Stem Cell Transplant for Myeloma: The New Landscape

Transcription

1 Stem Cell Transplant for Myeloma: The New Landscape Sergio A. Giralt, MD Chief, Adult Bone Marrow Transplant Service Division of Hematologic Oncology Department of Medicine Memorial Sloan-Kettering Cancer Center New York, New York

2 Case Study High Risk 56-year-old female with symptomatic myeloma Multiple lytic lesions Creatinine 1.5 mg/dl Marrow plasmacytosis 50% β2m 6 g/dl Cytogenetics by FISH del 13 and 17p-

3 Case Study Low-Risk Disease 56-year-old female with symptomatic myeloma Multiple lytic lesions Creatinine 1.5 mg/dl Marrow plasmacytosis 50% β2m 2 gm/dl Cytogenetics diploid

4 Multiple Myeloma Treatment Lines in Transplant- Eligible Patients Current Paradigm Frontline treatment Risk Stratification? Maintenance Relapsed Induction Consolidation Maintenance Rescue Bz/Dex Bz/Dex/Dox Bz/Thal/Dex Len/Dex SCT Observation Thal Thal/Pred Lenalidomide Bz Bz/Liposomal Dox Len/Dex Carfilzomib Bendamustine National Comprehensive Cancer Network. The NCCN Clinical Practice Guidelines in Oncology Multiple Myeloma (Version ). Accessed October 13, 2010.

5 THE TRANSPLANT QUESTIONS FOR 2011 Focusing on reducing burden of treatment Does everybody need triple therapy induction? Would a doublet (Rd) be sufficient for standard risk disease? Is VRD the new standard? No randomized trial data available Optimal duration of induction? 2 cycles vs 4 cycles vs best response? Define Timing of SCT Is SCT optional for patients achieving a CR? Should salvage SCT be offered to all relapsing patients SCT naïve or not? Focusing on improving therapy Incorporating new agents into conditioning regimens Reducing morbidity Preventing relapse

6 Early-vs-Late SCT Study? Optimal induction regimen A A A COLLECT HD THERAPY + SCT Maintenance A m A m A m HARVEST AND HOLD SCT UPON RELAPSE Risk profile

7 Melphalan/Prednisone/Lenalidomide (MPR) vs MEL200/ASCT Following Lenalidomide/Dexamethasone (Ld) Induction Lenalidomide: 25 mg, days 1 21 Low-dose Dex: 40 mg, days 1, 8, 15, 22 q 28 days 4 R A N D O M I Z E Consolidation n=402 <65 years R MPR (n=202) Melphalan: 0.18 mg/kg/d, days 1 4 Prednisone: 2 mg/kg/d, days 1 4 Lenalidomide: 10 mg/d, days 1 21 q 28 days 6 Tandem MEL200 ASCT stem cells mobilized with cyclophosphamide + G-CSF A N D O M I Z E No maintenance Maintenance lenalidomide: 10 mg/d, Days 1 21 q 28 days until relapse Primary end point: PFS Palumbo A et al. Blood. 2009;114:Abstract 350.

8 Patient Characteristics Age (median) < 55 years years > 60 years MPR (N=202) 58 33% 29% 38% MEL200 (N=200) 58 40% 23% 37% ISS Stage I / II / III, (%) 47 / 30 / / 29 / 24 Chromosome abnormalities t(4;14) t(14;16) Del 17 NA 16% 6% 17% 25% 13% 4% 13% 31% MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m 2 ; ISS, International Staging System; NA, not available

9 Progression Free Survival 49.4% Reduced Risk of Progression Median follow-up 26 months 2-years PFS Median PFS 1.00 MEL200 73% Not reached MPR 54% mos 0.75 Patients (%) HR P = Months MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m 2 ; PFS, progression free survival; HR, hazard ratio; mos, months

10 Overall Survival Median follow-up 26 months 2-years OS MEL200 90% 1.00 MPR 87% 0.75 Patients (%) HR P = Months MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m 2 ; OS, overall survival; HR, hazard ratio

11 Toxicities Grade 3-4 Hematologic AEs Grade 3-4 Non-hematologic AEs MPR (n=130) MEL200 (n=143) MPR (n=130) MEL200 (n=143) Neutropenia P<0.001 Systemic Infections P=0.001 P<0.001 Gastrointestinal P<0.001 Thrombocytopenia P<0.001 Second cancer P=0.25 Anemia P<0.001 Drop out for PD Drop out for AE P<0.501 P< Patients (%) Patients (%) MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m 2 ; AE, adverse event; PD, progressive disease

