalidomide in combination with zoledronic acid and the use of zoledronic acid alone in 68 SMM patients. Median PFS and mTTP were significantly better for the arm receiving thalidomide (both 2.4 years vs. both 1.2 years, respectively). Nevertheless adverse events were frequent. First of all, 80% of patients of the thalidomide arm experienced neuropathy versus 18% in the other arm. Grade 3 to 4 hematologic events accounted for 20% in the thalidomide arm versus 6% in the other. Finally, 63.3% of the patients who received thalidomide discontinued or refused to take the drug. Also no comparison between risk group of SMM could be made. In reports from Rajkumar et al40 and Detweiler-Short et al,41 thalidomide was delivered at the dose of 200 mg/d first and then escalated to 800 mg/d. Fifty-five percent had experienced a Grade 3 toxicity and 16% a Grade 4. Frequent side effects included peripheral neuropathy, rash, constipation, fatigue, and sedation. mTTP and PFS were both 35 months. Surprisingly, Barlogie et al39 found that achieving partial response or better status on thalidomide therapy was the only parameter associated with short time to therapy. Revlimid. Mateos et al42 published in 2013 the results of the PETHEMA study for high risk SMM. Criteria defined according
Claire Bories, Sundar Jagannath Table 2 Treatment Trials for Patients With Asymptomatic Multiple Myeloma Reference Hjorth et al35
Grignani et al34
Therapy
Date
Criteria Used for the Study
n
Outcome
Arm A: melphalan, prednisone at diagnosis Arm B: melphalan, prednisone at progression Arm A: melphalan, prednisone Arm B: observation
1983-1988
Durie and Salmon stage Ia with no bone disease
50
No difference on OS between the 2 arms mTTP in arm B: 12 months
1987-1989
Durie and Salmon stage Ia
44
mOS in arm A: 54 months mOS in arm B: 58 months mDR in arm A: 79 months mDR in arm B: 48 months mOS in arm A: 64 months mOS in arm B: 71 months PFS in arm A: 46 months PFS in arm B: 48 months
Riccardi et al36
Arm A: melphalan, prednisone at diagnosis Arm B: melphalan, prednisone at progression
1987-1993
Durie and Salmon stage Ia
145
D’Arena et al45
Arm A: pamidronate Arm B: observation Arm A: melphalan, prednisone Arm B: observation
1996-2003
177
Rajkumar et al,40 and Detweiler-Short et al41 Weber et al38
Thalidomide
1999-2002
IgG or IgA serum M-protein >2 g/dL and BMPC >10% and no bone disease and serum level of calcium 10% and no bone disease and serum level of calcium 10 g/dL, corrected serum calcium < 12 mg/dL, normal bone skeletal x-ray or a single lytic lesion, serum IgG or IgA < 5 or 3 g/dL, respectively, and daily light chain excretion < 4 g. b Criteria defined by Kyle and Greipp2. c Criteria defined by Alexanian3.
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to monoclonal component and BM PC or PETHEMA criteria were used to identify high-risk SMM. None of the patients presented CRAB criteria using standard evaluation. This open-label prospective phase III trial randomized high-risk SMM into 2 groups: one treated with lenalidomide with dexamethasone, the other as an observation group. For the treated group, induction consisted of 9 cycles of a daily dose of 25 mg lenalidomide, 21 days of each 28-day cycle with a daily dose of dexamethasone 20 mg on days 1 to 5 and 12 to 15. Maintenance therapy was given until progression but was limited for 2 years and consisted of a daily dose of lenalidomide 10 mg, 21 days of each 28-day cycle. Dexamethasone was added (at a daily dose of 20 mg on days 1 to 4 of each cycle) for patients in whom asymptomatic biologic progression occurred during the maintenance phase. One hundred nineteen patients were consecutively enrolled. After a median follow-up of 40 months, the results showed a significant advantage in term of time to progression to symptomatic disease (median not reached vs. 21 months) and overall survival (3-year survival rate was 94% vs. 80%) for the treated group. During the induction phase, complete or partial response was assessed for 79% of the patients treated and increased to 90% of the patients treated during maintenance therapy. Complete response, stringent complete response, and very good partial response rates counted together were 31.5% after induction therapy and 56% after maintenance therapy. The serious adverse event rate was 12% in the treated group versus 3% in the observation group. Infection, rash, asthenia, and hematologic events were most described. Of note, second primary tumors were reported in 6% of the patients in the treatment group and 2% in the observational group (nonsignificant results). To our knowledge this study was the first study published that showed a significant advantage in the treatment group. However, there are some limitations in this study. The definition of high-risk SMM is based on 2 different models. In the study, 40% of the patients met the flow cytometry criteria which are not widely available. No cytogenetics was available in both arms of treatment. Moreover, patients in the treatment group received dexamethasone when a biological progression was seen. In the other group only symptomatic progression was treated. Then, bone disease was assessed using a skeletal survey; the authors did not resort to MRI or
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other imaging. Finally, the mortality found in the observation group seemed to be more important and unusual for newly diagnosed patients.
