Developments in the Treatment of Multiple Myeloma Kenneth C. Anderson, M.D.
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1 Developments in the Treatment of Multiple Myeloma Kenneth C. Anderson, M.D. Kraft Family Professor of Medicine Harvard Medical School Director, Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute
2 Conflict of Interest: Kenneth C. Anderson, M.D. Consultancy: Celgene, Onyx, Sanofi Aventis, and Gilead Scientific Founder: Acetylon, Oncopep
3 Integration of Novel Therapy Into Myeloma Management Bortezomib, Lenalidomide, Thalidomide, Doxil, Carfilzomib, Pomalidamide Target MM in the BM microenvironment to overcome conventional drug resistance in vitro and in vivo Effective in relapsed/refractory, relapsed MM and now part of induction, consolidation, and maintenance therapy Nine FDA approvals in the last decade and median survival prolonged from 2-3 yrs to at least 5-7 yrs, with additional prolongation seen from maintenance New approaches needed to treat and ultimately prevent relapse
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5 Chromosomes and Prognosis in Multiple Myeloma For conventional low and high dose theapy: Nonhyperdiploid worse prognosis than hyperdiploid t(11;14), hyperdiplody -standard risk t(4;14), t(14;16),t(14;20), del(17p), del(13q14)- high risk For novel treatments Bortezomib, but not lenalidomide, can at least partially overcome t(4;14), del(13q14)- del(17p) p53 remains high risk
6 Combinations in the Upfront Treatment of MM Stewart AK, Richardson PG, San Miguel JF Blood 2009
7 Lenalidomide and Bortezomib/Lenalidomide-Based Consolidation Study details IFM Len consolidation (2 mos) Maintenance randomization: Len vs placebo n=572 Response data CR (IF ) 14% 20% < VGPR 58% 67% < p IFM VRD induction ASCT VRD consolidation (2 cycles) Len maintenance n=31 Preconsolidation Postconsolidation Postinduction Post- ASCT Postconsolidation scr 13% 26% 38% CR 10% 10% 10% VGPR 62% 68% 84% PR 94% 91% 94% 1 Attal et al. Haematologica 2011; 96 (s1): S23; oral presentation at IMW Roussel et al. ASH 2010 (Abstract 624), oral presentation
8 CALGB :LEN Maintenance significantly prolonged PFS & OS vs. placebo 5 PFS OS ASCT: autologous stem cell transplant; CALGB: Cancer and Leukemia Group B; HR: hazard ratio; LEN: lenalidomide; N/A: not applicable; OS: overall survival; PBO: placebo. McCarthy PL. N Engl J Med. 2012;366:
9 Lenalidomide Maintenance Therapy Meta- Analysis Oral Abstract #407 - Lenalidomide Maintenance Therapy In Multiple Myeloma: A Meta-Analysis Of Randomized Trials Monday, December 9, 2013: 11:30 AM There was significant prolongation of both PFS (HR 0.49, 95% CI, , p<0.001) and OS (HR 0.77, 95% CI, , p=0.013) with LM vs. placebo/no maintenance Singh M, et al. ASH Abstract 407.
10 Bortezomib induction and maintenance in ASCT NDMM, TE, sge y Randomization Bortezomib 1.3 mg/m2 i.v. 3 x VAD 3 x PAD Doxorubicin 9 mg/m 2 Dexameth 40 mg CAD + GCSF CAD + GCSF MEL PBSCT In GMMG 2 nd MEL PBSCT Allogeneic Tx MEL PBSCT In GMMG 2 nd MEL PBSCT Thalidomide maintenance 50 mg/day for 2 years Bortezomib Maintenance 1.3 mg/m 2 / 2 weeks for 2 years Sonneveld et al, ASH 2013
11 Results Bortezomib-based treatment consistently improves PFS (median 27 m vs 36 m) and OS (median 84 m vs not reached, p=0.05) in patients with newly diagnosed MM who are transplant eligible Bortezomib significantly improves the long-term outcome of patients presenting with renal failure (p<0.001) Sonneveld et al, ASH 2013
12 Carfilzomib With Thalidomide and Dexamethasone in ASCT Induction (4 28-day cycles) Intensification* (1 cycle) Consolidation (4 28-day cycles) Phase II open-label doseescalation trial (N=70) Carfilzomib, 20/27 mg/m 2 Days 1,2,8,9,15,16 Thalidomide, 200 mg Days 1-28 Dexamethasone, 40 mg Days 1,8,15,21 Carfilzomib, 27 mg/m 2 Days 1,2,8,9,15,16 Thalidomide, 50 mg Days 1-28 Dexamethasone, 40 mg Days 1,8,15,21 *High-dose melphalan 200 mg/m 2 plus ASCT Carfilzomib 27 mg/m 2 dose escalation: Cohort 1 treatment as above; Cohort 2 to 36 mg/m 2 ; Cohort 3 to 45 mg/m 2 ; Cohort 4 to 56 mg/m 2. Sonneveld P, et al. ASH Abstract 688.
