Multiple Myeloma: Miami, FL Current Treatment Paradigms and Future Directions December 18, 2009

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1 Welcome to Master Class for Oncologists Miami, FL December 18, 29 Session 5: 11: AM - 11:45 AM Multiple Myeloma: Current Treatment Paradigms and Future Directions Speaker: Kenneth C. Anderson, MD Chief, Division of Hematologic Neoplasia Dana-Farber Cancer Institute Kraft Family Professor of Medicine Harvard Medical School Presenter Disclosure Information Criteria for Diagnosis of Myeloma The following relationships exist related to this presentation: Dr Anderson receives consultant and research honoraria from Celgene Corporation, Novartis Pharmaceuticals Corporation, and Millennium Pharmaceuticals. Off Label/Investigational Discussion In accordance with Pri-Med Institute policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. MGUS < 3 g M spike < 1% PC AND Smoldering MM 3 g M spike OR 1% PC No anemia, bone lesions, normal calcium and kidney function Active MM 1% PC M spike + AND Anemia, bone lesions, high calcium, or abnormal kidney function Kyle RA. N Engl J Med 22;346: Integration of Novel Therapy Into Myeloma Management Multiple Myeloma: Current Treatment (USA) Adapted from National Comprehensive Cancer Network Practice Guidelines (29), lenalidomide, thalidomide, doxil Diagnosis Survival 3-5 yrs Survival < 6 mos without Rx ~12, deaths per yr Relapsed Disease Transient response Survival 1-3 yrs Relapsed/ Refractory Disease Shorter TTP Survival 6-9 mos Treatment of relapsed/refractory MM (single agent/combinations) Induction/first-line therapy Transplant/maintenance Initial Therapy Cyclophosphamide Melphalan, prednisone +/- thalidomide, +/- bortezomib, +/- lenalidomide Thalidomide + dex + dex combos + liposomal doxorubicin Lenalidomide + dex Non- Transplant Candidate Transplant Candidate Salvage Therapy: Repeat primary therapy (if relapse > 6 mos) Cyclophosphamide Etoposide, dex, cytarabine, cisplatin Thalidomide +/- dex Lenalidomide +/- dex +/- dex combos (eg, liposomal doxorubicin) Other novel therapies (clinical trials) Stem cell harvest, subsequent auto SCT (single vs double) +/- maintenance (thalidomide, bortezomib, lenalidomide) Investigational therapy (eg, allo-sct) 1

2 Integration of Novel Therapy Into Myeloma Management Newly Diagnosed Myeloma in Elderly Six FDA/EMEA drug approvals in last 5 years Median survival prolonged from 3-7 years (especially in younger patients) Three phase III combination trials ongoing for FDA approval An 85-year-old woman presents with fatigue, weakness, and lower back pain. On exam her BP is 1/6 with P 14. She is found to be confused with no focal neurologic deficits. Laboratory studies show: Hgb: 8. WBC: 43 Platelet: 126, Creatinine: 3. Albumin: 2.8 Calcium: 1. SPEP: 4.1 gm IgA kappa monoclonal protein 24-hour urine: Total protein 6 mg (45 mg BJ kappa) Bone marrow biopsy: 8% plasma cells Brenner, et al. Blood. 28:111: ; Kumar, et al. Blood. 28;111: Skeletal survey: shows diffuse osteoporosis with lytic lesions in multiple vertebral bodies in thoracic and lumbosacral spine, as well as humeri and femurs. MRI confirms patchy areas of marrow replacement diffusely. Newly Diagnosed Myeloma in Elderly: What would you recommend for initial therapy? 