Discussion In this review, we highlight the current state of the art in managing asymptomatic gammopathies. Numerous data about natural and molecular history, prognostic factors, and the possibility of treatments are now available but some weaknesses persist in the management of such PC dyscrasias. One subject of much debate remains treatment versus therapeutic abstention in patients with a diagnosis of SMM and a high risk of progression to MM. So far, no treatment has been recommended for patients with SMM and traditional “watch and wait” has been applied even for high-risk SMM. The Spanish trial42 is important because it highlights for the first time the benefit that patients in the high-risk category of SMM could obtain from therapy (revlimid and dexamethasone) which presents few side effects and has been shown to be effective in MM patients, notably in elderly people.48 However, within 2 years, half of the observation group has not progressed to a symptomatic disease. Therefore, treatment is still not recommended in SMM patients, even if they are found to be at high risk of progression until the definition of the high-risk category predicts at least an 80% risk of developing MM within 2 years. Criteria used to define MGUS or SMM have mostly been assessed by retrospective studies and need to be revised. Indeed, the optimal cutoff, newer imaging such as PET-CT and MRI, and genetics need to find a place in the definition of early phases of PC dyscrasias and their risk stratification. Considering imaging, the traditional skeletal survey remains the main examination to assess bone lesions. As for costs, availability and specificity are attractive factors for x-ray, but low sensitivity and limited areas of visualization can disturb its interpretation. However, bone disease is an essential aspect of MM that can affect a patient’s quality of life. Mateos and colleagues42 reported that approximately half of the high-risk SMM patients in the observation group had progressed to a bone disease. Thus better examinations
Claire Bories, Sundar Jagannath are needed. PET-CT and MRI are currently widely available and can be useful for bone disease assessment. Moreover, they inform on the soft tissue and BM involvement, which can predict for bone destruction and potentially serious functional damage. As it was reported in the German study,21 early identification of focal lesion in SMM patients could define a group of patients who will likely progress to a MM within 2 years. Repeated BM biopsy could be part of the monitoring of SMM patients, as are biochemical and hematological parameters, monoclonal protein, and serum free light chain. A BM plasmacytosis > 60% would predict progression to MM within 2 years. Finally, with a better definition of patients with an ultra-high risk of progression defined according to reproductive parameters, we should treat only patients who are more likely to progress, before they meet the CRAB criteria and therefore avoid a negative effect on their quality of life. Monoclonal gammopathy of undetermined significance, SMM, and MM represent the different stages of a common PC dyscrasia. MGUS is the earliest stage of such dyscrasia, in which a clone emerges. The clonal evolution follows the Darwinian model, with continued acquisition of driver mutations cumulatively over years resulting in incremental progression to increasingly malignant phenotypes.49 Early treatment objectives fall in 2 categories: the first is to aim to cure the disease by eradication of the earlier clones before emergence of more malignant, drug-resistant clones. The second is to modify microenvironment to prevent clonal evolution and delay the symptomatic progression caused by the emergence of a more aggressive clone. So far, most of the clinical trials have used drugs effective in MM treatment in monotherapy, or with steroids to avoid toxicities. However, patients with > 80% risk to progress to MM should be treated like they have a new diagnosis of MM, with best effective therapy. Landgren et al50 recently reported encouraging preliminary results of a phase I/II study for 12 highrisk patients with SMM defined according to Mayo Clinic or PETHEMA criteria who were treated with carfilzomib, lenalidomide, and dexamethasone, a regimen currently on trial for newly diagnosed MM that was also shown to induce a high rate of deep remission.51 In SMM patients, the best overall response rate was 100% after a median of 6 cycles with 100% of patients with a very good PR or more after 4 cycles, with an acceptable tolerance. To conclude, treatment for SMM, even with a high-risk SMM, is not recommended outside of clinical trials. A better definition of the risk including newer technologies could identify patients with a progression rate of 80% within 2 years, who should benefit from an effective multi-drugs therapy to avoid progression to symptomatic disease and preserve their quality of life.
Disclosure The authors have stated that they have no conflicts of interest.
