SOHO Supplement 2014

The Road to Treating Smoldering Multiple Myeloma Neha Korde,1,2 Sham Mailankody,1 Ola Landgren1,2 Abstract The management of smoldering multiple myeloma (SMM) has been a challenge to clinicians, ever since the condition was first characterized in 1980. While the risk of progression to symptomatic myeloma is greater for SMM (10% per year) compared to MGUS (1% per year), several SMM patients remain asymptomatic for years without evidence of disease progression. Early clinical trials focusing on early treatment of SMM have been equivocal with no clear benefit. However, the last decade has seen a greater understanding of the pathogenesis of plasma cell disorders, including SMM, and development of better therapeutics. A recent randomized trial has provided evidence of clinical benefit with early treatment of high-risk SMM. In this review, we summarize issues related to the early treatment of SMM including risk stratification and possible outcomes with therapy initiation. In the context of reviewing recent clinical trial data supporting early treatment, we define challenges faced by clinicians and provide future directions to the road to treating SMM. Clinical Lymphoma, Myeloma & Leukemia, Vol. 14, No. S3, S59-64 Published by Elsevier Inc. Keywords: High-risk SMM, MGUS, Minimal residual disease, Monoclonal protein, Plasma cells

Introduction Smoldering multiple myeloma (SMM) is an asymptomatic precursor plasma cell disorder defined as either having a monoclonal protein (M-protein)
3 g/dL and/or having
10% plasma cells in the bone marrow.1 Multiple myeloma (MM) is a symptomatic malignancy characterized by clonal plasma cells causing CRAB (hypercalcemia, renal insufficiency, anemia, and bone lytic lesions or fractures) end-organ damage. Almost all cases of MM are preceded by asymptomatic precursor disease states.2,3 The term, SMM, was coined and characterized by Kyle and colleagues and noted to carry an average risk of progressing to malignancy of 10% per year.4,5 In comparison, monoclonal gammopathy of unknown significance (MGUS) is an asymptomatic plasma cell condition defined as having M-protein < 3 g/dL and < 10% bone marrow plasma cells. The risk of MGUS transforming to symptomatic malignancy is 1% per year.6 Traditional clinical practice depended on careful surveillance for all asymptomatic precursor disease states, including for MGUS and SMM patients. 1 Multiple Myeloma Section, Lymphoid Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 2 Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY

Submitted: Feb 21, 2014; Revised: Mar 19, 2014; Accepted: Apr 3, 2014 Address for correspondence: Neha Korde, MD, Myeloma Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, NY, NY 10065 E-mail contact: [email protected]

2152-2650/$ - see frontmatter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.clml.2014.04.012

Risk models have further delineated SMM subcategories with “high-risk” approximately carrying a 75% progression risk at 5 years.7,8 Recent expert reviews have attempted to take this one step further by introducing the term, “ultraehigh-risk SMM,”9,10 and defining a group of SMM patients with
70% probability of progressing to symptomatic disease in 2 years. Although most agree on a need to identify asymptomatic SMM patients that behave biologically similar to MM because of the propensity toward symptomatic progression, a lack of consensus exists on defining high-risk SMM patients and implementing correct cost-effective tools and biomarkers required for the task. The most crucial argument for identifying these patients is that early intervention might improve clinical outcome in the correct setting. Until recently, studies had failed to show benefit of intervention for all asymptomatic SMM patients across the board. Mateos and Spanish Myeloma Group from Programa para el Tratamiento de Hemopatías Malignas/Grupo Espanol de Mieloma (PETHEMA/GEM) colleagues published landmark results of the Lenalidomide and Dexamethasone Treatment Versus Observation (QUIREDEX) study, demonstrating that treating high-risk SMM patients (n ¼ 119) with lenalidomide/dexamethasone (Len/Dex) improves time to symptomatic disease progression (not reached vs. 21 months; hazard ratio [HR], 0.18; P < .001) and 3-year overall survival (94% vs. 80%; HR, 0.31; P ¼ .03) compared with observation.11 These findings directly challenge current standards of approaching all SMM and MGUS patients with the same “watchful waiting” dogma by demonstrating that early intervention

