Multiple Myeloma Research Foundation Powerful thinking advances the cure 1 Management of Multiple Myeloma: Stem Cell Transplant David H. Vesole, MD, PhD CoDirector, Myeloma Division Director, Myeloma Research John Theurer Cancer Center Hackensack University Medical Center
Dr. David Vesole, Co-Chief, Multiple Myeloma at John Theurer Cancer Center at HackensackUMC presentation at the MMRF Clinical Insights program in April 2012.
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Multiple MyelomaResearch Foundation
Powerful thinking advances the cure1
Management of Multiple Myeloma:
Stem Cell Transplant
David H. Vesole, MD, PhD
Co-‐Director, Myeloma Division
Director, Myeloma Research
John Theurer Cancer Center
Hackensack University Medical Center
Multiple MyelomaResearch Foundation
Powerful thinking advances the cure2
3 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
Stem Cell Transplantation
• Myeloma and normal cells are killed by high-dose chemotherapy (eg, melphalan)
• Stem cells are ‘bone marrow-like cells’ harvested from the peripheral blood
• Sources of stem cells: – Autologous—cells collected from the patient – Allogeneic—cells collected from a donor
• Related or unrelated donors: blood stem cells or bone marrow
• Umbilical cord
4 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
Rationale for Stem Cell Transplant in the Treatment of MM
• HDC is more effective than conventional dose chemotherapy against myeloma – “More is better”
• Autologous or allogeneic (donor) stem cells can restore (eg, “rescue”) marrow function in patients after high dose chemotherapy
• Allogeneic BM or PBSC can provide an additional immune “graft vs. myeloma” effect and eliminates graft contamination by myeloma cells
• Offers opportunity for durable remissions
5 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
Autologous Stem Cell Transplant • Considered standard therapy worldwide • Patients must have acceptable liver, renal, pulmonary,
and cardiac function to be eligible for ASCT • High response rate (results confirmed the value of CR,
nCR, and VGPR on survival) • No overt age limitation • Low mortality (< 1%) (higher mortality in patients > 70
yrs; ~3%) • No donor limitation • Documented survival benefit • Still not curative for most patients • Double transplants are beneficial for some patients
Bensinger, 2009; Kumar, 2009; NCCN, 2010. CR = complete response; nCR = near complete response; VGPR = very good partial response.
6 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
Autologous Stem Cell Transplant
High Dose
Chemotherapy Autologous
Stem Cells
Autologous Stem Cells
-190oC Freezer
Mobilization and
Leukapheresis of Patient
Stem Cells
Cryopreservation of Patient Stem
Cells
Autologous Stem Cells
Thawing and infusion of patient stem cells
Multiple MyelomaResearch Foundation
Powerful thinking advances the cure7
8 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
Stem Cell Collection
• Harvesting sufficient stem cells is necessary for engraftment
• Most centers collect sufficient cells for two transplants
IFM/DFCI 2009 Study Newly Diagnosed MM Pts (SCT candidates)
VRDx3
VRD x 2
VRD x 5
Lenalidomide 12 mos
Melphalan 200mg/m2* +
ASCT
Induction
Consolidation
Maintenance
CY (3g/m2) MOBILIZATION Goal: 5 x106 cells/kg
VRDx3
CY (3g/m2) MOBILIZATION Goal: 5 x106 cells/kg
Randomize, stratification ISS & FISH
Collection
Lenalidomide 12 mos SCT at relapse
MEL 200 mg/m2 if <65 yrs , >65 yrs 140mg/m2
29 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
Role of ASCT in the Era of Novel Therapies
• Up-front ASCT has been the treatment of choice for eligible patients
• Addition of novel agents has improved outcomes with ASCT
• Best CR/VGPR and PFS rates are obtained with novel agents before and/or after ASCT
30 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
31 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
MAINTENANCE AFTER TRANSPLANT THERAPY
32 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
Why Maintenance Therapy?
• Can maintenance therapy: – prevent or delay disease progression? – convert partial responses to complete
responses? – improve overall survival?
33 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
Thalidomide as Post-transplantation Maintenance Therapy
• Thalidomide is effective as maintenance therapy – Longer progression-free survival (PFS) – Significant benefits only in patients with
– < 90% response at randomization – No Chr 13 deletion – Either β2M > 3 mg/L or < 3 mg/L
Response No
Maintenance Pamidronate Pamidronate
+ Thalidomide P Value
CR or VGPR, % 55 57 67 0.001 3-year EFS, % 36 37 52 0.009 OS at 4-year, % 77 74 87 <0.04
Bone events, % 24 21 18 0.4
Attal et al. Blood. 108:3289, 2006
34 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
35 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
!Lenalidomide Maintenance after Autologous Transplantation for Myeloma:!