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Asymptomatic Monoclonal Gammopathies 32. Cherry BM, Korde N, Kwok M, et al. Modeling progression risk for smoldering multiple myeloma: results from a prospective clinical study. Leuk Lymphoma 2013; 54:2215-8. 33. Kyle RA, Durie BG, Rajkumar SV, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia 2010; 24:1121-7. 34. Grignani G, Gobbi PG, Formisano R, et al. A prognostic index for multiple myeloma. Br J Cancer 1996; 73:1101-7. 35. Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I—a randomized study. Eur J Haematol 1993; 50:95-102. 36. Riccardi A, Mora O, Tinelli C, et al. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Br J Cancer 2000; 82:1254-60. 37. Witzig TE, Laumann KM, Lacy MQ, et al. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia 2013; 27:220-5. 38. Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 2003; 21:16-9. 39. Barlogie B, van Rhee F, Shaughnessy JD, et al. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood 2008; 112: 3122-5. 40. Rajkumar SV, Gertz MA, Lacy MQ, et al. Thalidomide as initial therapy for earlystage myeloma. Leukemia 2003; 17:775-9. 41. Detweiler-Short K, Hayman S, Gertz MA, et al. Long-term results of single-agent thalidomide as initial therapy for asymptomatic (smoldering or indolent) myeloma. Am J Hematol 2010; 85:737-40. 42. Mateos MV, Hernández MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 2013; 369:438-47.
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43. Musto P, Petrucci MT, Bringhen S, et al. A multicenter, randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma. Cancer 2008; 113:1588-95. 44. Martín A, García-Sanz R, Hernández J, et al. Pamidronate induces bone formation in patients with smouldering or indolent myeloma, with no significant anti-tumour effect. Br J Haematol 2002; 118:239-42. 45. D’Arena G, Gobbi PG, Broglia C, et al. Pamidronate versus observation in asymptomatic myeloma: final results with long-term follow-up of a randomized study. Leuk Lymphoma 2011; 52:771-5. 46. Lust JA, Lacy MQ, Zeldenrust SR, et al. Induction of a chronic disease state in patients with smoldering or indolent multiple myeloma by targeting interleukin 1b-induced interleukin 6 production and the myeloma proliferative component. Mayo Clin Proc 2009; 84:114-22. 47. Golombick T, Diamond TH, Manoharan A, Ramakrishna R. Monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and curcumin: a randomized, double-blind placebo-controlled cross-over 4g study and an open-label 8g extension study. Am J Hematol 2012; 87:455-60. 48. Facon T, Dimopoulos MA, Dispenzieri A, et al. Initial Phase 3 results of the First (Frontline Investigation of Lenalidomide þ Dexamethasone versus Standard Thalidomide) trial (MM-020/IFM 07 01) in newly diagnosed multiple myeloma (NDMM) patients (Pts) ineligible for stem cell transplantation (SCT). Proc ASH 2013; abstract 2. 49. Morgan GJ, Walker BA, Davies FE. The genetic architecture of multiple myeloma. Nat Rev Cancer 2012; 12:335-48. 50. Landgren O, Mailankody S, Kwok M, et al. Clinical and correlative pilot study of carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide extended dosing (CRd e R) in high risk smoldering multiple myeloma patients. Proc ASH 2013; abstract 1939. 51. Korde N, Zingone A, Kwok ML, et al. Phase II clinical and correlative study of carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide extended dosing (CRD-R) induces high rates of MRD negativity in newly diagnosed multiple myeloma (MM) patients. Proc ASH 2013; abstract 538.