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The Road to Treating SMM Table 1 Issues Related to Treating High-Risk SMM Lack of Consensus Regarding High-Risk and UltraeHigh-Risk Definitions Feasibility of Biomarkers and Assays Required to Define Risk Categories Cost-Effectiveness of Treatment Quality of Life During Treatment Biological Impact on Longitudinal Disease Course With Early Treatment Standardizing Diagnostic Workup to Distinguish Symptomatic Disease

in high-risk SMM individuals leads to improved outcomes. Two important features were incorporated into the study design compared with predecessors: (1) a well-tolerated, highly efficacious combination of drugs was chosen in the intervention arm; and (2) a high-risk SMM population was targeted instead of all SMM patients. Although the QUIREDEX trial answers a number of long-awaited questions and investigators must be applauded for a bold contribution to the research, a few issues remain before these practices are instituted into everyday clinical practice (Table 1). In our opinion, high-risk and ultraehigh-risk SMM patients should still be referred to clinical trials with biological end points (clonal evolution, minimal residual disease [MRD]) and clinical end points (time to progression, time to second line of treatment, cost-efficacy, screening populations, quality of life).

emergence of thalidomide years later. In the first SMM thalidomide study (n ¼ 16), 6 of 16 SMM and indolent MM patients (38%) demonstrated a partial response (PR).15 A few years later, Barlogie and colleagues reported a 25% PR rate in SMM patients (n ¼ 76) receiving thalidomide (200 mg/d) and monthly pamidronate. Surprisingly, patients achieving a PR had a shorter time to salvage therapy after progression. Moreover, investigators reported a 50% thalidomide discontinuation rate because of poor tolerability of the drug.18 A few studies have investigated the potential role of bisphosphonates and clinical benefit in SMM. A larger study conducted by Musto and colleagues17 compared zolendronic acid versus observation (n ¼ 163) and found decreased incidence of skeletalrelated events in the bisphosphonate arm (55.5% vs.78.3%; P ¼ .041). No difference was observed in progression rates between the 2 arms or median time to progression.17 In addition, a myriad of smaller trials have investigated or currently exploring the potential use of agents (green tea extract,21 curcumin,22 and anakinra19) with more benign side effect profiles and an aim to treat an essentially asymptomatic SMM population. Along with small sample sizes and heterogeneic end points, earlier SMM treatment trials usually had confounding weaknesses of treating all SMM patients while being unable to target those truly biologically similar to MM.

High-Risk SMM Definitions Early Treatment Trials in SMM Past clinical studies have failed to show major benefits in treating asymptomatic SMM patients (Table 2).11-20 A large part of these failures could be attributed to lack of efficacy and high toxicities. The first study to investigate initial versus deferred use of melphalan and prednisone in 50 asymptomatic MM patients failed to show benefit.13 Based on these results and other studies12,14 initiation of therapy in asymptomatic patients was not revisited until the

It is essential to recognize that SMM is comprised of a mixed population of patients that ultimately vary in clinical outcome if left untreated. Approximately half of all SMM patients remain asymptomatic without clinical disease after 5 years. Two prevailing risk models help determine risk stratification for SMM patients (Table 3).7,8,23,24 As mentioned earlier, high-risk SMM patients in both models are noted to have a 5-year progression rate of 72% to 76% with a median time to progression of < 2 years.7,8 Eligible

Table 2 Selected Clinical Trials in SMM

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Year

Regimen (Number of Patients)

Study/Study Design

Outcome

1988

VAD or MP (n ¼ 33)

Treat when symptoms develop

1993

MP upfront versus deferred (n ¼ 50)

2000

MP upfront versus deferred (n ¼ 145)

2001

Thalidomide (n ¼ 16)

2003

Thalidomide (n ¼ 28)

2008

Zolendronic acid versus control (n ¼ 163)

2008

Thalidomide/pamidronate (n ¼ 76)

2009

Anakinra (n ¼ 47)

2011

Pamidronate versus observation (n ¼ 177)

2013

Len/Dex versus observation (n ¼ 119)

Alexanian et al12 Retrospective series Hjorth et al13 Randomized Riccardi et al14 Randomized Rajkumar et al15 Single arm Weber et al16 Single arm Musto et al17 Randomized Barlogie et al18 Single arm Lust et al19 Single arm D’Arena et al20 Randomized Mateos et al11 Randomized

