Managing Multiple Myeloma
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Dr. David Vesole, Co-Chief, Multiple Myeloma at John Theurer Cancer Center at HackensackUMC presentation at the MMRF Clinical Insights program in April 2012.

Dr. David Vesole, Co-Chief, Multiple Myeloma at John Theurer Cancer Center at HackensackUMC presentation at the MMRF Clinical Insights program in April 2012.

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    Managing Multiple Myeloma Managing Multiple Myeloma Presentation Transcript

    • 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 Myeloma   Research Foundation1 Powerful thinking advances the cure
    • Multiple Myeloma Research Foundation2 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 cord3 Multiple Myeloma Research 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 remissions4 Multiple Myeloma Research 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 5 Multiple Myeloma Research FoundationCR = complete response; nCR = near complete response; VGPR = very good partial response. Powerful thinking advances the cureBensinger, 2009; Kumar, 2009; NCCN, 2010.
    • Autologous Stem Cell Transplant Mobilization and Autologous High Autologous Leukapheresis Stem Dose Stem of Patient Cells Chemotherapy Cells Stem Cells Autologous Cryopreservation Stem Thawing and of Patient Stem Cells infusion of patient Cells -190oC Freezer stem cells6 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • Multiple Myeloma Research Foundation7 Powerful thinking advances the cure
    • Stem Cell Collection•  Harvesting sufficient stem cells is necessary for engraftment•  Most centers collect sufficient cells for two transplants•  Stem cell mobilization options – Growth factors •  Neupogen® (G-CSF), Neulasta® •  Mozobil® – Chemotherapy •  Cytoxan (cyclophosphamide) •  Combination chemotherapy (DCEP, VDT-PACE, CDE)•  Bone marrow RARELY collected (except for donor transplant)8 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • Randomized Trial of Stem Cell Purging by CD34 Selection of PBSC for Myeloma 9 Multiple Myeloma Research Foundation Powerful thinking advances the cureStewart et al, 2001.
    • Autologous Stem Cell Transplant: Conventional Chemotherapy vs High-Dose + ASCT • Two large trials • IFM 90: 200 patients • MRC VII: 400 patients • Both reported: –  Higher response rates, longer remission duration, improved overall survival by 1-2 yrs • Current trials show approximately 30% of patients in continuous remission beyond 10 years10 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • Progression-Free and Overall Survival with novel induction followed by transplant Regimen PFS OS Bort/Dex 55% 3y 81% 3y VAD 45% 3y 77% 3y Bort/Thal/Dex 70% 3y 86% 3y## Thal/Dex 55% 3y 84% 3y## Len/Dex -> Transplant 92% 3y nr Len/Dex No Transplant* 79% 3y nr11 ## Tandem Tx + consolidation nr not randomized Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • Impact of Response on Outcome: OS After 1 or 2 Transplants 1.00 p = .0002 CR VGPR 0.75 PR 0.50 < PR 0.25 Median FU N = 849 0.00 0 1 2 3 4 5 6 7 8 12 Multiple Myeloma Research FoundationPR = partial response; FU = follow-up. Powerful thinking advances the cureHarousseau et al, 2006.
    • 13 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • Single Vs. Double Autografts for MM • Attainment of a CR/nCR is important for survival benefit • Patients in CR/VGPR after 1 autograft do not benefit from second autograft –  Confirmed in 2 trials –  Large US trial (BMT CTN 0702) re- addressing one versus two transplants • Only patients with PR/SD currently receiving a 14 second transplant (outside of a clinical trial)SD = stable disease; CTN = Clinical Trials Network. Multiple Myeloma Research Foundation Powerful thinking advances the cureBensinger, 2009.
    • First Randomized Trial in MM: 1962 •  A controlled trial of urethane treatment in multiple myeloma. •  Randomized 83 patients with treated or untreated multiple myeloma to receive urethane or a placebo consisting of a cherry- and cola-flavoured syrup. •  No difference was seen in objective improvement or in survival in the two treatment groups. In fact, the urethane-treated15 patients died1966; 27: 328-342 Blood earlier Multiple Myeloma Research Foundation Blood. 1966;27:328-42 Powerful thinking advances the cure
    • 16 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • 17 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • Lenalidomide + Low- or High-Dose Dex ECOG E4A03 Lenalidomide High-Dose SCT or Dexamethasone Continue Newly 1:1   Off Study 1:1   (LD) Diagnosed Multiple Myeloma Lenalidomide N = 445 Low-Dose Continue On Dexamethasone Study (Ld) Primary EndpointLenalidomide:  25  mg  daily,  days  1-­‐21  in  a  28-­‐day  cycle   Response at 4 monthsHigh-­‐dose  Dex:  40  mg,  d1-­‐4,  9-­‐12,  17-­‐20  (total  480  mg)    Low-­‐dose  Dex:  40  mg,  d1,  8,  15,  22  (total  160  mg)  Aspirin:  325  mg   18Rajkumar SV, et al. Lancet Oncology, 11: 29 - 37, 2010 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • Landmark Analysis 431 patients alive! at 4 cycles! Off therapy ! Primary therapy ! at 4 cycles! beyond 4 cycles! N = 183! N = 248! ! ! No transplant! Transplant ! Rd! RD! N = 93 ! N = 90 ! N = 140! N = 108! (median age: 69)! (median age: 57)! (median age: 66)! (median age: 65)! ! ! 19 Multiple Myeloma Research Foundation Powerful thinking advances the cureRajkumar et al, 2010.