Final analysis of a prospective randomized study of the Intergroupe Francophone du Myélome !
(IFM 2005-02 trial) !!!!!Michel Attal, Valerie Cances Lauwers , Gerald Marit, Denis Caillot, Thierry Facon, Cyrille Hulin, Philippe Moreau, , Claire Mathiot, Murielle Roussel, Catherine Payen, Hervé Avet-Loiseau, and Jean-Luc Harousseau for the IFM.!
CALGB 100104
A Phase III Randomized, Double-Blind Study of Maintenance Therapy With Lenalidomide (CC 5013) or Placebo Following Autologous Stem Cell
Transplantation for Multiple Myeloma
McCarthy et al
36 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
37 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
38 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
Efficacy Data from Newly Diagnosed Multiple Myeloma Studies
Median PFS/TTP Lenalidomide Arm vs
Control
Disease Progression
Risk Reduction
IFM 2005/021 42 vs 24 months 50% (p<0.00000001)
CALGB 1001042 42 vs 22 months 61% (p<0.0001)
1. Attal et al. ASH 2010 2. McCarthy et al. ASH 2010
39 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
ASH Data on Second Malignancies IFM1 CALGB2
Revlimid
Placebo
Revlimid
Placebo
N 307 307 231 229 Solid 6(2.0%) 1(0.3%) 10(4.3%) 5(2.2%) Hematological 11(3.5%) 2(0.7%) 5(2.2%) 1(0.4%) Total 17(5.5%) 3(1.0%) 15(6.5%) 6(2.6%)
• Among 845 ndMM patients treated with Revlimid there were 45 second malignancies (5.4%), which is within the expected background incidence
• Among 689 ndMM patients treated with placebo there were 11 second malignancies (1.6%), which is below the expected background incidence
1. Attal et al. ASH 2010 2. McCarthy et al. ASH 2010
40 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
Median age, y (no. of pa3ents)
Induc3on therapy
Maintenance dose, dura3on of treatment
Improvement in quality of response
EFS or PFS* OS* Tolerance
HOVON/GMMG: Sonneveld et al46 (2010)
57 (N = 613) PAD
Bortezomib 1.3 mg/m2, biweekly, for 2 y; thalidomide 50 mg/d for 2 y
(A) CR/nCR 50% 3-‐y PFS 3-‐y OS G3 and G4
PNP
≥ VGPR 65% (A) 48% (A) 78% (A) 16%
VAD (B) CR/nCR 38% (B) 42% (B) 71% (B) 7%
≥ VGPR 61% P = .047 P = .048
Maintenance and consolidation studies with bortezomib in combination with thalidomide or prednisone
41 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
Drug Dose/regimen Dura3on of therapy
Impact on
Risk groups Tolerance Level of evidence/
rade of recommenda3on
Comments Quality of response PFS OS
Thalidomide 50* (100) mg/d
Up to 1 y,† no correla3on between dura3on and outcome‡
Yes Yes
Yes, preferen3ally if not part of the induc3on regimen; yes, in meta-‐analysis
No benefit In FISH defined high-‐risk pa3ents§ Possible benefit in pa3ents with abnormal metaphase cytogene3cs and GEP-‐defined high risk
PNP, fa3gue and other limi3ng dose and dura3on of therapy
I/A
Poor tolerance in some (par3cularly elderly) pa3ents; not recommended for pa3ents with FISH defined high-‐risk profile
Lenalidomide
10‖ (5-‐15) mg/d con3nuously or days 1-‐21, every 28 d
Un3l PD or intolerance Yes Yes
Presently shown in one-‐third of studies
Does not overcome nega3ve impact of FISH-‐defined unfavorable cytogene3cs
Few discon3nua3ons because of AEs
I/A
Unprecedented extension of PFS, increase in OS in 1 of 3 studies; usually well tolerated, increased risk for secondary primary malignancies
Bortezomib‖ 1.3 mg biweekly 2 y or un3l PD or intolerance Yes¶ Yes¶ Yes¶
Ac3ve in pa3ents with renal failure and cytogene3c risk groups
PNP grades 3 or 4: 16% (based on intravenous administra3on)
Not applicable
Only comparison between PAD-‐ASCT bortezomib with VAD-‐ASCTthalidoavailable
Summary of benefits and limitations of maintenance therapy with novel drugs for clinical decision making
42 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
Whether lenalidomide maintenance therapy should be routinely offered to patients is controversial among experts. Some consider the marked gain in PFS and the survival advantage observed in one of the 2 studies in younger patients as a strong argument for therapy, whereas others weigh the increased incidence of SPMs as an important risk and so prefer to wait for more mature survival data before making specific recommendations.
