Smoldering Myeloma: Leave them alone!

Smoldering Myeloma: Leave them alone! David H. Vesole, MD, PhD Co-Director, Myeloma Division Director, Myeloma Research John Theurer Cancer Center Hackensack University Medical Center Prevalence 1960 2002 Smoldering MM 16% of MM (1000/6179) Progression rate MGUS 1% per year SMM 10 25% per year 1

Progression to Symptomatic MM MGUS: up to 2 percent of persons 50 years of age or older and about 3 percent of those older than 70 years For SMM, maximum risk in the first 5 years Risk factors: Higher M spike, higher plasma cell burden, type of M protein, Abnormal free light chain ratio, circulating plasma cells Kyle et al, NEJM, Volume 356:2582 2590, June 21, 2007 Risk stratification based on bone marrow plasmacytosis, serum M protein, and serum immunoglobulin free light chain (FLC) ratio. Patients are assigned 1 point for meeting each of the following criteria: bone marrow clonal plasma cells 10%; serum M protein 3 g/dl; and serum immunoglobulin FLC ratio either less than 0.125 or > 8. The median times to progression for 1, 2, or 3 risk factors are 10, 5.1, and 1.9 years, respectively. 2

Risk stratification schemes for SMM Mayo Clinic for SMM patients Risk factors: plasma cells >10%, M protein > 3 g/dl, FLC ratio < 0.125 or > 8 No. of risk ikfactors No. of patients t (%) 20 year progression, % RR 1 76 (28) 25 1 2 115 (42) 51 2.0 3 82 (30) 76 3.0 Total 273 (100) 51 N/A Spanish study group for SMM patients Risk factors: 95% apc, immunoparesis 0 28 (31) 4 1 1 22 (25) 46 11.5 2 39 (44) 72 18 Total 89 (100) 46 N/A Smoldering MM 100 p < 0.001 Gr 1:TTP 1.9 y 80 PCsBM Infiltration 10% Gr 2: TTP: 5 y Probability of Progression (%) 60 Gr 3: TTP 10 y 40 20 0 0 5 10 15 Years Serum M protein 3 g/dl Serum FLC ratio < 1/8 or > 8 No. of risk factors No. Rel risk 1 81 1 2 114 1.9 (1.2 2.9) 3 78 4.0 (2.6 6.1) Mateos et al., Abstract #991 Kyle RA, et al. N Engl J Med. 2007; 356:2582-90 Dispenzieri A, et al. Blood. 2008;111:785-9. 3

Bisphosphonates Treatment of SMM Pamidronate (n =12) no direct anti tumor effect (Martin et al Br J Haematol 118:239 243, 2002) Pamidronate randomized triial: decrease SRE bu no prolongation of TTP or OS (Musto et al Leukemia and Lymphoma 44:1545 1548, 2003) Zoledronic acid randomized trial: decrease in SRE but no impact on TTP or OS (Musto et al Cancer 113:1588 1595, 2008) Treatment of SMM Alkylating Agents and Corticosteroids MP vs Obs (n = 50) no difference in response rate at time of PD, no difference in DOR or OS (Hjorth et a leur J Haematol 50:95 102, 1993) MP vs Obs (n = 44) median survival similar 54 vs 58 mo (Grignani et albr J Cancer 73:1101 1107, 1996) MP vs Obs (n = 145) no difference in survival (Riccardi et al Br J Cancer 82:1254 1260, 2000) 4

Treatment of SMM Thalidomide Mayo Clinic (N =29): RR 34% (Rajkumar et al Leukemia 17:775 779, 2003) Comparison (29 pts on thal study) with historical control (57 pts) 2 year PFS: 47% (untreated) vs 63% (Thal) MD Anderson (n = 28): RR 36% (Weber et al J Clin Oncol 21:16 19, 2003) Arkansas (n = 74); RR42%, median time to progression 7 years; PN dose reduction 86%, DC d 50% (200 mg/d) (Barlogie et al Blood 112:3122 3125, 2008) 63% (47% in historical controls) Rajkumar SV. Leukemia 2003; 17:775-9 5