    • E4A03: OS According to Transplant or No Further Treatment at 4 Cycles E4A03: Primary Therapy Beyond 4 Cycles ASCT after 4 cycles LD or Ld 100 Ld 100 LD Ld Survival Probability 80 80Survival Probability LD 60 60 79% 92% 40 3-yr OS rate 40 3-yr OS rate 20 20 P=NS P=NS 0 0 0 6 12 18 24 30 36 0 6 12 18 24 30 36 Time (mo) Time (mo) Response ≥ PR, % 91 CR (IF-, serum/urine), % 2220 Multiple Myeloma Research Foundation CR + VGPR, % 56 Powerful thinking advances the cure
    • Outcomes in pts Age <65 Progression Free Survival Overall Survival21 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • Survival: ASCT vs Ld/LD 1-yr mortality No Early SCT: Early SCT Overall 0.94 (0.91, 0.96) 0.99 (0.97, 1.00) Age <65 0.94 (0.90, 0.98) 0.99 (0.96, 1.00) 65≤ Age <70 0.96 (0.91, 1.00) 0.94 (0.83, 1.00) Age ≥70 0.92 (0.88, 0.97) 1.00 (1.00, 1.00)22 Multiple Myeloma Research Foundation Siegel et al Blood 2010 Powerful thinking advances the cure
    • Response, n (%) All pts (N=66) Phase II (N=35) CR 19 (29) 13(37) nCR 7 (11) 7 (20) VGPR 18 (27) 6 (17) PR 22 (33) 9 (26) CR+nCR 26 (39) 20 (57) (90% CI) (29, 50) (42, 71) CR+nCR+VGPR 44 (67) 26 (74) (90% CI) (56, 76) (59, 86) At least PR 66 (100) 35 (100) (90% CI) (96, 100) (92, 100)•  Response improvement seen in 42/56 pts (75%) from C4–8 and 20/38 pts (53%) beyond C8•  Median (range time to best overall response) was 2.1(0.6,20) mo•  31 pts (47%) have proceeded to ASCT 23 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • 24 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • Upfront Regimens for Multiple Myeloma Regimen   ORR   VGPR   CR   Reference   Len/Dex   91   56   22   Rajkumar   VRD   100   74   44   Richardson   VCD   91   60   39   Reeder   VTD   90   62   19   Cavo   VCRD   96   39   32   Kumar   Note:  some  of  these  are  a-er  induc3on  followed  by  transplant  and  others  maximal  response.   ORR=overall  response  rate.   VCD=bortezomib/cyclophosphamide/dexamethasone. VGPR=very  good  par3al  response.   VTD=bortezomib/thalidomide/dexamethasone.   CR=complete  response.   VCRD=bortezomib/cyclophosphamide/lenalidomide/25 VRD=bortezomib/lenalidomide/dexamethasone. dexamethasone.   Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • C:UsersDavidPicturesMy Pictures London 2011IMG_1279.JPG26 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • BMT  CTN  0702   MEL  200   MEL 200 Lenalidomide MEL  200   VRD x 4 Lenalidomide MEL  200   Lenalidomide27 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • IFM/DFCI 2009 Study Newly Diagnosed MM Pts (SCT candidates) Randomize, stratification ISS & FISH VRDx3 Induction VRDx3 CY (3g/m2) MOBILIZATION CY (3g/m2) Goal: 5 x106 cells/kg Collection MOBILIZATION Goal: 5 x106 cells/kg Melphalan 200mg/m2* + VRD x 5 ASCT Consolidation VRD x 2Lenalidomide 12 mos Maintenance Lenalidomide 12 mos SCT at relapse28 MEL 200 mg/m2 if <65 yrs , Multiple Myeloma Research Foundation >65 yrs 140mg/m2 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 ASCT29 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • 30 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • MAINTENANCE AFTER TRANSPLANT THERAPY31 Multiple Myeloma Research 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?32 Multiple Myeloma Research 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 No PamidronateResponse Pamidronate P Value Maintenance + ThalidomideCR or VGPR, % 55 57 67 0.0013-year EFS, % 36 37 52 0.009OS at 4-year, % 77 74 87 <0.04Bone events, % 24 21 18 0.433 Multiple Myeloma Research Foundation Powerful thinking advances the cureAttal et al. Blood. 108:3289,
    • 34 Multiple Myeloma Research 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.! A Phase III Randomized, Double-Blind Study of Maintenance Therapy With Lenalidomide (CC 5013) or Placebo Following Autologous Stem Cell Transplantation for Multiple Myeloma CALGB 10010435 Multiple Myeloma Research Foundation McCarthy et al Powerful thinking advances the cure