Asymptomatic Monoclonal Gammopathies Claire Bories,1 Sundar Jagannath2 Abstract Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) represent the earlier phases of plasma cell dyscrasias. Their definition is based on absence of end-organ damage with presence of a malignant clone that grows in the bone marrow. They share, as a common feature, the risk of progression to a symptomatic disease. MGUS progression risk is approximately 1% per year, and SMM has a risk of progression of 10% for the first 5 years which tapers off over time. The main purpose of identification of these earlier phases of the plasma cell dyscrasia was to identify patients who do not warrant treatment with chemotherapy, in whom the risk of treatment outweighs the benefit. Over the years, the definitions have not been modified to incorporate developments in imaging (magnetic resonance or positron emission and computed tomography), or genomics to identify patients at highest risk of progression within 2 years, where wait and watch might not be an appropriate option. In the absence of such definition, patients who have only a 50% chance of progression within 2 years are being offered therapy, which might also not be an optimal approach. In this review, we provide an overview of the definition, current prognostic factors, and risk stratifications in asymptomatic gammopathies, and discuss clinical trial outcomes in high-risk SMM. Clinical Lymphoma, Myeloma & Leukemia, Vol. 14, No. S3, S78-86 ª 2014 Elsevier Inc. All rights reserved. Keywords: MGUS, Prognosis, Risk stratification, Smoldering Myeloma, Treatment of high-risk smoldering myeloma
Introduction Asymptomatic gammopathies represent early stages of plasma cell (PC) dyscrasias, also named monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) or asymptomatic myeloma. The term MGUS was introduced at the end of the late 1970s by Kyle to denote a presence of a monoclonal protein in persons without evidence of multiple myeloma (MM), macrogloblinemia, amyloidosis, or other related PC or lymphoproliferative disorder.1 The term smoldering myeloma was introduced by Kyle and Greipp2 in 1980 to describe a group of patients with 10% PC in the bone marrow (BM) and a serum M-protein 3 g/dL who had an indolent course of disease and did not require treatment for 5 years after diagnosis. The same year, Alexanian3 coined the term indolent myeloma to describe patients with 15% of BM PC, < 3 lytic lesions, minimal monoclonal protein level depending on the type of immunoglobulin of 25 g/L for immunoglobulin (Ig)G and 10 g/L for IgA and a time to progression > 2 years. The current definition of smoldering 1
Service des Maladies du Sang, CHRU Lille, France Department of Hematology/Oncology, Mt Sinai Medical Center, New York, NY
2
Submitted: Feb 21, 2014; Accepted: May 19, 2014 Address for correspondence: Sundar Jagannath, MD, Mt Sinai Medical Center, Hematology/Oncology, 1 Gustave L. Levy Place, Box 1185, New York, New York 10029 E-mail contact: [email protected]
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or asymptomatic myeloma was determined by the International Myeloma Working Group (IMWG) consensus in 20034 that included 10% BM PC and/or serum M-protein 3 g/dL without end organ damage. The major objective was to use simple tests to identify patients who did not merit treatment where the risk of treatment outweighed the benefit. This definition was universally adopted for the simplicity and reproducibility. As we now know, MGUS consistently precedes MM.5 MGUS and SMM carry the potential of becoming symptomatic and progressing into the MM disease. Therefore risk stratification was developed to identify patients with greater risk for progression to symptomatic disease. During the past decade, dramatic progress has been made in disease assessment. Tumor cytogenetics, fluorescence in situ hybridization (FISH) analysis, flow cytometry, and genomic studies have shed better understanding of the biology of the disease and newer imaging techniques with higher resolution that can survey the skeleton such as magnetic resonance imaging (MRI) and positron emission tomography (PET)-computed tomography (CT) have allowed earlier detection of skeletal involvement. The advent of novel agents with lower toxicity and greater depth of response has also made treatment more attractive than conventional chemotherapy of the past. Recently, investigators from Spain have shown in a randomized trial that early treatment intervention of asymptomatic myeloma patients at high risk for progression not only delays disease progression but also improves survival. This has set the stage for a critical review of asymptomatic myeloma patients who are candidates for early intervention.
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2014.05.004