Fig 3. (A) Event free survival was similar in patients with multiple myeloma (MM) evolved from monoclonal gammopathy of undetermined significance (MGUS)/SMM and other subgroups. (B) Overall survival was similar in patients with MM evolved from MGUS/SMM and other subgroups. Barlogie et al BJH 2007; 136: 393 Multivariate analysis of factors predicting for complete response, event free survival and overall survival all patients All patients Factor % HR (95% CI) P-value Complete response (n = 637) Prior MGUS/SMM 7 0 45 (0 25,0 81) 0 007 Thalidomide arm 49 1 54 (1 24,1 91) <0 001 LDH > upper normal limit 27 1 28(1 00,1 62) 1 0 045045 Event-free survival (n = 654) Prior MGUS/SMM 7 1 12 (0 71,1 76) 0 637 Thalidomide arm 49 0 75 (0 59,0 95) 0 016 LDH > upper normal limit 27 1 51 (1 17,1 96) 0 002 Cytogenetic 30 1 55 (1 22,1 98) <0 001 abnormalities Albumin < 35 g/l 18 1 52 (1 14,2 02) 0 004 B2M 35 mg/l 36 1 47 (1 14,1 88) 0 003 IgA isotype 24 1 45 (1 12,1 89) 0 006 CR (time dependent) 52 0 64 (0 49,0 83) 0 001 Overall survival (n = 654) Prior MGUS/SMM 7 1 04 (0 59,1 81) 0 900 LDH > upper normal limit 27 1 66 (1 22,2 25) 0 001 Cytogenetic 30 1 88 (1 41,2 52) <0 001 abnormalities Albumin < 35 g/l 18 1 85 (1 33,2 56) <0 001 CR (time dependent) 52 0 52 (0 37,0 72) <0 001 6

QuiRedex: Study Design Multicenter, open label, randomized phase III trial Evaluated newtreatment regimen for smoldering MM vs current standard of care Patients with high risk smoldering MM Induction 9 x 28 day cycles Lenalidomide 25 mg/day on Days 1 21 + Dexamethasone 20 mg/day on Days 1 4, 12 15 Maintenance 28 day cycles Lenalidomide 10 mg/day on Days 1 21 (Low dose dexamethasone added at time of biologic progression) 2 yrs (N = 126) No Treatment No Treatment Primary endpoint: TTP to symptomatic MM Secondary endpoints: response, duration of response, safety and tolerability, PFS, OS Mateos MV, et al. ASH 2011. Abstract 991. 7

QuiRedex: Response Majority of patients responded to lenalidomide plus dexamethasone Response, % Responses improved with maintenance ITT Population With Median of 9 Induction Cycles (Range: 1-9) (n = 57) After Completion of 9 Induction Cycles (n = 51) After Median of 15 Maintenance Cycles (Range: 2-31) (n = 50) ORR 86 96 96 Stringent CR 7 8 16 CR 12 of 14 patients either 7 improved to PR or 8 had SD after receiving 12low dose dexamethasone during lenalidomide maintenance VGPR 11 12 16 PR 61 68 52 Mateos SD MV, et al. ASH 2011. Abstract 14 991. 4 4 QuiRedex: Safety 3 cases of second primary malignancies reported in treatment arm Adverse Event, % Lenalidomide + Dexamethasone (n = 57) No Treatment (n = 62) Grade 1/2 Grade 3 Grade 1/2 Anemia 28 2 -- Neutropenia 20 5 -- Thrombocytopenia 13 2 -- Asthenia 20 7 11 Constipation 18 -- 2 Diarrhea 24 2 4 Rash 33 4 -- Paresthesias 5 -- -- Tremor 13 -- 2 Infection 46 6 26 Mateos Deep MV, vein et thrombosis al. ASH 2011. Abstract 991. 5 -- 8

Len dex vs no treatment: TTP to active disease (n = 119) ITT analysis Median follow-up: 32 months (range 12 49) [Len 25*21 d + dex 20*4*2]q28 *9 then len 10 q21 Proportio on of patients alive 10 1.0 0.8 0.6 0.4 0.2 0.0 No treatment Median TTP: 23m 37 Progressions (59%) 20 patients: bone disease 7 patients: renal failure Lenalidomide + dex Median TTP: NR 9 Progressions (15%) 5 pts:early disc then DP 4 pts:symptomatic DP HR: 6.0; 95% IC (2.9 12.6); p < 0.0001 0 5 10 Mateos et al., Abstract #991 15 20 25 Time from inclusion 30 35 40 45 QuiRedex: TTP to Symptomatic MM and OS Significant increase in TTP with vs without treatment 10 1.0 Proportion of Patients Alive 0.8 0.6 0.4 0.2 0 0 5 10 15 20 25 30 35 40 45 Lenalidomide + dexamethasone No treatment Median TTP Lenalidomide + dexamethasone: NR No treatment: 23 mos HR: 6.0 (95% CI: 2.9 12.6; P <.0001) Median follow up: 32 mos (range: 12 49) Mos From Inclusion Significantly prolonged OS with vs without treatment Median 3 yr OS (from study inclusion): 93% vs 76%; P =.04 Median 5 yr OS (from diagnosis): 94% vs 79%; P =.03 Mateos MV, et al. ASH 2011. Abstract 991. 9