1. Melphalan prednisone 2. Melphalan prednisone thalidomide 3. Melphalan prednisone lenalidomide 4. Melphalan prednisone bortezomib 5. Melphalan prednisone bortezomib thalidomide IFM 1/1 Study Protocol: In Newly Diagnosed Pts > 75 yrs with MM 12 cycles MP every 6 weeks Melphalan.2 mg/kg/d Day 1-4 Prednisone 2 mg/kg/d Day 1-4 Double Blind + Clodronate was given to all pts. No anticoagulant prophylaxis was planned. Placebo 2 caps 5 mg/d 18 months, continuously Thalidomide 2 caps 5 mg/d 18 months, continuously Hulin C, et al. J Clin Oncol. 27;25(18 suppl):441s. Abstract 81. Response to Treatment: Best Response at 12 months Results 232 Patients: Intent to Treat Analysis At least PR (5%) At least VGPR (9%) Complete Remission 8% 7% 1% 23% 31% 61% MP-Thalidomide MP-Placebo P =.1 Progression free survival Time to progression Overall survival MPT MP log rank 24.1 mo 19 mo P =.1 ( ) ( ) 27 mo 2.9 mo P =.9 ( ) ( ) 45.3 mo 27.7 mo P =.33 (38.3-not ( ) reached) Hulin C, et al. J Clin Oncol. 27;25(18 suppl):441s. Abstract. 81. Hulin C, et al. J Clin Oncol. 27;25(18 suppl):441s. Abstract

3 Phase I/II Trial of MP Plus Lenalidomide (MPR) for Newly Diagnosed MM MPR vs MPT: Response Rate Patients > 65 years of age (median age: 71 years; range, years), newly diagnosed, symptomatic disease Maximum 9 cycles of: Lenalidomide 5-1 mg/day for 21 days, every 4-6 weeks Melphalan mg/kg for 4 days, every 4-6 weeks Prednisone 2 mg/kg for 4 days, every 4-6 weeks Melphalan (mg/kg/day) Lenalidomide (mg/day) Patients Cohort Cohort Cohort Cohort *Best response. MPR (N = 21)* Cohort 3 (.18-1) 5 48% 3 24% 24% 25 33% 19% % CR VGPR PR MR SD/PD MPT (N = 129)* Historical Control 16% 37% 21% 4% 5% 13% CR VGPR PR MR SD/PD Palumbo A, et al. J Clin Oncol. 26;24(18S):7518. Reproduced with permission from Palumbo A, et al. Presented at: American Society of Hematology. 26 Annual Meeting. Abstr. 8; Palumbo A, et al. Lancet. 26;367(9513): VISTA: VELCADE as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone VISTA Initial Analysis: Superior Responses and Duration of Response with VMP vs MP Randomized, international, phase III trial of VMP vs MP in previously untreated MM patients who were not candidates for HDT-ASCT Patients: Symptomatic multiple myeloma/end organ damage with measurable disease 65 yrs or < 65 yrs and not transplant-eligible; KPS 6% R A N D O M I Z E VMP Cycles mg/m 2 IV: days 1,4,8,11,22,25,29,32 Melphalan 9 mg/m 2 and prednisone 6 mg/m 2 days 1-4 Cycles mg/m 2 IV: days 1,8,22,29 Melphalan 9 mg/m 2 and prednisone 6 mg/m 2 days x 6-week cycles (54 weeks) in both arms MP Cycles 1-9 Melphalan 9 mg/m 2 and prednisone 6 mg/m 2 days 1-4 San Miguel, et al, ASH. 28 Abstract 65. Primary Endpoint: TTP Secondary Endpoints: CR rate, ORR, TTR, DOR, PFS, TNT, OS, QoL (PRO) VMP was significantly superior for all efficacy endpoints Substantial CR rate in this patient population; more than 3% of patients aged 75 years VMP MP p-value Best response by EBMT criteria Overall response rate (ORR), % <1-3 Complete response (CR)* 3 4 <1-3 Median time to first response*, months <1-3 Median time to CR* <1-3 Median duration of response (DOR), months All responders Patients achieving CR *Medians shown for responding patients; p-values based on total study population; CR by International Uniform Response Criteria for VMP vs MP was 33% vs 4%, p<1-3 San Miguel et al. N Engl J Med. 28; 359: San Miguel et al, ASH 28 Abstr 65 Time to progression: ~52% reduced risk of progression with VMP OS: Confirmed survival benefit with VMP ~36% reduced risk of death on VMP Patients without event (%) VMP: 24. months (83 events) MP: 16.6 months (146 events) HR =.483, P <.1 VMP MP Time (months) Number of patients at risk: VMP: MP: San Miguel, et al. N Engl J Med. 28; 359:96-17; EHA 28;11. Abstract 473. San Miguel, et al, ASH 28. Abstract 65. Subjects w/o event (%) Median follow-up=25.9 months 3 VMP: median OS not reached (75 deaths); 3-year OS rate=72% 2 MP: median OS not reached (111 deaths); 3-year OS rate=59% 1 HR =.644, P= Time (months) 43% of MP patients who received subsequent therapy received bortezomib upon progression Patients received bortezomib > 4 cycles: OS at 1 & 2 years: 98.5% & 89% San Miguel, et al, ASH 28. Abstract 65. VMP MP 3

4 VMP vs VMPT in Elderly Newly Diagnosed Patients Responses 393 patients (older than 65 years) randomized from 58 Italian centers Patients: Symptomatic multiple myeloma/end organ damage with measurable disease 65 yrs or < 65 yrs and not transplant-eligible; creatinine 2.5 mg/dl R A N D O M I Z E VMP Cycles mg/m 2 IV: days 1,8,15,22* Melphalan 9 mg/m 2 and prednisone 6 mg/m 2 days x 5-week cycles in both arms VMPT Cycles mg/m 2 IV: days 1,8,15,22* Melphalan 9 mg/m 2 and prednisone 6 mg/m 2 days 1-4 Thalidomide 5 mg/day continuously NO MAINTENANCE Until relapse MAINTENANCE 1.3 mg/m 2 IV: days 1,15 Thalidomide 5 mg/day continuously VMPT (N=177) VMP (N=177) P-value CR 39% 21% <.1 > VGPR 55% 45% <.1 3 years 8% 78%.56 3 years 74% 7%.28 3 years 88% 87%.75 * 61 VMP patients and 7 VMPT patients were treated with biweekly infusions of bortezomib Palumbo, et al. ASH 28. Abstract 652. Palumbo, et al ASH 28. Abstract Newly Diagnosed Myeloma in Elderly What would you recommend for initial therapy? 1. Melphalan prednisone 2. Melphalan prednisone thalidomide 3. Melphalan prednisone lenalidomide 4. Melphalan prednisone bortezomib 5. Melphalan prednisone bortezomib thalidomide Newly Diagnosed Myeloma in Transplant Candidate A 54-year-old plumber develops acute lower back pain. He has been in excellent health and his exam is remarkable only for tenderness in the lumbosacral spine. Laboratory studies show: Hgb: 9.2 WBC: 62 Platelets: 186, Creatinine: 2.6 B2M: 5.6 Albumin: 3.8 SPEP: 4.1 gm IgG kappa monoclonal protein 24-hour urine: Total protein 95 mg (BJ kappa 7) Bone marrow biopsy: 6% plasma cells. Skeletal survey shows compression fracture at L1 with multiple small lytic lesions in the skull and right humerus. MRI of the LS spine confirms collapse of L1 with patchy areas of marrow replacement. Use of Dexamethasone With or Without Thalidomide in Frontline Therapy 2. Newly Diagnosed Myeloma in Transplant Candidate What would you recommend as initial therapy? 1. Thalidomide dexamethasone 2. Lenalidomide dexamethasone 3. dexamethasone 4. Vincristine adriamycin dexamethasone 5. Lenalidomide bortezomib dexamethasone ECOG E1A: Phase III, randomized, controlled trial Newly diagnosed, untreated, symptomatic MM (N = 27) Thal/Dex arm Thalidomide 2 mg/day PO + Dexamethasone 4 mg/day on Days 1-4, 9-12, 17-2 (n = 13) Dex alone arm Dexamethasone 4 mg/day on Days 1-4, 9-12, 17-2 (n = 14) Repeated monthly for 4 mos CR/PR/ Stable Stem-cell transplant or continue therapy at physician s discretion Stop therapy Any progression Note: Use of prophylactic anticoagulant not required Rajkumar SV, et al. J Clin Oncol. 26;24(3):