Diagnosis Epidemiology Monoclonal Gammopathy of Undetermined Significance. Kyle et al6 reported a prevalence of 3.2% of MGUS in a population older than 50 years, with a male predominance (4% vs. 2.7%). This number increased with advanced age and was almost 4 times as high among persons 80 years of age or older. IgG monoclonal protein was mostly reported (68.9%), IgM accounted for 17.2%, IgA isotype was seen in 10.8%, and biclonal protein in 3.2%. The light chain was k in 62% of the patients and l in 37.9%. When considering the light chain MGUS, the prevalence changed to 4.2% in a population older than 50 years (light chain MGUS: 0.8%).7 Smoldering Multiple Myeloma. Since the criteria defining the SMM were established by the IMWG,4 studies report a median age of diagnosis between 60 and 70 years.8-10 SMM represents almost 8% of all diagnoses of MM and are predominantly IgG SMM (74%) or IgA (22.5%).8 At the time of presentation of SMM Spanish group noted, 28% had a previous diagnosis of MGUS.9 Current Criteria. Definitions of MGUS and SMM are given in Table 1.11 Three subgroups of MGUS have been described by Rajkumar et al, from the Mayo Clinic in 201011: non-IgM MGUS, IgM MGUS, and light chain MGUS. Smoldering multiple myeloma is a point of transition between MGUS and MM and must meet both criteria: a serum M-Protein (IgA or IgG) 30 g/L and/or BM clonal PC infiltration 10%, and absence of hyper Calcemia, Renal impairment, Anemia, Bone disease (CRAB) criteria. The point of transition between light chain MGUS and light chain MM is called idiopathic Bence Jones proteinuria and meet the following criteria: urinary monoclonal protein in urine protein electrophoresis 500 mg per 24 hours and/or clonal BM PC 10%, no immunoglobulin heavy-chain expression on immunofixation, and absence of endorgan damage. Cytogenetics. Few studies have described the chromosome abnormalities encountered in the precursor diseases of MM. The paucity of PC in the BM of patients, together with the low proliferative capacity of these cells are a barrier for establishing a conventional karyotype. FISH analysis might be an alternative to study the genetic background of PC dyscrasias. Chiecchio et al12 have reported cytogenetic finding in 189 MGUS patients, 127 SMM patients, and 400 patients with newly diagnosed MM using FISH analysis. Deletion 13, deletion of p53, IgH heavy chain locus translocation, and ploidy were studied in all groups of PC dyscrasias. Most of the patient had copy number changes or at least 1 chromosomal alteration for the region tested (89% in MGUS, 98% in SMM, and 99% in MM). A lower frequency of del13 was seen in the premalignant conditions than in MM. The incidence of 16q23 and TP53 deletion was also significantly progressively increased from MGUS to MM. Rearrangement involving the IgH heavy chain locus were detected with similar frequencies for t(6;14), t(11;14), and t(14;16). t(4;14) was rare in MGUS but presented the same incidence in SMM and MM. IgH
rearrangement involving 4p16, 6p21, 11q13, 16q23, and 20q11 were highly associated with a nonhyperdiploid karyotype in the 3 different groups. These results highlight that none of the chromosomal aberrations are exclusive to a single diagnostic group but rather consist of many overlapping oncogenic events from MGUS to MM.
Gene Expression Profiling Advances in molecular biology and genetics have demonstrated distinct genetic subtypes of the MM disease. Gene expression profiling (GEP) of purified CD138-positive (CD138þ) PC has been used to identify distinct molecular subgroups of MM and a highrisk group in myeloma validated by the IMWG in 2009.13 Because MGUS consistently precedes MM,5 genomic analysis of asymptomatic monoclonal gammopathies might be relevant in characterizing the molecular pathway associated with progression. However, GEP analysis might be a challenge in MGUS because it depends on the ability to isolate aberrant CD138þ clonal PC, which is low in MGUS by definition. Dhodapkar et al14 have shown, in a cohort of 126 patients from the SWOG intergroup who had available GEP data, that all major molecular subtypes of MM were detected in MGUS (n ¼ 39) and SMM (n ¼ 87) patients. Indeed, patients with SMM had a greater proportion of hyperdiploid subtype and a lower proportion of cyclin D2 subtype than patients with MGUS. In comparison with the MGUS cohort, the SMM cohort had a greater proportion of GEP signature of high-risk, according to the GEP-70 model.15
Prognosis Monoclonal Gammopathy of Undetermined Significance. Kyle et al16 reported a large series of 1384 patients with IgG, IgA, IgM, or biclonal MGUS. The cumulative probability of progression to MM, lymphoma, amyloidosis, Waldenström macroglobulinemia, chronic lymphocytic leukemia, or plasmacytoma was approximately 1% per year and this risk of progression remained the same after 25 years or more. Prognostic Factors. Risk factors for progression in the MGUS condition have been well described in the literature and include a broad spectrum of parameters. Isotype (IgA or IgM) and level of the monoclonal component,10,16-18 or the light chain-associated,10 BM PC infiltration,10,18 evolution of serum M-protein level,19 immunoparesis (diminution of the uninvolved immunoglobulins),10,18 presence of a Bence Jones proteinuria,10,18 DNA ploidy,10 proportion of abnormal BM PC within the BM PC compartment (aPC/BMPC) identified using flow cytometry10,19 have been the most described risk factors in MGUS. Although MRI or PET-CT is not recommended for evaluation in case of MGUS, investigators noted that detection of 2 or more focal lesions without lytic lesion predicted for earlier progression to MM.20 Of note, Dispenzieri et al7 have shown that risk of progression for light chain MGUS is not significantly different from the low-risk MGUS: 0.3% a year (vs. 0.6% for the other MGUS). However, light chain MGUS patients have increased incidence of renal impairment and they have to be worked up for light chain deposition disease or amyloidosis.
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Type of Monoclonal Gammopathy
Premalignancy With a Low Risk of Progression (1%-2% Per Year)
Premalignancy With a High Risk of Progression (10% Per Year)
IgG and IgA (Non-IgM) Monoclonal Gammopathiesa
Non-IgM MGUS All 3 criteria must be met: Serum monoclonal protein 70% in the first 2 years.
