Induction Therapy For Multiple Myeloma: Two vs Three Drug Regimen and Role of Risk Stratification Ravi Vij MD Associate Professor Section of BMT and Leukemia Washington University School of Medicine

Trends in Overall Survival of MM 1.0 Diagnosis period Median OS 1996–2006 45 months 1971–1996 30 months (P<0.001) 0.8 2001–2006 OS, overall survival. 0.6 Survival 0.4 Trends in Overall Survival of MM Kumar et al studied survival in 387 patients who were treated at the Mayo Clinic from 1971–2006 and experienced a first relapse after ASCT Patients were divided into 2 cohorts, those with a relapse date on or before December 31, 2000 and those with a later relapse date Median overall survival (OS) was longer for patients who relapsed after 2000 compared with those who relapsed prior to this date (23.9 vs 11.8 months) Improved outcome of patients with MM has been observed in recent years, both in the relapsed setting as well as at diagnosis Reference Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516-2520. 1971–1976 1989–1994 0.2 1977–1982 1995–2000 1983–1988 2001–2006 20 40 60 80 100 120 140 Time from diagnosis (Months) Kumar SK, et al. Blood. 2008;111:2516-2520.

CR and MM Is CR an adequate surrogate for OS? Are all CRs as durable? Should we strive for CR pre-transplant? What is the role of HDCT for patients in CR pre-transplant?

CR associated with OS prolongation in post-induction and post-transplant settings1-3 Chemotherapy Alone Chemotherapy and ASCT CR associated with OS prolongation in post-induction and post-transplant settings Assessing the prognostic impact of achieving CR has been difficult because of the use of different definitions of CR.1 [Harousseau/p3139/c2/para3/lines1-3] Although not all studies show a correlation between CR and OS in MM, CR generally indicates patients who are likely to live longer.2 [Wang/p500/fig1] Many studies have demonstrated that CR is usually associated with longer overall survival.1[Harousseau/p3140/c2/para1/lines1-9] These findings have been demonstrated in both the postinduction and posttransplant settings.3[Lahuerta/p5778/table3] 1. Harousseau J-L et al. Blood. 2009;114(15):3139-3146. 2. Wang M et al. Bone Marrow Transplant. 2010;45(3):498-504. 3. Lahuerta JJ et al. J Clin Oncol. 2008;26(35):5775-5782. Survival by response for 291 patients with MM (age <70 y) who received chemotherapy alone (left) and 375 who proceeded to ASCT (right) (CR vs PR or NR P<0.01) 1. Lahuerta et al. J Clin Oncol. 2008;26(3):5775-5782. 2. Alexanian et al. Bone Marrow Transplant. 2001;27:1037-1043. 3. Wang, et al. Bone Marrow Transplant. 2010;45(3):498-504.

Importance of CR in Elderly MM > 65 yrs > 75 yrs Gay F et al. Blood. 2011;117(11):3025-3031)

Approach to Treatment of MM Clearly not a transplant candidate based on age, performance status and comorbidity Conventional Therapy Potential transplant candidate Non-alkylator based induction x 4 cycles Stem cell harvest

Bortezomib-Based Induction Prior to SCT Trial Regimen N CR+VGPR Post-Induction (%) CR+VGPR Post-ASCT (%) PFS P Value Cavo et al, 2010 VTD vs TD 236 238 62* 28 82* 64 68% at 3 yr 56% at 3 yr .0057 Moreau et al, 2011 IFM 2007/02 VD vTD 99 100 36 49‡ 58 74§ Median 30 months Median 26 mo .22 *P <.001; †P =.001; ‡P =.05; §P =.02 GMMG= German Multiple Myeloma Group; SCT = stem cell transplant; CR = complete response; VGPR = very good partial response; PAD = bortezomib (V)/AD; T = thalidomide; VAD = vincristine, doxorubicin (A), dexamethasone (D); vTD = reduced-dose bortezomib. Cavo M, et al. Lancet. 2010;376:2075-2085. Harousseau JL, et al. J Clin Oncol. 2010;28:4621-4629. Sonneveld P, et al. ASH Annual Meeting Abstracts. 2010;116(21):40. http://web.educationalconcepts.net/Newsletter/MMY015AE1/MMY015AE1.pdf. Accessed July 17, 2012. Moreau P, et al. Blood. 2011;118: 5752-5758.

MPT vs MP in Elderly MM Fayers PM et alBlood.2011;118(5):1239-1247

Overall Survival Median survival: MP 32.7 months (95% CI, 30.5-36.6 months) MPT 39.3 months (95% CI, 35.6-44.6 months). HR 0.83 (95% CI: 0.73-0.94) P=0.004

MPR vs MP in Elderly MM Palumbo et al. N Engl J Med 2012;366:1759-69.

Bortezomib in Transplant Ineligible MM Study Regimen N ORR CR/nCR Outcomes VISTA San Miguel et al. Mateos et al. Phase III VMP MP 344 338 71% 35% 33% 4% 5 yr OS: 46% 5 yr OS: 34.4% UPFRONT Niesvizky et al. VMP/Vel VTD/Vel VD/Vel 300 73% 79% 31% 36% 34% ORR: overall response rate; CR: complete response; nCR: near complete response; OS: overall survival; TTP: time to progression; PFS: progression free survival; VMP: Bortezomib-melphalan-dexamethasone; MP: Melphalan-Prednisone; VTP: Bortezomib-thalidomide-dexamethasone; VTD: bortezomib-thalidomide-dexamethasone; VD: bortezomib-dexamethasone; VMPT-VT: bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance

UPFRONT Study

MM-020: Len + Low-dose Dex vs MPT in Previously Untreated MM Lenalidomide 25 mg/day, days 1–21, every 28 days Dexamethasone* 40 mg/day, days 1, 8, 15, 22, every 28 days Until PD Inclusion criteria Previously untreated MM Age  65 years or not a candidate for transplantation No neuropathy of grade > 2 CICr > 30 ml/min 18 four-week cycles or until PD Lenalidomide 25 mg/day, days 1–21, every 28 days Dexamethasone* 40 mg/day, days 1, 8, 15, 22, every 28 days Melphalan 0.25 mg/kg/day, days 1–4, every 42 days Prednisone 2.0 mg/kg/day, days 1–4, every 42 days Thalidomide* 200 mg/day, days 1–42, every 42 days 12 six-week cycles or until PD MM-020 study design: lenalidomide plus low-dose dexamethasone given until PD or for 18 four-week cycles versus melphalan, prednisone, and thalidomide for 12 six-week cycles in patients with previously untreated multiple myeloma who are either ≥ 65 years old or not candidates for stem cell transplantation. ClCr = creatinine clearance; MM = multiple myeloma; PD = progressive disease. Celgene Corporation. Protocol CC-5013-MM-020/IFM 07-01. 2007; data on file. N = 1,590 Centres in EU, Switzerland, USA and Canada *In patients older than 75 years Dexamethasone 20 mg/day Thalidomide 100 mg/day Melphalan 20 mg/kg/day Protocol CC-5013-MM-020/IFM 07-01. 2007; data on file, Celgene Corporation

Conclusions Three drug induction regimen are associated with higher CR rates compared to two drug regimen. In the transplant eligible population prospective trials have shown a higher CR rate and PFS for two drug regimen. Follow-up is too short for analyses of OS. In the transplant ineligible population three drug regimes of thalidomide and bortezomib have a OS advantage compared with MP. Whether non-melphalan containing two drug regime may be equivalent is the subject of ongoing trials. We have entered an era of risk stratification for deciding therapy. However no consensus has emerged on treatment paradigms.