13 Carfilzomib/Thalidomide/ Dexamethasone: Response and AEs Patient Response, % High-risk* Patients Standard Risk Patients All Patients CR/sCR VGPR PR *t(4;14) and/or del(17p) and/or 1q and/or ISS3. Grade 3/4 AEs 5% by carfilzomib dose: 20/27 mg/m 2 =GI toxicity, 16%, skin, 12%; metabolism, 10%; myelotoxicity, 8%; fatigue, 8%; cardiovascular, 6% 20/36 mg/m 2 =metabolism, 10%; myelotoxicity, 8%; GI toxicity, 5% Neuropathy < 5% in both cohorts Sonneveld P, et al. ASH Abstract 688.
14 Impact of Novel Agents in the Treatment of Elderly Pts with Newly Diagnosed MM Substantial improvements in PFS and OS Median PFS (mos) Median OS (mos) MP MPT VMP 7,8, % (3-yr OS)* MPR-R 9 31 N/A VMP-VT/VP % (3-yr OS)* VMPT-VT % (3-yr OS)* *Median OS not reached N/A: not available 1 Palumbo et al. Blood 2008; 112: Facon et al. Lancet 2007; 370: Hulin et al. J Clin Oncol 2009; 27: Waage et al. Blood 2010; 116: Wijermans et al. J Clin Oncol 2010; 28: Beksac et al. Eur J Haematol 2011;86: San Miguel et al. N Engl J Med 2008; 359(9): ; Supplementary Appendix 8 Mateos et al. J Clin Oncol 2010; 28(13): Palumbo et al. ASH 2010 (Abstract 622) 10 Mateos et al. Lancet Oncol 2010; 11(10): Palumbo et al. ASH 2010 (Abstract 620)
15 FIRST Trial: Study Design 15 Screening Active Treatment + PFS Follow-up Phase LT Follow-Up RANDOMIZATION 1:1:1 Arm A Continuous Rd Arm B Rd18 Arm C MPT LEN + Lo-DEX Continuously LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28 LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28 MEL + PRED + THAL 12 Cycles 1 (72 wks) MELPHALAN PREDNISONE THALIDOMIDE 0.25mg/kg D1-4/42 2mg/kg D1-4/42 200mg D1-42/42 PD or Unacceptable Toxicity PD, OS and Subsequent anti-mm Tx Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL 2 (100 mg D1-42/42); MEL mg/kg D1 4 Stratification: age, country and ISS stage ISS, International Staging System; LT, long-term; PD, progressive disease; OS, overall survival 1 Facon T, et al. Lancet 2007;370: ; 2 Hulin C, et al. JCO. 2009;27: Facon T, et al. Blood. 2013;122:abstract 2.
16 FIRST Trial: Final Progression-free Survival 16 Patients (%) Median PFS Rd (n=535) 25.5 mos Rd18 (n=541) MPT (n=547) Hazard ratio Rd vs. MPT: 0.72; P = Rd vs. Rd18: 0.70; P = Rd18 vs. MPT: 1.03; P = % (Rd) 20.7 mos 21.2 mos 20 23% (Rd18) 23% (MPT) Time (months) Rd Rd MPT mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone. Facon T, et al. Blood. 2013;122:abstract 2.