IMWG consensus on maintenance therapy in multiple myeloma
Ludwig et al Blood. 2012;119:3003-3015.
43 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
44 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
Allogeneic Stem Cell Transplantation
• High response rate • Graft-versus-myeloma immune effect • High mortality
– 10-20% with non-myeloablative transplants – 20-40% with ablative transplants
• Age limitation (Medicare does not pay for alloTx)
• Donor limitation • Documented long-term survival-20% ? CURE • Limited number of allogeneic SCTs still
performed in US
45 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
46 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
Tandem Autologous or Autologous è Non-Ablative Allograft for MM
Kumar SK, et al. Mayo Clin Proc. 2009;84:1095-‐1110 (revised and updated, June 2010).
FISH • Del 17p • t (14;16) • t (14;20)
GEP • High risk signature
FISH • t (4;14)†
Cytogen3c dele3on 13 or hypodiploidy
PCLI ≥3%
All others including • Hyperdiploidy • t (11;14)§ • t (6;14)
High Risk Standard Risk*‡
*Note that a subset of pa3ents with these factors will be classified as high risk by GEP. †Prognosis is worse when associated with high beta-‐2 M and anemia. ‡LDH >ULN and beta-‐2 M >5.5 may indicate worse prognosis. §t (11; 14) may be associated with plasma cell leukemia.
mSMART 2.0: Classification of Multiple Myeloma
mSMART=Stra3fica3on for Myeloma And Risk-‐adapted Therapy. FISH=Fluorescence in situ hybridiza3on. GEP=gene expression profiling. PCLI=Plasma cell labeling index.
50 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
51 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
Bortezomib Administration: Impact on del(17p13) on PFS and OS.
Neben K et al. Blood 2012;119:940-948
For all patients with del(17p13), the median PFS times (A) and 3-year OS rates (B) in the bortezomib-based treatment arm B were better compared with the standard arm A.
52 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
Clinical Trials of Interest in US involving SCT with or without maintenance
Phase Sponsor Regimen
3 CTN0702 Single Autologous Transplant With or Without Consolidation Therapy Versus Tandem Autologous Transplant With Revlimid Maintenance
2 CTN Revlimid as Maintenance Therapy Post Allogeneic Hematopoietic Cell Transplantation for High-risk Multiple Myeloma
3 DFCI IFM Velcade Revlimid, Dexamethasone induction, consolidation, with or without autologous transplant followed by Revlimid maintenance
2 UCLA Autologous Peripheral Blood Progenitor Cell Transplantation With Velcade Maintenance as Treatment for Intermediate- and Advanced-Stage Multiple Myeloma
3 MSK Revlimid Plus Low-dose Dexamethasone (Rd x 4 Cycles) Then Stem Cell Collection Followed by Randomization to Continued Rd or Stem Cell Transplantation (SCT) Plus Maintenance Revlimid
2 COH Tandem High-Dose Therapy With Melphalan and Total Marrow Irradiation (TMI) With Peripheral Blood Progenitor Cell Support and Revlimid Maintenance
2 FHCRC Tandem Autologous HCT / Nonmyeloablative Allogeneic HCT From HLA-Matched Related and Unrelated Donors Followed by Velcade Maintenance Therapy for Patients With High-Risk Multiple Myeloma
2 FHCRC Velcade and Zolinza as Maintenance Therapy After Autologous Stem Cell Transplant
53 Multiple MyelomaResearch Foundation
Powerful thinking advances the cure
Conclusions • Autologous transplant remains a standard of care
(maintenance may be beneficial)
• New drug combinations for frontline therapy are under evaluation
– Bortezomib, lenalidomide, steroids, liposomal doxorubicin, cyclophosphamide • Improved EFS with transplant • Effect on OS with or without transplant are
unknown
• Allogeneic transplants are still investigational but may be a reasonable option for high-risk or relapsed young patients