Current Management of Asymptomatic Monoclonal Gammopathies Initial Work-Up and Management The more recent guidelines for managing asymptomatic gammopathies have been described by IMWG in 2010 and took
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Asymptomatic Monoclonal Gammopathies into account the risk stratification of the asymptomatic PC dyscrasias.
Monoclonal Gammopathy of Undetermined Significance The IMWG recommends a complete history and physical examination with emphasis on symptoms evoking MM or amyloidosis be done. The first evaluation includes a complete blood count, serum calcium and creatinine values, and a quantitative test for urine protein, with an electrophoresis and immunofixation performed if proteinuria is found.33 The recommendations then differ according to the risk defined by the Mayo Clinic.17 Patients diagnosed incidentally with a monoclonal gammopathy and noted to be low-risk with nothing to suggest MM or amyloidosis would be monitored 6 months after diagnosis and if stable every 1-2 years with serum protein electrophoresis. A BM biopsy and a skeletal survey would be optional for those patients. Patients with intermediate- and high-risk MGUS should undergo a BM examination with conventional cytogenetics and FISH, and if available, PC labeling index and a search for circulating PC in the peripheral blood using flow cytometry. All of the evaluations should be repeated within 6 months and then annually.33
Smoldering Multiple Myeloma Complete evaluation including serum protein electrophoresis, complete blood count, measurement of calcium and creatinine values, 24-hour urine collection for electrophoresis, and immunofixation should be performed at diagnosis and 2 to 3 months after to confirm the SMM. BM biopsy should be performed to establish the diagnosis of SMM. An MRI scan of the spine and pelvis is also recommended.33 For the first year, all patients with smoldering myeloma should be monitored at 3-month intervals; then low-risk patients can be monitored every 6 to 12 months; intermediate risk patients should be monitored every 3 to 6 months; and high-risk patients should be monitored at 3-month intervals. For high-risk patients with an increasing paraprotein level, annual BM and skeletal imaging using MRI or PET-CT is recommended. Close monitoring is mandatory in high-risk smoldering myeloma to facilitate early intervention before end organ damage.
Treatment
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Current IMWG recommendations33 for the management of asymptomatic gammopathies is the so called “watch and wait” until symptomatic disease. However, clinical trials have been conducted in asymptomatic patients to delay the progression to a symptomatic disease. The recent drugs used in MM therapies have fewer side effects than the conventional chemotherapies, and can be taken into consideration to delay the time of occurrence of a symptomatic disease; however, treating asymptomatic PC disorders could lead to drug resistance or clonal selection of a more aggressive disease. Treatments that have primarily been tried in smoldering myeloma include alkylating agents such as melphalan,34-36 immunomodulating drugs such as thalidomide,37-41 and more recently
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lenalidomide,42 bisphosphonates (zoledronic acid),37,43 pamidronate,39,44,45 interleukin 1 receptor antagonist,46 and curcumin.47 In Table 2, outcomes are summarized.2,3,34-47 Melphalan. In the 1980s and 1990s, 3 trials reported the effect of the combination of melphalan and prednisone in Durie and Salmon stage 1 myeloma disease. No advantage in overall survival was seen in the treated patients versus the nontreated and moreover, deferring treatment was found to be a reasonable alternative because no advantage was seen when initiating the treatment at diagnosis versus at progression in terms of overall survival. Bisphosphonates. Bisphosphonates have entered clinical practice as a useful adjunct for the treatment of symptomatic MM, providing, in controlled trials, a reduction of skeletal-related events (SRE). Therefore, some trials investigated their potential antitumoral effects and their potential ability to reduce bone turnover in SMM patients. The trial of Musto and colleagues43 reported in 163 SMM patients the effect of zoledronic acid given once a month as an infusion of 4 mg during 1 year versus observation. No difference in terms of progression was seen between the 2 groups. Many patients (44.4%) had disease progression with an mTTP of 67 months in the bisphosphonate group versus 45.1% of the patient with an mTTP of 59 months in the observational group. However, SREs were less frequent in the treated group compared with the observational group (55.5% vs. 78.3%). Similar conclusions were made by D’Arena et al45 in a comparison of the effect of pamidronate versus observation in 177 patients with SMM. Those results were counterbalanced by the adverse events reported, such as osteonecrosis of the jaw, hypocalcemia or fever. Thalidomide. The effects of thalidomide used alone or in combination with bisphosphonate in SMM have been reported. Witzig et al37 presented a phase III trial comparing the use of thalidomide in combination with zoledronic acid and the use of zoledronic acid alone in 68 SMM patients. Median