5 Use of Dexamethasone With or Without Thalidomide in Frontline Therapy ECOG Phase III Response after 4 cycles P =.2 63% 41% Response* ThaI/Dex (n = 99) Dex alone (n = 1) 73% 5% Corrected Response 4% % Complete Response DVT Gr > 3 Grade 3 or 4 toxicity ThaI/Dex (n = 12) Dex alone (n = 12) 17% 3% 7% 4% 34% 18% 7% 11% Neuropathy All Gr > 4 Gr > 3 toxicity Deaths ECOG Phase III trial of lenalidomide plus high-dose dexamethasone vs lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma R A N D O M I Z A T I O N Len + Dex (RD) x4 cycles Len + Low dose Dex (Rd) x 4 cycles Less than PR Thal + Dex x 4 4 months Pts can go off study CR/PR/Stable 445 pts * in serum M protein and urine M protein in serum M protein (no available urine M protein) Rajkumar SV, et al. ASH 27. Abstract 74. ECOG Phase III Response to Therapy ECOG Phase III Serious Adverse Events: Non-Hematologic Arm A Arm B P-value Response in 4 cycles ( PR) 79% 68%.8 VGPR within 4 cycles 42% 24% <.8 Toxicity RD Rd Fishers Exact Type (Grade 3+) P-value DVT/PE 26% 12% <.1 Infection/Pneumonia 16% 9%.43 Any non-hem toxicity (Grade 3) 66% 8% <.1 Best Overall Response ( PR) 81% 7%.9 VGPR 51% 4%.4 CR (IF-)* 17% 14%.428 Toxicity of any type (Grade 4) 21% 14% <.1 RD = Len + Dex; Rd = Len + low dose Dex Rajkumar, et al. ASH 28. Rajkumar, et al, ASH 28. ECOG Phase III Overall Survival ECOG Phase III Results of Primary Therapy beyond 4 cycles with Rd Median Follow up: 12.5 months RD = Len + Dex; Rd = Len + low dose Dex DMC closed study; immediate crossover to Rd was mandated Survival Probability % 87% Rd RD Primary Rd (n = 14) Overall Response Rate 91% CR* (IF-) 22% CR + VGPR 57% 2 P<.1 Grade 3 non-hem toxicity** 26% Time in Months RD = Len + Dex; Rd = Len + low dose Dex RD Rd Numbers at Risk *measured in serum or urine ** 52% with RD Rajkumar. et al, ASH 28. Rajkumar, et al. ASH 28. 5

6 IFM Trial VAD vs Vel-Dex Induction Pre-transplant Response To Induction Evaluable Patients Randomization Stratified by β 2 -microglobulin level (> 3 mg/l vs 3 mg/l) and presence of chromosome 13 abnormalities (by FISH analysis) VAD (A1+A2) N = 21 Vel-Dex (B1+B2) N = 214 P-value A1 A2 B1 B2 VAD x 4 VAD x 4 Induction Vel-Dex x 4 Vel-Dex x 4 Melphalan 2mg/m 2 + ASCT DCEP x 2 Consolidation DCEP x 2 Melphalan 2mg/m 2 + ASCT Transplant 1 Melphalan 2mg/m 2 + ASCT Melphalan 2mg/m 2 + ASCT CR CR+nCR > VGPR > PR MR+SD PD Death 1.4% 6.7% 16% 65% 28% 4.3% 2.9% 6.1% 15% 39% 82% 13% 4.7%.5% <.1 <.1 Harousseau JL, et al. ASH 27. Abstract 45. Second ASCT or RIC allo if < VGPR Harousseau, et al. ASH 28. Response by IRC assessment Impact of Cytogenetics on Post-Induction Responses ( VGPR) Response to First ASCT Evaluable Patients Chr 13 (by FISH) deletion β2m>3/δ13 normal/ne t(4;14) and/or Δ (17p) deletion normal/ne VAD (A1+A2) n=13 15% n=139 15% n=65 15% n=29 17% n=213 15% Vel-Dex (B1+B2) n=11 47% n=139 3% n=63 43% n=4 4% n=2 37% P-value < <.1 CR CR + ncr > VGPR > PR MR/SD/PD No ASCT VAD (A1+A2) N = 213 9% 19% 38% 79% 4% 17% Vel-Dex (B1+B2) N = % 37% 57% 84% 3% 13% P-value.16 <.1.3 NS Harousseau, et al, ASH 28. Harousseau, et al, ASH 28. and Lenalidomide Therapy IFM/DFCI 29 Study Newly Diagnosed MM Pts (SCT Candidates) Lenalidomide induces caspase 8 mediated apoptosis of MM cells in BM in vitro and in vivo; Dex (caspase 9) enhances response (2) RVD x 3 Randomize Induction RVD x 3 Synergistic MM cell toxicity of lenalidomide with bortezomib in vitro and in vivo (dual apoptotic signaling) CY (3g/m2) MOBILIZATION Goal: 5 x1 6 cells/kg Collection CY (3g/m 2 ) MOBILIZATION Goal: 5 x1 6 cells/kg Phase I-II trials show that majority (58%) of patients refractory to either agent alone respond to the combination. Melphalan 2mg/m 2 * + ASCT Consolidation RVD x 5 Phase I-II trials show that 1% of patients with newly diagnosed MM respond, with 74% CR/VGPR. Richardson et al, ASH 27 and 28. Richardson PG, et al. ASCO 28. Abstract 852. RVD x 2 Revlimid 18 mos Maintenance Revlimid 18 mos SCT at relapse 6