No differences in response rates or survival No differences in response rates or survival PR or better in 6 of 16 (37.5%) Response rates 36% SREs in zoledronic versus control was 56% versus 78% (P ¼ .041); no difference in median TTP Median TTP 7 years; PR requiring earlier salvage therapy; 50% discontinuation rate PR in 5 of 47 (11%); median PFS 37.5 months No difference in progression rate and overall survival. SREs in pamidronate versus control was 39% versus 73% (P ¼ .009) 3-Year OS Len/Dex versus observation was 94% versus 80% (HR, 0.31; P ¼ .03); median TTP Len/Dex versus observation was NR versus 21 months (HR, 0.18; P < .001)

Abbreviations: HR ¼ hazard ratio; Len/Dex ¼ lenalidomide, dexamethasone; MP ¼ melphalan, prednisone; NR ¼ not reached; OS ¼ overall survival; PFS ¼ progression-free survival; SRE ¼ skeletal related event; TTP ¼ time to progression; VAD ¼ vincristine, doxorubicin, and dexamethasone.

Clinical Lymphoma, Myeloma & Leukemia September 2014

Neha Korde et al Table 3 Risk Models for Identifying High-Risk SMM Mayo Clinic for SMM (n [ 273)7 Risk Factors: BMPC ‡10%, M-protein ‡3 g/dL, FLC Ratio 8 Number of Risk Factors 1 2 3

Spanish PETHEMA for SMM (n [ 89)8

SWOG S0120 for SMM (n [ 79)23

Risk Factors: Immunoparesis, ‡95% aPCs

Risk Factors: Involved FLC >25 mg/dL, M-protein ‡3 g/dL, GEP7024 Risk Score > L0.26

5-Year Progression

Number of Risk Factors

5-Year Progression

Number of Risk Factors

5-Year Progression

25% 51% 76%

0 1 2

4% 46% 72%

0 1 2þ

3% 29% 71%

Abbreviations: aPC ¼ abnormal plasma cell; BMPC ¼ bone marrow plasma cell percentage; FLC ¼ free light chain; GEP70 ¼ 70-gene expression model; M-protein ¼ monoclonal protein; PETHEMA ¼ Programa para el Tratamiento de Hemopatías Malign; SMM ¼ smoldering multiple myeloma; SWOG ¼ Southwest Oncology Group.

patients in the QUIREDEX study had to demonstrate bone marrow plasma cell infiltration
10% and M-protein
3 g/dL (immunoglobulin A
2 g/dL or Bence Jones protein
1 g per 24 hours) or at least having 1 of the 2 aforementioned criteria,
95% phenotypic aberrant plasma cells and evidence of immunoparesis in uninvolved immunoglobulins (> 25%).11 In essence, the study included “intermediate-risk” and “high-risk” SMM patients. A recent publication demonstrates a third risk model proposed by the Southwest Oncology Group S0120 study group incorporating gene expression profiling as an additional parameter (Table 3).23 Although these nuances might be taken lightly at first glance, this point illustrates that a validated consensus definition of high-risk SMM still remains to be accepted. Results from our National Cancer Institute prospective MGUS and SMM natural history study comparing the Mayo Clinic and the PETHEMA models for SMM showed that among 38 of 77 high-risk PETHEMA SMM patients enrolled in the study, only 4 of 38 (11%) were also classified as high risk according to the Mayo Clinic model. The remaining patients were nonehigh-risk using the Mayo Clinic model, 22 of 38 (58%) were intermediate-risk, and 12 of 38 (32%) were low-risk. Thus, when comparing the 2 models head-to-head in a cohort of SMM patients, there was significant discordance

(P < .0001) between the 2 models in classifying patients as highrisk versus nonehigh-risk.25 Despite discordance, it might be that the 2 models are “additive” to each other rather than exclusive. One model might represent tumor biology and the other disease burden. Regardless, this has yet to be demonstrated in an all-inclusive multivariate analysis and long-term follow-up is needed to see if these findings remain true. Other studies have identified other potential high-risk features in the SMM population, such as progressive focal lesions on magnetic resonance imaging (MRI),26 high-risk according to the 70-gene expression model,23,24 evolving M-protein quantities,27 and certain cytogenetic abnormalities (ie, del 17p, þ1q21, t(4,14); Table 4).8,23,26-33 Importantly, before treatment of high-risk SMM is adopted as standard clinical practice, supplemental investigations are needed to determine how intervention benefits patients with these additional features. Outcomes, including modulation of disease biology after treatment, have not been evaluated in these patients with scrutiny. At the moment, patients with high-risk characteristics should still be recommended for clinical trials. In addition, critics of the QUIREDEX study state that immunophenotypic flow cytometry conducted in the trial to identify aberrant plasma cells in high-risk SMM patients is technically

