Presentation on theme: "Ravi Vij MD Associate Professor Section of BMT and Leukemia"— Presentation transcript:
1 Induction Therapy For Multiple Myeloma: Two vs Three Drug Regimen and Role of Risk Stratification Ravi Vij MDAssociate ProfessorSection of BMT and LeukemiaWashington University School of Medicine
2 Trends in Overall Survival of MM 1.0Diagnosis period Median OS1996– months1971– months(P<0.001)0.82001–2006OS, overall survival.0.6Survival0.4Trends in Overall Survival of MMKumar et al studied survival in 387 patients who were treated at the Mayo Clinic from 1971–2006 and experienced a first relapse after ASCTPatients were divided into 2 cohorts, those with a relapse date on or before December 31, 2000 and those with a later relapse dateMedian 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 diagnosisReferenceKumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and theimpact of novel therapies. Blood. 2008;111(5):1971–19761989–19940.21977–19821995–20001983–19882001–200620406080100120140Time from diagnosis (Months)Kumar SK, et al. Blood. 2008;111:
3 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?
4 CR associated with OS prolongation in post-induction and post-transplant settings1-3 Chemotherapy AloneChemotherapy and ASCTCR associated with OS prolongation in post-induction and post-transplant settingsAssessing 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):2. Wang M et al. Bone Marrow Transplant. 2010;45(3):3. Lahuerta JJ et al. J Clin Oncol. 2008;26(35):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): Alexanian et al. Bone Marrow Transplant. 2001;27: Wang, et al. Bone Marrow Transplant. 2010;45(3):
5 Importance of CR in Elderly MM > 65 yrs> 75 yrsGay F et al. Blood. 2011;117(11): )
6 Approach to Treatment of MM Clearly not a transplant candidatebased on age, performance statusand comorbidityConventional TherapyPotential transplantcandidateNon-alkylator basedinduction x 4 cyclesStem cell harvest
7 Bortezomib-Based Induction Prior to SCT TrialRegimenNCR+VGPR Post-Induction (%)CR+VGPR Post-ASCT (%)PFSP ValueCavo et al, 2010VTDvsTD23623862*2882*6468% at 3 yr56% at 3 yr.0057Moreau et al, 2011IFM 2007/02VDvTD991003649‡5874§Median 30 monthsMedian 26 mo.22*P <.001; †P =.001; ‡P =.05; §P =.02GMMG= 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: Harousseau JL, et al. J Clin Oncol. 2010;28: Sonneveld P, et al. ASH Annual Meeting Abstracts. 2010;116(21):40. Accessed July 17, Moreau P, et al. Blood. 2011;118:
8 MPT vs MP in Elderly MMFayers PM et alBlood.2011;118(5):
10 MPR vs MP in Elderly MMPalumbo et al. N Engl J Med 2012;366:
11 Bortezomib in Transplant Ineligible MM StudyRegimenNORRCR/nCROutcomesVISTASan Miguel et al.Mateos et al.Phase IIIVMPMP34433871%35%33%4%5 yr OS: 46%5 yr OS: 34.4%UPFRONTNiesvizky et al.VMP/VelVTD/VelVD/Vel30073%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
13 MM-020: Len + Low-dose Dex vs MPT in Previously Untreated MM Lenalidomide 25 mg/day, days 1–21, every 28 daysDexamethasone* 40 mg/day, days 1, 8, 15, 22, every 28 daysUntil PDInclusion criteriaPreviously untreated MMAge 65 years or not a candidate for transplantationNo neuropathy of grade > 2CICr > 30 ml/min18 four-week cycles or until PDLenalidomide 25 mg/day, days 1–21, every 28 daysDexamethasone* 40 mg/day, days 1, 8, 15, 22, every 28 daysMelphalan 0.25 mg/kg/day, days 1–4, every 42 daysPrednisone 2.0 mg/kg/day, days 1–4, every 42 daysThalidomide* 200 mg/day, days 1–42, every 42 days12 six-week cycles or until PDMM-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 ; data on file.N = 1,590Centres in EU, Switzerland, USA and Canada*In patients older than 75 yearsDexamethasone 20 mg/dayThalidomide 100 mg/dayMelphalan 20 mg/kg/dayProtocol CC-5013-MM-020/IFM ; data on file, Celgene Corporation
16 ConclusionsThree 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.