Len dex vs no treatment: OS from inclusion (n = 119) Median follow-up: 32 months (range 12 49) 1.0 Lenalidomide + Dex tion of patients alive Proport 0.8 0.6 0.4 0.2 0.0 No treatment p=0.04 Lenalidomide + Dex: 93% at 3 years No treatment: 76% at 3 years 0 5 10 15 20 25 30 35 40 45 50 Mateos et al., Abstract #991 Time from inclusion QuiRedex: Conclusions Improved outcomes with lenalidomide and dexamethasone induction plus maintenance lenalidomide vs no treatment in smoldering MM [1] Significantly prolonged TTP, OS Addition of low dose dexamethasone to maintenance lenalidomide maintained disease stabilization in most cases of biologic progression [1] Well tolerated, with most adverse events grade 1/2 [1] Drug related toxicities should be considered when evaluating risk/benefit Question remains regarding effect of treatment at this disease stage Delay progression only or alter natural history also Ongoing phase II/III ECOG trial evaluating single agent lenalidomide vs observation in smoldering MM; suspended in December 2011 [2] 1. Mateos MV, et al. ASH 2011. Abstract 991. 2. ClinicalTrials.gov. NCT01169337. 10

E3A06: Eligibility Diagnosis asymptomatic high risk disease No immediate need for chemotherapy Nolyticlesions lesions on skeletal surveys andnono hypercalcemia (i.e., 11 mg/dl) Bone marrow plasmacytosis with 10% plasma cells or sheet of plasma cells by bone marrow aspiration and/or biopsy Abnormal serum free light chain (FLC) ratio (< 0.125 or > 8.0) by serum FLC assay Measurable monoclonal protein in the serum 1.0 g/dl or urine 200 mg/24 hrs E3A06: Objectives Primary Study the risk of grade 3 4 non hematologic adverse events in patients with asymptomatic high risk smoldering multiple myeloma treated with lenalidomide. (Phase II) Compare the progression free survival (PFS) of patients with asymptomatic high risk smoldering multiple myeloma treated with lenalidomide versus observation alone. (Phase III) Secondary Assess the response of patients treated with lenalidomide. (Phase II) Describe the gene expression profile (GEP) and cytogenetic risk classification and evaluate baseline immune and MRI parameters in these patients. (Phase II) Determine and compare the response rate, time to progression, 1 year PFS probability, and the overall survival of patients treated with lenalidomide versus observation alone. (Phase III) Estimate the incidence of adverse events of these regimens in these patients. (Phase III) Evaluate the impact of therapy within GEP defined risk groups and GEP as a prognostic marker. (Phase III) Study the effects of lenalidomide on laboratory markers of immune function. (Phase III) Study the prognostic value of MRI detected asymptomatic bone disease on clinical outcome. (Phase III) Evaluate the prognostic effect of baseline high risk cytogenetic abnormalities on clinical outcome. (Phase III) Compare the quality of life of patients treated with these regimens. (Phase III) 11

Diagnosis & Management of High Risk SMM 12

Goal What are the best risk factors today to identify patients with high risk SMM? To identify patients with high risk SMM with 90% chance to develop symptomatic MM at 2 years in order to: prevent end organ damage possibly extend survival avoid unnecessary treatment in low risk SMM What are potential new risk factors that we should look for? Bone imaging (wbmri, PET CT) Changes in dflc and e GFR Total concentration FLC (i.e. > 1000 mg/l) BMPCs (i.e. 60%) Number of circulating plasma cells 13

Should we treat some patients with SMM? Len dex is a promising and attractive option All efforts to plan an early treatment in asymptomatic MM patients should be focused on high risk patients Long term follow up is required to actually confirm the benefit, especially in OS Results of other trials that they are being conducted are needed In the near future, we could offer early treatment to a selected high risk of patients with the confidence that they are going to obtain a significant benefit Does the survival benefit seen in the Spanish trial outweigh the risks? Should we change practice? The present data of the QuiRedex trial do not support change of practice! High risk patients are encouraged to enroll into clinical trials 14

Conclusions Treatment of SMM should only be considered in the context of a clinical Consensus opinion of IMWG No proven survival advantage with conventional Rx OR transplant Short and Long term toxicities need to be delineated? Second malignancies We need to better define High Risk SMM The use of bisphosphonates is not clear, especially in light of the MRC data 15