Table 4 Potential High-Risk SMM Features Features BMPC ‡60% Serum Involved/Uninvolved FLC ‡100 Progressive Lesions on Whole-Body MRI >1 FL on Whole-Body MRI Evolving Type of SMM GEP7024 Risk Score > L0.26 aPCs ‡95% t(4;14) or del 17p or D1q21

Reference

n/Total n

Comments

30

Rajkumar et al Kastritis et al31 Larsen et al32 Merz et al26 Hillengass et al33 Rosinol et al27 Dhodapkar et al23 Perez-Persona et al8 Neben et al28

21/655 7/96 90/586 31/63 23/149 22/53 31/87 56/93 88/248

Rajkumar et al29

44/351

 Median TTP ¼ 7 months (95% CI, 1.0-12.9)  Median TTP ¼ 8 months  Median TTP ¼ 15 months (95% CI, 9-17)  Median TTP from second MRI ¼ 9 months (95% CI, 7-36)  Median PFS of >1 FL ¼ 13 months  Median TTP of evolving type ¼ 16 months  24-month TTP estimate ¼ 51.2%  Median TTP of
95% aPCs ¼ 34 months Adverse prognosis  del(17p13) median TTP ¼ 2.04 years  t(4,14) median TTP ¼ 2.91 years  þ1q21 median TTP ¼ 3.86 years Median TTP  t(4,14) was 28 months  Deletion 17p was 24 months

Abbreviations: aPC ¼ abnormal plasma cell; BMPC ¼ bone marrow plasma cell percentage; FL ¼ focal lesion; FLC ¼ free light chain; GEP70 ¼ 70-gene expression model; MRI ¼ magnetic resonance imaging; PFS ¼ progression-free survival; SMM ¼ smoldering multiple myeloma; TTP ¼ time to progression.

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The Road to Treating SMM difficult and expensive. Indeed, results of a recent survey study polling myeloma centers across the United States suggest that there are vast differences among how institutes conduct their own multiparametric flow cytometry for MM patients, differing in sensitivity and CD antigens being tested.34 Despite variations in methodology across institutes and depth of technical expertise required, it is of the authors’ opinion that multiparametric flow cytometry (used to identify high-risk SMM patients and assess MRD) should be standardized by the international myeloma community while taking feasibility into account. PETHEMA investigators exemplify how such a technical assay can be incorporated into clinical studies effectively. Other investigators have demonstrated reproducibility of such techniques in large-scale clinical trials.35 Such techniques should be used as a launching pad to have a meaningful dialogue regarding standardizing methodologies with the aim to identify high-risk SMM patients and establish MRD definitions. Adding complexity to the matter, a number of other studies have identified additional features that might aid clinicians in targeting SMM patients for early treatment, deeming them to be “ultraehigh-risk” with > 70% probability of progressing to symptomatic disease within the first 2 years of diagnosis (Table 4).9,10 Such features include bone marrow plasma cell infiltration
60%,30 serum free light chain ratio of involved/ uninvolved
100,31,32 and focal lesions on MRI.33 Based on data from the Swedish Myeloma Registry (2008-2011), Kristinsson

et al36 recently reported high-risk SMM (bone marrow plasma cell infiltration
10% and M-protein
3 g/dL) only accounting for up to 4.2% of all MM patients or 0.14 cases per 100,000 persons. In this context, the incidence of ultraehigh-risk SMM is currently unknown and likely less than high-risk SMM. Because of the propensity for these ultraehigh-risk patients to develop symptomatic disease, recommendations are shifting toward starting treatment earlier and approaching them as having “early MM.”9,10 Because of the unique opportunity that high-risk and ultraehigh-risk SMM patients present during their disease course and the relatively low prevalence rates, these asymptomatic patients should still be referred to clinical trials with detailed characterization of disease biology and defined eligibility criteria.