PFS and mTTP were significantly better for the arm receiving thalidomide (both 2.4 years vs. both 1.2 years, respectively). Nevertheless adverse events were frequent. First of all, 80% of patients of the thalidomide arm experienced neuropathy versus 18% in the other arm. Grade 3 to 4 hematologic events accounted for 20% in the thalidomide arm versus 6% in the other. Finally, 63.3% of the patients who received thalidomide discontinued or refused to take the drug. Also no comparison between risk group of SMM could be made. In reports from Rajkumar et al40 and Detweiler-Short et al,41 thalidomide was delivered at the dose of 200 mg/d first and then escalated to 800 mg/d. Fifty-five percent had experienced a Grade 3 toxicity and 16% a Grade 4. Frequent side effects included peripheral neuropathy, rash, constipation, fatigue, and sedation. mTTP and PFS were both 35 months. Surprisingly, Barlogie et al39 found that achieving partial response or better status on thalidomide therapy was the only parameter associated with short time to therapy. Revlimid. Mateos et al42 published in 2013 the results of the PETHEMA study for high risk SMM. Criteria defined according
Claire Bories, Sundar Jagannath Table 2 Treatment Trials for Patients With Asymptomatic Multiple Myeloma Reference Hjorth et al35
Grignani et al34
Therapy
Date
Criteria Used for the Study
n
Outcome
Arm A: melphalan, prednisone at diagnosis Arm B: melphalan, prednisone at progression Arm A: melphalan, prednisone Arm B: observation
1983-1988
Durie and Salmon stage Ia with no bone disease
50
No difference on OS between the 2 arms mTTP in arm B: 12 months
1987-1989
Durie and Salmon stage Ia
44
mOS in arm A: 54 months mOS in arm B: 58 months mDR in arm A: 79 months mDR in arm B: 48 months mOS in arm A: 64 months mOS in arm B: 71 months PFS in arm A: 46 months PFS in arm B: 48 months
Riccardi et al36
Arm A: melphalan, prednisone at diagnosis Arm B: melphalan, prednisone at progression
1987-1993
Durie and Salmon stage Ia
145
D’Arena et al45
Arm A: pamidronate Arm B: observation Arm A: melphalan, prednisone Arm B: observation
1996-2003
177
Rajkumar et al,40 and Detweiler-Short et al41 Weber et al38
Thalidomide
1999-2002
IgG or IgA serum M-protein >2 g/dL and BMPC >10% and no bone disease and serum level of calcium 10% and no bone disease and serum level of calcium 10 g/dL, corrected serum calcium < 12 mg/dL, normal bone skeletal x-ray or a single lytic lesion, serum IgG or IgA < 5 or 3 g/dL, respectively, and daily light chain excretion < 4 g. b Criteria defined by Kyle and Greipp2. c Criteria defined by Alexanian3.
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to monoclonal component and BM PC or PETHEMA criteria were used to identify high-risk SMM. None of the patients presented CRAB criteria using standard evaluation. This open-label prospective phase III trial randomized high-risk SMM into 2 groups: one treated with lenalidomide with dexamethasone, the other as an observation group. For the treated group, induction consisted of 9 cycles of a daily dose of 25 mg lenalidomide, 21 days of each 28-day cycle with a daily dose of dexamethasone 20 mg on days 1 to 5 and 12 to 15. Maintenance therapy was given until progression but was limited for 2 years and consisted of a daily dose of lenalidomide 10 mg, 21 days of each 28-day cycle. Dexamethasone was added (at a daily dose of 20 mg on days 1 to 4 of each cycle) for patients in whom asymptomatic biologic progression occurred during the maintenance phase. One hundred nineteen patients were consecutively enrolled. After a median follow-up of 40 months, the results showed a significant advantage in term of time to progression to symptomatic disease (median not reached vs. 21 months) and overall survival (3-year survival rate was 94% vs. 80%) for the treated group. During the induction phase, complete or partial response was assessed for 79% of the patients treated and increased to 90% of the patients treated during maintenance therapy. Complete response, stringent complete response, and very good partial response rates counted together were 31.5% after induction therapy and 56% after maintenance therapy. The serious adverse event rate was 12% in the treated group versus 3% in the observation group. Infection, rash, asthenia, and hematologic events were most described. Of note, second primary tumors were reported in 6% of the patients in the treatment group and 2% in the observational group (nonsignificant results). To our knowledge this study was the first study published that showed a significant advantage in the treatment group. However, there are some limitations in this study. The definition of high-risk SMM is based on 2 different models. In the study, 40% of the patients met the flow cytometry criteria which are not widely available. No cytogenetics was available in both arms of treatment. Moreover, patients in the treatment group received dexamethasone when a biological progression was seen. In the other group only symptomatic progression was treated. Then, bone disease was assessed using a skeletal survey; the authors did not resort to MRI or
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other imaging. Finally, the mortality found in the observation group seemed to be more important and unusual for newly diagnosed patients.