7 Phase II: Evolution Study Design Enrollment to Phase II portion of the study is ongoing. 2. Newly Diagnosed Myeloma in Transplant Candidate What would you recommend as initial therapy? RANDOMIZATION VDR (Vc, Dex, Rev) Up to eight 21-day cycles VDCR (Vc, Dex, Cy, Rev) Up to eight 21-day cycles VDC (Vc, Dex, Cy) Up to eight 21-day cycles Induction Eligible patients could undergo ASCT after 4 cycles. Vc Up to four 42-day cycles Maintenance 1. Thalidomide dexamethasone 2. Lenalidomide dexamethasone 3. dexamethasone 4. Vincristine adriamycin dexamethasone 5. Lenalidomide bortezomib dexamethasone Kumar, et al. ASH 28. Abstract 93. MM-9 and MM-1: Two Phase III Trials of Len + Dex in Relapsed/Refractory MM 3. Myeloma Salvage Therapy A 56-year-old woman with myeloma underwent thalidomide dexamethasone induction therapy followed by high dose melphalan and autologous stem cell transplantation. Although she achieved complete response, recurrent monoclonal protein and bone marrow plasmacytosis were observed 9 months post-transplant. Appropriate salvage therapies include: 1. Lenalidomide dexamethasone 2. dexamethasone 3. pegylated doxorubicin 4. All of the above North American MM-9 (48 centres USA/Canada): Weber International MM-1 (51 centres Europe/Australia/Israel): Dimopoulos Inclusion criteria 3 prior therapies No Dex resistance Normal hepatic function Sr. Cr. < 2.5mg/dL Len 25 mg days 1 21 Placebo days Dex 4 mg, days 1 4, 9 12, courses Placebo days 1 28 Dex 4 mg, days 1 4, 9 12, 17 2 Continue until PD Same, except Dex days 1 4 Primary endpoint: TTP (by Bladé criteria) Secondary endpoints: OS, RR, safety, 1st skeletal-related event, PS Additional stratification by β 2 M ( 2.5 mg/ml vs > 2.5 mg/ml), prior transplant ( vs 1), and prior MM treatment regimens (1 vs > 1) Dimopoulos M, et al. N Engl J Med. 27;357(21): Weber DM, et al. N Engl J Med. 27;357(21): MM-9/MM-1: Response & Duration of Response MM-9/MM-1: Time to Progression Best response, n (%) MM-9 MM-1 Len/Dex (n = 176) Placebo/Dex (n = 175) Len/Dex (n = 176) Placebo/Dex (n = 175) Overall response 18 (61)* 35 (2) 16 (6)* 42 (24) Complete response 25 (14)* 24% 1 (1) 2% 28 (16)* 25% 6 (3) 5% Near complete response 18 (1) 2 (1) 15 (9) 3 (2) Partial response 65 (37) 32 (18) 62 (35) 33 (19) 1 MM p<.1* Time to progression (months) 1 MM p<.1* Len/Dex, No prior Thal Len/Dex, Prior Thal Placebo/Dex, No prior Thal Placebo/Dex, Prior Thal Time to progression (months) Stable disease 54 (31) 12 (58) 53 (3) 97 (55) Progressive disease 5 (3) 25 (14) 3 (2) 25 (14) Not evaluable 1 (6) 14 (8) 14 (8) 11 (6) Duration of Response 16 Months 5 Months 17 Months 8 Months *P-value <.1 for comparison with Placebo/Dex counterpart, as tested with continuity-corrected Pearson chi square test. Dimopoulos M, et al. N Engl J Med. 27;357(21): Weber DM, et al. N Engl J Med. 27;357(21): Median time to progression (months) Len/Dex Placebo/Dex P-value* MM <.1 MM <.1 *`P-value from log-rank test. Dimopoulos M, et al. N Engl J Med. 27;357(21): Weber DM, et al. N Engl J Med. 27;357(21):