Assessing Technical Methodology in SMM and MM Trials In addition to homogenizing definitions of SMM and MM, technical methodology for disease assessments should be standardized across all clinical trials and carefully analyzed. The PETHEMA QUIREDEX study methodology raises key questions on how one should confirm the asymptomatic diagnosis of SMM among eligible patients. For instance, by definition, SMM patients demonstrate M-protein
3 g/dL or bone marrow plasma cells > 10%. In the QUIREDEX trial, bone marrow plasma cell enumeration was determined from bone marrow aspiration rather than bone marrow

Figure 1 Potential Biological Disease Outcomes for Treating or Observing High-Risk SMM. No Treatment of High-Risk SMM Resulting in Clinical Progression in Certain High-Risk SMM Patients (Left). See Tables 3 and 4 for High-Risk SMM Definitions. Treatment Scenario 1 Demonstrates Eradication of Disease After Early Treatment (Center Left). Treatment Scenario 2 Shows That Early Institution of Therapy Results in Chronic Asymptomatic Disease State (Center Right). Scenario 3 Illustrates the Potential for Selection of Aggressive Resistant Myeloma Clones With Early Treatment (Right). These Potential Outcomes Highlight the Ongoing Need for Clinical Trials That Characterize Disease Biology End Points After Early Treatment

Reproduced from Waxman et al. Smoldering (asymptomatic) multiple myeloma: revisiting the clinical dilemma and looking into the future. Clin Lymphoma Myeloma Leuk 2010; 10:248-57.46

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Neha Korde et al core biopsy and CD138 immunohistochemistry. From our own National Institutes of Health natural history study on MGUS and SMM, we have found that morphology-based cell counts performed using bone marrow aspiration differentials underestimate plasma cellularity by approximately half compared with CD138 immunohistochemistry core biopsy staining (unpublished data). The implication of such a finding suggests that the patients enrolled in the trial might actually have had higher plasma cell burden, perhaps portending a worse disease outcome. Although patients were randomized to observation versus treatment with Len/Dex, this might have influenced the ability to demonstrate an overall survival benefit in a population with more aggressive disease burden. Similarly, patients in the QUIREDEX study were assessed using skeletal surveys at baseline to confirm lack of myelomatous lesions before enrolling in the study. Of note, 30% to 50% of bone destruction is required before it is detectable using radiograph37 despite remaining the gold standard of assessing symptomatic MM disease. Growing evidence suggests that more sensitive imaging techniques can detect early lesions in asymptomatic SMM patients38 with up to 30% of SMM patients demonstrating bone marrow infiltration patterns similar to MM on whole-body MRI.39 General clinical consensus guidelines already suggest that patients with suspicious bone disease should be worked up with these modalities, such as computed tomography, MRI, and positron emission tomography.40 Importantly, PETHEMA investigators did not disclose whether these techniques were subsequently used to make the determination if SMM patients had symptomatically progressed to clinical disease. Use of such modalities at later time points but not at baseline would undoubtedly have consequences for the trial’s primary end point, time to symptomatic progression, and how the study’s enrolled “asymptomatic” population was defined initially.

A Second Look at QUIREDEX Results A critical look at the QUIREDEX study reveals a few details that warrant mention.11 As stated earlier, the trial’s primary end point was time to symptomatic disease progression. In the treatment arm, patients received 9 cycles of Len/Dex, followed by 24 months of low-dose lenalidomide maintenance. Investigators intervened on treatment arm patients with increasing M-protein levels (“biochemical progression”) during the maintenance period with the addition of dexamethasone to the regimen and subsequent increases in lenalidomide dosing if disease control was not achieved. In contrast, the observation arm was monitored for clinical progression and received no medical intervention until after symptoms developed. Patients in the treatment arm were monitored differently and systematically treated based on rising M-protein levels compared with the symptom-based monitoring of the observation arm. As a result, different monitoring strategies would likely have consequences on end points, perhaps widening the gap between time to progression and overall survival between the 2 arms. PETHEMA authors carefully noted that control arm patients were not treated with Len/Dex because of a lack of approval as firstline therapy in the country. Instead, observation patients who progressed were treated with either bortezomib-based regimens 63 (53%) or induction therapy followed by autologous stem-cell transplant 33 (28%).11 Given the heterogeneity of how newly