12 Conclusions MPR MEL200 P value CR 20% 25% P= months 54% 73% P= months 87% 90% P=0.19 Less G3-4 hematologic toxicity in MPR arm (P<0.001) Less mucositis and infections in MPR arm (P<0.001) No difference in term of early deaths Significantly longer PFS after ASCT (P<0.001) Longer follow up is needed to assess OS MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m 2 ; CR, complete response; PFS, progression-free survival; OS, overall survival; ASCT, autologus stem cell transplantation

13 E4A03: Landmark Analysis at Median Follow-up of 36 mo 431 patients alive at 4 cycles Off therapy at 4 cycles n=183 Primary therapy beyond 4 cycles n=248 no transplant N=93 (median age 68) Transplant n=90 (median age 57) Ld n=140 (median age 66) LD n=108 (median age 65) Rajkumar SV et al. The Lancet Oncology, Volume 11, Issue 1, Pages 29-37, January 2010 eastern cooperative oncology group

14 Outcomes in pts Age <65 Progression Free Survival Overall Survival eastern cooperative oncology group

15 The Concept of Burden of Therapy Symptom burden is the combined impact of all symptoms (related to disease or therapy) on the ability of persons to function as they did prior to onset of their disease and/or therapy. Early Late

16 Preventing relapse

17 Tales of Two Cases Case 1 55-year-old female presents with asymptomatic anemia of 10 gm/dl and total serum protein 10 gm/l Workup reveals 30% plasma cells Cytogenetic diploid IgA kappa peak of 3.2 β2m of 3.0 Receives 4 cycles of Bz/Thal/Dex Followed by Auto SCT on day 60 documented stringent CR Case 2 55-year-old female presents with asymptomatic anemia of 10 gm/dl and total serum protein 10 gm/l Workup reveals 30% plasma cells Cytogenetic t(4;14) IgA kappa peak of 3.2 β2m of 3.0 Receives 4 cycles of Bz/Thal/Dex Followed by Auto SCT on day 60 documented paraprotein peak of 0.4 g/dl Both have a 10/10 sibling donor available.

18 BMT CTN 0102 Study Schema Multiple Myeloma meeting eligibility criteria *Biologic assignment occurred when HLA-typing results were available after enrollment. High-dose melphalan (200 mg/m2) + autologous PBSC transplant Biologic assignment* HLA typing of all patients with siblings Eligible HLA-matched sibling donor 60 to 120 days No eligible HLA-matched sibling donor Non-myeloablative conditioning TBI 200 cgy allogeneic PBSC transplant High-dose melphalan (200 mg/m2) + autologous PBSC transplant Randomization Randomization occurred once patients were assigned to auto-auto Observation Thalidomide Dexamethasone x12 months. PRIMARY ENDPOINT : 3yr Progression Free Survival

19 1 st Autologous Transplant N=710 No Sibling Donor Auto-Auto N=484 Sibling Donor Auto-Allo N=226 High Risk N=48 Standard Risk N=436 Standard Risk N=189 High Risk N=37 Main groups compared

20 Survival Outcomes after the First Transplant: Auto-Auto vs. Auto-Allo: Allo: Intent-to to-treat treat analysis Progression-free Survival Overall Survival Auto/Auto, 3yr Auto/Auto, 3yr Auto/Allo, 3yr Probability, % Auto/Allo, 3yr p-value = 0.67 p-value = Months # at risk: Auto/Auto Auto/Allo Mp10_5.ppt

21 Survival Outcomes after the First Transplant: Auto-Auto vs. Auto-Allo: Allo: Intention-to to-treat treat analysis Progression-Free Survival Overall Survival Auto/Allo, 3yr Auto/Allo, 3yr Auto/Auto, 3yr Auto/Auto, 3yr P-value = NS P-value = NS 0 0 Months Number at risk: Auto/Auto Auto/Allo (Combines Mp10_17 & _18) Mp10_19.ppt

22 The new standard of care

23 IFM-Len Maintenance PFS According to Response Preconsolidation 1.00 PR or SD 1.00 VGPR or CR P<10-5 P= Placebo Lenalidomide Placebo Lenalidomide HR = CI 95% [ ] HR = CI 95% [ ] Attal M et al. Blood. 2009;114: Abstract 529. Attal M et al. J Clin Oncol. 2010;28: Abstract 8018.