    • 36 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • 37 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • Efficacy Data from Newly Diagnosed Multiple Myeloma Studies Median PFS/TTP Disease Lenalidomide Arm vs Progression Control 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 20102.  McCarthy et al. ASH 2010 38 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • ASH Data on Second Malignancies IFM1 CALGB2 Revlimid Placebo Revlimid PlaceboN 307 307 231 229Solid 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 incidence1.  Attal et al. ASH 2010 392.  McCarthy et al. ASH 2010 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • Maintenance and consolidation studies with bortezomib in combination with thalidomide or prednisone Median   Maintenance   Improvement   Induc3on   age,  y  (no.   dose,  dura3on   in  quality  of   EFS  or  PFS*   OS*   Tolerance   therapy   of  pa3ents)   of  treatment   response   (A)  CR/nCR   G3  and  G4   3-­‐y  PFS   3-­‐y  OS   50%   PNP  HOVON/ Bortezomib  1.3  GMMG:   mg/m2,   57  (N  =  Sonneveld   PAD   biweekly,  for  2   613)  et  al46   y;  thalidomide   ≥  VGPR  65%   (A)  48%   (A)  78%   (A)  16%  (2010)     50  mg/d  for  2  y     (B)  CR/nCR   VAD   (B)  42%   (B)  71%   (B)  7%   38%   ≥  VGPR  61%   P  =  .047     P  =  .048     40 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • Summary of benefits and limitations of maintenance therapy with novel drugs for clinical decision making Impact  on   Level  of  evidence/ Dura3on  of   Quality  of  Drug   Dose/regimen   PFS   OS   Risk  groups   Tolerance   rade  of   Comments   therapy   response   recommenda3on   No  benefit  In   Poor  tolerance   FISH  defined   in  some   high-­‐risk   Yes,   (par3cularly   Up  to  1  y,†  no   pa3ents§   PNP,  fa3gue  and   preferen3ally  if   elderly)   correla3on   Possible  benefit   other  limi3ng   not  part  of  the   pa3ents;  not  Thalidomide   50*  (100)  mg/d     between   Yes   Yes   in  pa3ents  with   dose  and                            I/A   induc3on   recommended   dura3on  and   abnormal   dura3on  of   regimen;  yes,  in   for  pa3ents   outcome‡   metaphase   therapy   meta-­‐analysis   with  FISH   cytogene3cs  and   defined  high-­‐ GEP-­‐defined  high   risk  profile   risk     Unprecedente d  extension  of   Does  not   PFS,  increase  in   10‖  (5-­‐15)  mg/d   overcome   OS  in  1  of  3   Presently  shown   Few   con3nuously  or   Un3l  PD  or   nega3ve  impact   studies;  usually  Lenalidomide   Yes   Yes   in  one-­‐third  of   discon3nua3ons                            I/A   days  1-­‐21,  every   intolerance   of  FISH-­‐defined   well  tolerated,   studies   because  of  AEs   28  d     unfavorable   increased  risk   cytogene3cs   for  secondary   primary   malignancies     Only   comparison   Ac3ve  in  pa3ents  PNP  grades  3  or   between  PAD-­‐ 2  y  or  un3l  PD  or   with  renal  failure  4:  16%  (based  on   ASCT  Bortezomib‖   1.3  mg  biweekly   Yes¶   Yes¶   Yes¶   Not  applicable   intolerance   and  cytogene3c   intravenous   bortezomib   41 Multiple Myeloma risk  groups   administra3on)   with  VAD-­‐ Research Foundation ASCTthalidoava Powerful thinking advances the cure ilable  
    • IMWG consensus on maintenance therapy in multiple myelomaWhether lenalidomide maintenance therapyshould be routinely offered to patients iscontroversial among experts. Some consider themarked gain in PFS and the survival advantageobserved in one of the 2 studies in youngerpatients as a strong argument for therapy,whereas others weigh the increased incidence ofSPMs as an important risk and so prefer to waitfor more mature survival data before makingspecific recommendations. 42 Multiple Myeloma Research Foundation Ludwig et al Blood. 2012;119:3003-3015. Powerful thinking advances the cure
    • 43 Multiple Myeloma Research 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 still44 performed in US Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • 45 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • Tandem Autologous or Autologous è Non-Ablative Allograft for MM Intent to Treat N = 80 N = 82 46 Multiple Myeloma Research Foundation Powerful thinking advances the cureBruno et al, 2007.