diagnosed MM patients were handled in the observation arm, differences in overall survival could theoretically be attributed to efficacy of regimens chosen rather than timing of treatment initiation. Finally, Mateos and colleagues reported best responses in the treatment group completing induction and receiving maintenance therapy (n ¼ 50; median of 15 cycles): 6 (12%) stringent complete response (CR), 13 (26%) CR, and 9 (18%) very good PR.11 The fundamental question becomes: “Is this good enough in an era in which patients achieving near complete response (nCR) or higher is 74% to 78% in other upfront drug regimens?”41,42 A number of recent articles have addressed the issue of cure versus disease control strategies in MM.43,44 Indeed, one could possibly argue that such concepts are even more relevant when considering earlier treatment intervention in an asymptomatic SMM population. In fact, as one considers mounting evidence of intraclonal heterogeneity45 and patterns of clonal dominance being modulated by drug regimens,46 mechanisms to understand these patterns in the high-risk and ultraehigh-risk SMM setting are crucial to answer with clinical trials (Figure 1).47

Are We Ready to Treat High-Risk SMM? In lieu of QUIREDEX results, it seems that the era of watchful waiting strategies for all SMM is over. However, a number of logistical details and questions need to be addressed, as we tread through treatment options for SMM in the future. For the time being, “high risk” and “ultraehigh-risk” SMM patients should still be recommended for clinical trials (Table 4). Ultraehigh-risk SMM might be treated under MM categorical headings in the near future because of the aggressive nature and functional early MM similarities, however, this subset should be clearly delineated and precharacterized in eligibility criteria according to international community consensus. Novel therapeutics (carfilzomib/lenalidomide/ dexamethasone, anti-Dickkopf1, siltuximab, elotuzumab) are being investigated in ongoing clinical trials in the SMM setting with a promise to add more to our understanding of early MM disease biology. Future investigations will be fundamental in adequately treating patients with early MM or SMM truly at risk of developing symptomatic disease.

Disclosure The authors have stated that they have no conflicts of interest.

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The Road to Treating SMM 8. Perez-Persona E, Vidriales MB, Mateo G, et al. New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood 2007; 110:2586-92. 9. Mateos MV, San Miguel JF. New approaches to smoldering myeloma. Curr Hematol Malig Rep 2013; 8:270-6. 10. Rajkumar SV, Kyle RA. Haematological cancer: treatment of smoldering multiple myeloma. Nat Rev Clin Oncol 2013; 10:554-5. 11. Mateos MV, Hernandez MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 2013; 369:438-47. 12. Alexanian R, Barlogie B, Dixon D. Prognosis of asymptomatic multiple myeloma. Arch Intern Med 1988; 148:1963-5. 13. Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rodjer S, Westin J. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage Iea randomized study. Myeloma Group of Western Sweden. Eur J Haematol 1993; 50:95-102. 14. 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. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer 2000; 82:1254-60. 15. Rajkumar SV, Dispenzieri A, Fonseca R, et al. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia 2001; 15:1274-6. 16. 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. 17. 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. 18. Barlogie B, van Rhee F, Shaughnessy JD Jr, 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. 19. 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 1 {beta}-induced interleukin 6 production and the myeloma proliferative component. Mayo Clin Proc 2009; 84:114-22. 20. 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. 21. Zonder J. Green tea extract in treating patients with monoclonal gammopathy of undetermined significance and/or smoldering multiple myeloma. ClinicalTrialsgov. http://clinicaltrials.gov/ct2/show/NCT00942422. Accessed July 2014. 22. 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. 23. Dhodapkar MV, Sexton R, Waheed S, et al. Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). Blood 2014; 123:78-85. 24. Shaughnessy JD Jr, Zhan F, Burington BE, et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 2007; 109:2276-84. 25. 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. 26. Merz M, Hielscher T, Wagner B, et al. Predictive value of longitudinal whole-body magnetic resonance imaging in patients with smoldering multiple myeloma. Leukemia, Published online February 18, 2014; http://dx.doi.org/10.1038/leu.2014.75.

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Clinical Lymphoma, Myeloma & Leukemia September 2014

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