Discussion In this review, we highlight the current state of the art in managing asymptomatic gammopathies. Numerous data about natural and molecular history, prognostic factors, and the possibility of treatments are now available but some weaknesses persist in the management of such PC dyscrasias. One subject of much debate remains treatment versus therapeutic abstention in patients with a diagnosis of SMM and a high risk of progression to MM. So far, no treatment has been recommended for patients with SMM and traditional “watch and wait” has been applied even for high-risk SMM. The Spanish trial42 is important because it highlights for the first time the benefit that patients in the high-risk category of SMM could obtain from therapy (revlimid and dexamethasone) which presents few side effects and has been shown to be effective in MM patients, notably in elderly people.48 However, within 2 years, half of the observation group has not progressed to a symptomatic disease. Therefore, treatment is still not recommended in SMM patients, even if they are found to be at high risk of progression until the definition of the high-risk category predicts at least an 80% risk of developing MM within 2 years. Criteria used to define MGUS or SMM have mostly been assessed by retrospective studies and need to be revised. Indeed, the optimal cutoff, newer imaging such as PET-CT and MRI, and genetics need to find a place in the definition of early phases of PC dyscrasias and their risk stratification. Considering imaging, the traditional skeletal survey remains the main examination to assess bone lesions. As for costs, availability and specificity are attractive factors for x-ray, but low sensitivity and limited areas of visualization can disturb its interpretation. However, bone disease is an essential aspect of MM that can affect a patient’s quality of life. Mateos and colleagues42 reported that approximately half of the high-risk SMM patients in the observation group had progressed to a bone disease. Thus better examinations
Claire Bories, Sundar Jagannath are needed. PET-CT and MRI are currently widely available and can be useful for bone disease assessment. Moreover, they inform on the soft tissue and BM involvement, which can predict for bone destruction and potentially serious functional damage. As it was reported in the German study,21 early identification of focal lesion in SMM patients could define a group of patients who will likely progress to a MM within 2 years. Repeated BM biopsy could be part of the monitoring of SMM patients, as are biochemical and hematological parameters, monoclonal protein, and serum free light chain. A BM plasmacytosis > 60% would predict progression to MM within 2 years. Finally, with a better definition of patients with an ultra-high risk of progression defined according to reproductive parameters, we should treat only patients who are more likely to progress, before they meet the CRAB criteria and therefore avoid a negative effect on their quality of life. Monoclonal gammopathy of undetermined significance, SMM, and MM represent the different stages of a common PC dyscrasia. MGUS is the earliest stage of such dyscrasia, in which a clone emerges. The clonal evolution follows the Darwinian model, with continued acquisition of driver mutations cumulatively over years resulting in incremental progression to increasingly malignant phenotypes.49 Early treatment objectives fall in 2 categories: the first is to aim to cure the disease by eradication of the earlier clones before emergence of more malignant, drug-resistant clones. The second is to modify microenvironment to prevent clonal evolution and delay the symptomatic progression caused by the emergence of a more aggressive clone. So far, most of the clinical trials have used drugs effective in MM treatment in monotherapy, or with steroids to avoid toxicities. However, patients with > 80% risk to progress to MM should be treated like they have a new diagnosis of MM, with best effective therapy. Landgren et al50 recently reported encouraging preliminary results of a phase I/II study for 12 highrisk patients with SMM defined according to Mayo Clinic or PETHEMA criteria who were treated with carfilzomib, lenalidomide, and dexamethasone, a regimen currently on trial for newly diagnosed MM that was also shown to induce a high rate of deep remission.51 In SMM patients, the best overall response rate was 100% after a median of 6 cycles with 100% of patients with a very good PR or more after 4 cycles, with an acceptable tolerance. To conclude, treatment for SMM, even with a high-risk SMM, is not recommended outside of clinical trials. A better definition of the risk including newer technologies could identify patients with a progression rate of 80% within 2 years, who should benefit from an effective multi-drugs therapy to avoid progression to symptomatic disease and preserve their quality of life.
Disclosure The authors have stated that they have no conflicts of interest.
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