24 CALGB : Time to Progression Median follow up is 1 year Probability Lenalidomide Placebo Time Since ASCT (days) McCarthy PL et al. J Clin Oncol. 2010;28: Abstract 8017.

25 The Transplant Agenda What we should be trying to answer

26 Role of Consolidation Therapy Hypothesis Incorporation of new agents as post transplant consolidation will improve EFS compared to consolidation with second autologous HCT.

27 BMT CTN 0702 A Trial of Single Autologous Transplant with or without RVD Consolidation versus Tandem Transplant and Maintenance Therapy.

28 BMT CTN 0702: SCHEMA Lenalidomide Maintenance * Register and Randomize MEL 200mg/m 2 VRD x 4* MEL 200mg/m 2 Lenalidomide Maintenance** Lenalidomide Maintenance** * Bortezomib 1.3mg /m2 days 1, 4, 8,11 Lenalidomide 15mg days Dexamethasone 40mg days 1, 8, 15 **Lenalidomide 15 mg daily x 3years

29 Randomized Tandem ASCT Trials Study N Post- ASCT Rx Attal, 2003 Fermand, 2003 Goldschmidt, 2005 Sonneveld, 2004 Cavo, 2007 CR/VGPR rate (%) Single Tandem Median PFS (months) Single Tandem Median OS (months) Single Tandem 399 α IFN * 48 58* 277 None α IFN NYR* 23 NYR 303 α IFN * α IFN * * p< 0.05

30 Salvage Stem Cell Transplantation What comes after high dose melphalan conditioning?

31 Options for 2 ASCTs in Multiple Myeloma Tandem ASCT Salvage ASCT Induction therapy Induction Therapy High-dose Therapy + ASCT High-dose Therapy + ASCT +/- ImiD maintenance High-dose Therapy + ASCT +/- ImiD maintenance Re-induction therapy High-dose Therapy + ASCT? Comparative PFS and Overall Survival? IMiD=immunomodulatory derivative

32 Second Salvage ASCT for Relapsed Myeloma Princess Margaret Hospital (N=79) Median 60 years (39-72) Median TTP after 1 st transplant 2.72 years ( ) Median interval between transplants 3.61 years ( ) NRM 2.5% Response after 2 nd transplant: 15% CR/nCR, 78% PR, 8% MR/SD Results after 2 nd transplant based on TTP after 1 st transplant Group N Median PFS (mos) Median OS (mos) All <24 mos mos >36 mos NYR Mikhael J, et al. Blood 2009; 114: abstract #1217

33 Second Salvage ASCT for Myeloma Study N NRM (%) Median TTP after 1 st ASCT (mo) Median TTP after 2 nd ASCT (mo) Median OS after 2 nd ASCT (mo) Mikhael/ Fenk/ * 52* Olin/ * Burzynski/ Elice/ Quazilbash/ < * Sirohi/ Outcome better if >24 month TTP after 1 st ASCT * Outcome better if >12 month TTP after 1 st ASCT 1 Mikhael J, et al. Blood 2009; 114: abstract #1217; 2 Fenk R, et al. Blood 2009; 114: abstract # 3418; 3 Olin RL, et al. Bone Marrow Transplant 2009; 43: ; 4 Burzynski J, et al. Leuk Lymphoma 2009; 50: ; 5 Elice F, et al. Am J Hematol 2006; 81: ; 6 Quazilbash MH, et al. Cancer 2006; 106; ; 7 Sirohi B, et al. bone Marrow Transplant 2002;

34 Second Salvage AlloSCT for Myeloma Study N Median FU (mo) Response rate (CR) (%) Median PFS (mos) Median OS (mos) Gerull/ ~6 ~16 Quazilbash/ (31) Majolino/ ~28 ~30 van Dorp/ (4) de Lavallade/ ~24 ~36 Kroger/ (46) Gerull S, et al. Bone Marrow Transplant 2005; 36: ; 2 Quazilbash MH, et al. Cancer 2006; 106; ; 3 MajolinoI et al. Leuk Lymphoma 2007; 48: ; 4 van Dorp S, et al. Neth J Med 2007; 65: ; 5 de Lavallade H, et al. Bone Marrow Transplant 2008; 41: ; 6 Kroger N, et al. Br J Haematol 2010; 148:

35 Improving on High Dose Melphalan Increasing the dose Tandem stem cell transplantation Melphalan + Amifostine Pharmacomodulation of melphalan Bortezomib-Melphalan Arsenic melphalan Vorinostat melphalan Combining with other agents Radiotherapeutics-Targeted or not Other chemotherapy agents

36 Proposals Randomize Phase II Picking a Winner 1ry Endpoint 3 months Prior 15% - Desired 30% Randomize Investigational Maintenance Therapy Elo+Rev Elo+MLN90 78 Elo+BTZ Other 18 month PFS greater than 50%

37 Reducing Burden of Therapy Reducing SCT toxicities Better risk stratification and disease monitoring

38 Incidence of Moderate to Severe Symptoms Campagnaro et al. %

39 Current Interventions Nausea/Vomiting 5HT antagonists Pain Opiates Cytopenias Filgrastim Erythropoietin Diarrhea Octreotide Mucositis Opiates Palifermin Fatigue Isolated treatment of symptoms No understanding of the effects of control of one symptom over another Efficacy of interventions generally measured only in one dimension

40 Gene Polymorphisms [505] Influence of Genetic Single Nucleotide Polymorphisms in CYP3A4, CYP3A5, GSTP1, GSTM1, GSTT1 and MDR1 Genes on Survival and Treatment Related Toxicity in Patients with Multiple Myeloma Treated in the HOVON 24 Trial. Pieter Sonneveld et al. Patients with different haplotypes of CYP3A4, GSTP1, GSTM1, GSTT1 genes did not have significant differences of OS, PFS, EFS, Response Rate as determined by multivariate analysis with all clinical variables. Mutant GSTP1(Ile/Val) more toxicity (p=0.003) Mutant MDR1 C3435T or absence of GSTP1 Ile105Val lower RR p=0.01 Mutant allele CYP3A5 gene had increased toxicity (p=0.040), improved OS (p=0.01) and PFS (p=0.04) and a decrease in TTP (p=0.03).

41 MDASI Scores at Different Time Points Post SCT mdasinadir mdasibaseline

42 Symptoms, Toxicities, and Cytokines Wang et al, J Clin Oncol

43 Randomized Phase II LD/HD CD34 Symptom Severity by CD34 Positive Cells Infused x10^6 CD34 Cells/Kg 10-15x10^6 CD34 Cells/Kg Mean of 5 Most Severe Symptoms Baseline Conditioning Regimen Day of Transplant Nadir of WBC Hospital Discharge 30 days post BMT Time

44 Reducing Burden of Therapy by Better Risk Stratification or better disease monitoring

45 Multiple Myeloma Treatment Lines in Transplant- Eligible Patients Current Paradigm Frontline treatment Risk Stratification? Maintenance Relapsed Induction Consolidation Maintenance Rescue Bz/Dex Bz/Dex/Dox Bz/Thal/Dex Len/Dex SCT Observation Thal Thal/Pred Lenalidomide Bz Bz/Liposomal Dox Len/Dex Carfilzomib Bendamustine National Comprehensive Cancer Network. The NCCN Clinical Practice Guidelines in Oncology Multiple Myeloma (Version ). Accessed October 13, 2010.

46 Total Therapy Comparable Outcomes in Standard-Risk Patients 100% OVERALL SURVIVAL 100% EVENT-FREE SURVIVAL 80% 60% 40% (42/235) (13/129) 80% 60% 40% (52/235) (17/129) 20% 20% 0% Years from Enrollment 0% Years from Enrollment ONSET OF CR CR DURATION 100% 100% (14/149) 80% (79/129) 80% (5/79) 60% 40% (149/235) 60% 40% 20% 20% 0% Years from Enrollment 0% Years from Onset of CR

47 Monitoring Disease CR Definition Does Matter With Regards to Depth of Remission Number of Myeloma Cells At diagnosis Partial response 50% reduction in M protein Near complete remission immunofixation positive only Complete remission immunofixation negative MRD Nonquantitative ASO-PCR Quantitative ASO-PCR flow cytometry Rate of molecular CR with HDT is 5%

48 Summary High dose melphalan with autologous stem cell support remains the standard of care for consolidation therapy for patients with chemosensitive disease Current therapy with high dose melphalan followed by maintenance therapy results in more than 70% major responses and median remission durations of around years. Moving forward minimizing toxicities, developing more effective conditioning regimens and better risk stratification will allow us to provide each patient with the best chance of a long life with myeloma control, good quality of life with the least treatment burden