    • BMT CTN 0102 Study Schema 1st Autologous Transplant N=710 No Sibling Donor Sibling Donor Auto-Auto Auto-Allo N=484 N=226 High Standard Standard High Risk Risk Risk Risk N=48 N=436 N=189 N=37 Main groups compared47 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • Survival Outcomes after the First Transplant: Auto-Auto vs. Auto-Allo: Intent-to-treat analysis 100 Progression-free Survival Overall Survival 100 Auto/Auto, 80% @ 3yr 90 Auto/Auto, 46% @ 3yr 90 80 80 Auto/Allo, 77% @ 3yr 70 70 Probability, % 60 60 50 50 Auto/Allo, 43% @ 3yr 40 40 30 30 20 20 10 10 p-value = 0.67 p-value = 0.19 0 0 Months 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 48 48# at risk: 48 436 424 406 395 370 348 305 107 79 Multiple Myeloma Research FoundationAuto/Auto 436 395 348 292 242 213 178 54 189 183 167 160 156 143 124 43 27 Powerful thinking advances the cure 42 Mp10_5.ppt
    • mSMART 2.0: Classification of Multiple Myeloma High  Risk   Intermediate Risk Standard  Risk*‡   FISH   FISH   All  others   •  Del  17p   •  t  (4;14)†   including     •  t  (14;16)   • Hyperdiploidy   •  t  (14;20)   Cytogen3c   •  t  (11;14)§     dele3on  13  or   •  t  (6;14)   GEP   hypodiploidy         •  High  risk     signature   PCLI  ≥3%     mSMART=Stra3fica3on  for  Myeloma  And  Risk-­‐adapted  Therapy.   FISH=Fluorescence  in  situ  hybridiza3on.   GEP=gene  expression  profiling.   PCLI=Plasma  cell  labeling  index.   *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.  49 §t  (11;  14)  may  be  associated  with  plasma  cell  leukemia.   Multiple Myeloma Research Foundation Powerful thinking advances the cure Kumar  SK,  et  al.  Mayo  Clin  Proc.  2009;84:1095-­‐1110  (revised  and  updated,  June  2010).      
    • 50 Multiple Myeloma Research Foundation Powerful thinking advances the cure
    • Bortezomib Administration: Impact on del (17p13) on PFS and OS. 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.51 Multiple Myeloma Research Foundation Powerful thinking advances the cure Neben K et al. Blood 2012;119:940-948
    • Clinical Trials of Interest in US involving SCT with or without maintenancePhase Sponsor Regimen Single Autologous Transplant With or Without Consolidation Therapy Versus Tandem 3 CTN0702 Autologous Transplant With Revlimid Maintenance Revlimid as Maintenance Therapy Post Allogeneic Hematopoietic Cell Transplantation 2 CTN for High-risk Multiple Myeloma Velcade Revlimid, Dexamethasone induction, consolidation, with or without autologous 3 DFCI IFM transplant followed by Revlimid maintenance Autologous Peripheral Blood Progenitor Cell Transplantation With Velcade 2 UCLA Maintenance as Treatment for Intermediate- and Advanced-Stage Multiple Myeloma Revlimid Plus Low-dose Dexamethasone (Rd x 4 Cycles) Then Stem Cell Collection 3 MSK Followed by Randomization to Continued Rd or Stem Cell Transplantation (SCT) Plus Maintenance Revlimid Tandem High-Dose Therapy With Melphalan and Total Marrow Irradiation (TMI) With 2 COH Peripheral Blood Progenitor Cell Support and Revlimid Maintenance Tandem Autologous HCT / Nonmyeloablative Allogeneic HCT From HLA-Matched 2 FHCRC Related and Unrelated Donors Followed by Velcade Maintenance Therapy for Patients With High-Risk Multiple Myeloma52 Multiple Myeloma 2 FHCRC Velcade and Zolinza as Maintenance Therapy After Autologous Stem Cell Transplant Research 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 53 Multiple Myeloma Research Foundation Powerful thinking advances the cureEFS = event-free survival.
    • 54 Multiple Myeloma Research Foundation Powerful thinking advances the cure