8 Overall Survival (Pooled MM9/1) Phase 3 APEX Trial: vs Dexamethasone for Relapsed MM *p=.21 Len/Dex, median 35 months Placebo/Dex, median 31 months (includes 47% of patients who crossed over to receive Lenalidomide) Overall survival (months) International, randomized, open-label study in relapsed or refractory MM (N = 669) comparing single agent bortezomib to HD dex Endpoints Primary: TTP Secondary: survival, response rate (RR) and duration, time to skeletal events (TSE), grade 3 infection, safety Companion crossover study available to pts progressing on HD dex *P-value from log rank test. Data up to January 27. Anagnostopoulos MA, et al. Haematologica. 27;92(suppl 2):171. Abstract PO-661. Richardson PG, et al. N Engl J Med. 25;352(24): Updated APEX Efficacy Data: Response Rates Time to Progression (N = 669) ORR with improved from 38% to 43% 78% improvement in median TTP with bortezomib Updated analysis Primary analysis P <.1 P <.1 6 Response % % 27% PR 7% ncr 9% CR 38% 25% PR 7% ncr 6% CR 18% <1% ncr 16% PR <1% CR Dex Median TTP: bortezomib 6.2 mos vs dexamethasone 3.5 mos Richardson PG, et al. Blood. 27;11(1): Richardson PG, et al. N Engl J Med. 25;352(24): Updated Results of APEX Trial Alkaline Phosphatase Levels During Treatment in APEX SURVIVAL Overall and 1-Year Survival Alkaline phosphatase (ALP) and response in 315 pts 29.8 mos 23.7 mos P =.272 8% 6% 4% 2% % > 25% ALP < 25% ALP CR/PR, P <.1 PR, P <.1 CR, P =.1476 A 25% increase in ALP from baseline to wk 6 was strongly associated with CR + PR and longer TTP. Superior survival despite > 62% of HD dex pts crossing over to bortezomib 1-yr survival rate: 8% vs 67%; P =.2 Markers of osteoblastic activation (such as ALP) during bortezomib treatment may predict response and response duration in pts with MM. Richardson PG, et al. Blood. 27;11(1): Zangari M, et al. Br J Haematol. 25;131(1):

9 Pegylated Doxorubicin- Study Time to Progression R A N D O M I Z A T I O N BZ 1.3 mg/m 2 D 1, 4, 8, 11 every 21d for up to 8 cycles 646 pts: Relapsed and/or refractory MM Stratifications: 1. B 2 M ( 2.5, > 2.5 but 5.5, > 5.5) 2. Response vs PD on initial therapy Treated until: -PD - Unacceptable toxicity - 8 cycles administered (continued if MM still responding) BZ as above + Pegylated liposomal doxorubicin 3 mg/m 2 on D4 Orlowski RZ, et al. J Clin Oncol. 27;25(25): Primary endpoint: TTP Secondary: OS, ORR, safety 2 Percent of Pts Progression-Free mos Statistical analysis: HR (95% CI): 1.82 ( ) P =.4 Days PLD mos Orlowski RZ, et al. J Clin Oncol. 27;25(25): Updated Response Rates Updated Overall Survival Total (CR + ncr + PR)* (N = 31) PLD + (N = 33) P-value 44% 52%.5 CR + ncr* 13% 17% NS PR 31% 35% NS CR + VGPR** 2% 3%.7 Percent of Subjects Alive Censored Died PLD + 82% 18% HR (95% CI): 1.41 (1.2;1.97) P <.5 75% 25% PLD + * Modified EBMT Criteria ** IMWG 26 Criteria Time, days Harousseau JL, et al. ASCO 27. Abstract 82. Harousseau JL, et al. ASCO 27. Abstract Myeloma Salvage Therapy A 56-year-old woman with myeloma underwent thalidomide dexamethasone induction therapy followed by high dose melphalan and autologous stem cell transplantation. Although she achieved complete response, recurrent monoclonal protein and bone marrow plasmacytosis were observed 9 months post-transplant. Appropriate salvage therapies include: 1. Lenalidomide dexamethasone 2. dexamethasone 3. pegylated doxorubicin 4. All of the above 4. Myeloma Salvage Therapy A 43-year-old woman with myeloma receives thalidomide dexamethasone induction followed by high dose melphalan and autologous stem cell transplantation. Six months later myeloma returns and she receives bortezomib dexamethasone without response. Doxil bortezomib is given, again without response. Lenalidomide dexamethasone is given, but progressive myeloma is noted. 1. Repeat autologous transplant 2. dexamethasone 3. pegylated doxorubicin 4. Salvage therapy on protocol 9

