Should some patients with Smoldering Myeloma receive treatment? Yes-High Risk SMM should S. Vincent Rajkumar Professor of Medicine Mayo Clinic

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1 Should some patients with Smoldering Myeloma receive treatment? Yes-High Risk SMM should S. Vincent Rajkumar Professor of Medicine Mayo Clinic Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Mayo Clinic College of Medicine Mayo Clinic Comprehensive Cancer Center Progression of SMM versus MGUS SMM- Not a distinct biologic entity Kyle R et al. N Engl J Med 2007;356:

2 High Risk SMM Probability of Progression to Active Multiple Myeloma or Primary Amyloidosis in Patients with Smoldering Multiple Myeloma among Three Risk Groups Kyle R et al. N Engl J Med 2007;356:

3 Circulating PC in SMM Witzig TE, Br J Haematol 1994;87: PCLI 1 PCLI <1 Percent progressing Follow up from diagnosis of smoldering multiple myeloma (years) Madan S. Mayo Clin Proc 2010

4 Risk of progression to myeloma or related disorder in 273 patients with SMM Dispenzieri, A. et al. Blood 2008;111: Copyright 2008 American Society of Hematology. Copyright restrictions may apply. The case for observation First do no harm 50% of SMM remain progression free after 5 years No biomarkers to distinguish SMM from MM Only Alkylators and Steroids 2 small RCTS - no survival benefit Hjorth M, Eur J Haematol 1993;50(2): Riccardi A, Br J Cancer 2000;82(7):

5 Efficacy of MGUS Follow up Optimal Variable (N=80, 69%) SMM Dx preceding symptomatic MM, N (%) 24 (30%) Mechanism of MM Dx, N (%) Complications Symptoms Follow Up Incidental Non available 36 (45%) 20 (25%) 13 (16%) 9 (11%) 2 (3%) Diagnosis requiring hospitalization, N (%) 39 (49%) Multiple bone lesions at MM Dx, N (%) 45 (56%) Bianchi G, et al. Blood epub Rajkumar SV. Cecil Textbook of Medicine, 24th Edition, 2011

6 Strategies for Early Therapy Identify Biomarkers with 90% positive predictive value for progression within 2 years Randomized trials with survival benefit Biomarker Strategy

7 Bone Marrow Plasma Cell 60% Rajkumar SV et al. N Engl J Med 2011; N Engl J Med 2011; 365: Other Biomarkers of High Predictive Value FLC ratio 100 High levels of circulating plasma cells High proliferative rate Abnormal immunophenotype as defined by the Spanish Group

8 Randomized Trials Thalidomide in SMM PFS OS Rajkumar SV, et al. Leukemia 2003;17:775-9

9 Thalidomide plus Zoledronic Acid versus Zoledronic Acid in SMM 100 Arm A; N=35; median 2.4 years 80 Arm B; N=33; median 1.03 years Stratified log-rank p-value 0.02 %Progression Free Time (years) Rajkumar SV, et al. unpublished A Multicenter, Randomised, Open-label, Phase III Study of Lenalidomide/Dexamethasone versus Therapeutic Abstention in high-risk Smoldering QuiRedex MM MV Mateos, L López-Corral, MT Hernández, J de la Rubia, JJ Lahuerta, P Giraldo, J Bargay, L Rosiñol, A Oriol, J García-Laraña, l Palomera, F de Arriba, F Prósper, ML Martino, AI Teruel, J Hernández, G Estevez, M Mariz, A Alegre, JL Guzman, N Quintana, JL García, JF San Miguel. On behalf of Spanish Myeloma Group (PETHEMA/GEM)

10 QuiRedex: Len-dex vs no treatment PCs BM 10% plus M-protein 30 g/l or PCs BM 10% or M-protein 30 g/l but BM apc/npc > 95% plus immunoparesis Time elapsed from diagnosis to inclusion not superior to 5 years No CRAB (hypercalcemia, anemia, bone lesions, renal impairment) or symptoms Len-dex vs no treatment: TTP to active disease (n = 119) ITT analysis Median follow-up: 32 months (range 12 49) Proportio on of patients alive 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 followed by PD 4 pts:symptomatic PD HR: 6.0; 95% IC ( ); p < Time from inclusion

11 Len-dex vs no treatment: OS from diagnosis (n = 119) Median follow-up: 38months (range 14 96) 1.0 Lenalidomide + Dex of patients alive Proportion No treatment HR: 5.01; 95% IC (1 22); p=0.03 Lenalidomide + Dex: 94% at 5 yrs No treatment: 79% at 5 yrs Time from inclusion Initial Therapy of MM E3A06: Phase III High-Risk Smoldering Myeloma* Lenalidomide vs. observation PI: Sagar Lonial R A N D O M IZ A TI O N Lenalidomide Observation CR/PR/ Stable Prog. anytime Continue therapy till prog. or toxicity Off Rx * Concept approved by CTEP eastern cooperative oncology group