10 Phase II trial of Pomalidomide in Relapsed/ Refractory Myeloma Best Response Phase II trial, 6 patients A confirmed response is defined to be a CR, PR or VGPR as assessed by the International Myeloma Working Group Uniform Response criteria. Starting Dose: Pomalidomide: 2 mg p.o. daily days 1-28 Dexamethasone: 4 mg p.o. days 1, 8, 15 & 22 Aspirin: 325 mg p.o. days 1-28 Among the first 37 patients, there were 13 lenalidomide refractory patients, with responses seen in 29%. Median follow-up 4 months Confirmed Response N = 6 scr 1 (2%) VGPR 14 (23%) PR 2 (33%) SD 11 (18%) PD 13 (22%) NE 1 (2%) ORR 58% CR +VGPR 25% Lacy, et al. ASH 28. Abstract 866 Lacy, et al. ASH 28. Abstract 866 Carfilzomib in Relapsed Refractory (N = 39) and Hsp 9 Inhibitor Therapy of 1 responses during the first cycle Hsp 9 gene and protein overexpressed in MM; bortezomib further upregulates hsp 9 (22). % of subjects *95% CI 13%-42% Only 1 of 26 patients with bortezomib refractory MM achieved PR. As of July 28 Jagannath, et al, ASH 28. Abstract 864. CBR=26%* 13% 13% PR (n = 5) MR (n = 5) 41% SD (n = 16) 28% PD (n = 11) Hsp 9 inhibitor and bortezomib induces synergistic cytotoxicity and overcome bortezomib resistance in vitro and in vivo (23-4) Phase I/II clinical trials show safety and that hsp 9 inhibitor can sensitize or overcome resistance to bortezomib (25-6) (Richardson et al, ASH 26) Phase III trial of bortezomib/hsp 9 inhibitor vs bortezomib in relapsed MM for FDA approval m2 Blockade of iquitinated Protein Catabolism Vorinostat- HDAC6 Tubacin LBH dynein HDAC6 HDAC6 dynein Microtubule Protein protein aggregates (toxic) 26S proteasome Aggresome Trial of LBH alone and with Lysosome Autophagy Effective for treatment of relapsed/refractory MM Overall response (PR + CR) ~38-43% > SD ~9% Effective despite prior bortezomib therapy Overall response ~29-35% SD ~41-53% Overall response refractory pts > PR ~29-38% SD refractory pts ~42-5% Well-tolerated: Fatigue, diarrhea, thrombocytopenia Phase III trial of bortezomib and SAHA vs bortezomib in relapsed MM ongoing for FDA approval Hideshima T, et al. Clin Cancer Res. 25; 11(24 pt 1): Catley L, et al. Blood. 26;18(1): Weber, et al. ASH 28. Abstract

11 Slide 58 m2 Could not locate this ref. I'm not sure whether the other statements on the slide need refs. mkish, 9/23/28

12 Conclusions and Future Directions 4. Myeloma Salvage Therapy A 43-year-old woman with myeloma receives thalidomide dexamethasone induction followed by high dose melphalan and autologous stem cell transplantation. Six months later myeloma returns and she receives bortezomib dexamethasone without response. Doxil bortezomib is given, again without response. Lenalidomide dexamethasone is given, but progressive myeloma is noted. 1. Repeat autologous transplant 2. dexamethasone 3. pegylated doxorubicin 4. Salvage therapy on protocol 1. All patients should receive novel therapies included in initial therapies to improve OR, CR, EFS and OS. 2. The role of high dose therapy in the context of novel therapies is under evaluation. 3. Novel proteasome inhibitors and immunomodulatory drugs offer promise in relapsed disease. 4. Molecularly based rationally designed combination therapies are under evaluation in phase III clinical trials (ie, bortezomib with hsp 9 inhibitor, Akt inhibitor, and HDAC inhibitor). Questions & Answers Thank you for attending Master Class for Oncologists? 11