17 FIRST Trial: Consistent PFS Benefit Across Subgroups 17 Subgroup Age > 75 Age 75 Gender: female Gender: male Asia Europe North America and Pacific ISS stage: I or II ISS stage: III CrCI < 30 ml/min CrCI ml/min CrCI ml/min CrCI 80 ml/min ECOG PS Grade 0 ECOG PS Grade 1 ECOG PS Grade 2 LDH < 200 IU/l LDH 200 IU/l Cytogenetics High-risk Cytogenetics Non-high Risk ITT patients Hazard ratio (HR) and 95% CI HR (95% Cl) 0.81 ( ) 0.68 ( ) 0.73 ( ) 0.71 ( ) 0.61 ( ) 0.77 ( ) 0.64 ( ) 0.70 ( ) 0.75 ( ) 0.76 ( ) 0.66 ( ) 0.74 ( ) 0.71 ( ) 0.54 ( ) 0.81 ( ) 0.80 ( ) 0.69 ( ) 0.96 ( ) 1.23 ( ) 0.69 ( ) 0.72 ( ) Favoring Rd Favoring MPT ITT, intention to treat; ITT comparison for continuous Rd vs. MPT Facon T, et al. Blood. 2013;122:abstract 2. Cytogenetics high-risk included t(4;14), t(14;16), del(17p)
18 FIRST Trial: TTP and Time to 2 nd Anti-myeloma Therapy 18 Time to Progression Time to 2 nd AMT Median TTP Median Time to 2 nd AMT 100 Rd (n=535) 32.5 mos Rd18 (n=541) 21.9 mos MPT (n=547) 23.9 mos 100 Rd (n=535) 39.1 mos Rd18 (n=541) 28.5 mos MPT (n=547) 26.7 mos Patients (%) Patients (%) Hazard ratio Rd vs. MPT: 0.68; P= Rd vs. Rd18: 0.62; P Rd18 vs. MPT: 1.11; P= TTP (months) 20 0 Hazard ratio Rd vs. MPT: 0.66; P< Rd vs. Rd18: 0.74; P= Rd18 vs. MPT: 0.88; P= Time to 2 nd AMT (months) Rd Rd18 MPT Rd Rd18 MPT Facon T, et al. Blood. 2013;122:abstract 2.
19 FIRST Trial: Conclusions 19 Continuous Rd significantly extended PFS, with an OS benefit vs. MPT PFS: HR= 0.72 (P= ) Consistent benefit across most subgroups Rd better than Rd18 (HR= 0.70, P= ) 3 yr PFS: 42% Rd vs. 23% Rd18 and MPT Planned interim OS: HR= 0.78 (P= ) Rd was superior to MPT across all other efficacy secondary endpoints Safety profile with continuous Rd was manageable Hematological and non-hematological AEs were as expected for Rd and MPT Incidence of hematological SPM was lower with continuous Rd vs. MPT In NDMM transplant-ineligible patients, the FIRST Trial establishes continuous Rd as a new standard of care Facon T, et al. Blood. 2013;122:abstract 2.
20 Progression-Free and Overall Survival All Patients Median PFS 4-year OS MPR-R 31 months MPR-R 59% MPR 14 months MPR 58% 100 MP 13 months 100 MP 58% 20 Patients (%) HR P <.001 HR P =.135 Patients (%) HR P =.648 HR P = Time (Months) Time (Months) TTP HR advantages were similar: MPR-R vs MP = 0.337; MPR vs MP = HR, hazard ratio; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melphalan, prednisone, lenalidomide with lenalidomide maintenance; OS, overall survival; PFS, progression-free survival; TTP, time to progression.
21 Second Primary Malignancies All Patients PD/Death Hematologic SPM Solid Tumor MPR-R 100 MPR 100 MP Patients (%) Time (Months) Time (Months) Time (Months) SPM, n (IR per 100 per year) MPR-R (n = 150) MPR (n = 152) MP (n = 153) Total Invasive SPMs 12 (3.04) 10 (2.57) 4 (0.98) Hematologic 7 (1.75) 6 (1.54) 1 (0.24) Solid tumors 5 (1.26) 5 (1.28) 3 (0.74) Non-melanoma skin cancer 2 (0.50) 5 (1.29) 6 (1.50) IR, incidence rate; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melphalan, prednisone, lenalidomide with lenalidomide maintenance; PD, progressive disease; PY, person-year; SPM, second primary malignancy.
22 152 patients Treatment schema 75 years or younger with co-morbidities At baseline: geriatric assessment (ADL, IADL, Charlson) VP Nine 35-day courses Vsc: 1.3 mg/sqm, d 1,8,15,22 P: 50 mg, 3 times wk MAINTENANCE 28-day course until relapse Vsc: 1.3 mg/sqm, d 1, 15 VMP Nine 35-day courses Vsc: 1.3 mg/sqm, d 1,8,15,22 M: 2 mg, 3 times wk P: 50 mg, 3 times wk VCP Nine 35-day courses Vsc: 1.3 mg/sqm, d 1,8,15,22 C: 50 mg, 3 times wk P: 50 mg, 3 times wk MAINTENANCE 28-day course until relapse Vsc: 1.3 mg/sqm, d 1, 15 MAINTENANCE 28-day course until relapse Vsc: 1.3 mg/sqm, d 1, 15 Vsc, subcutaneous bortezomib; C, cyclophosphamide; M, melphalan; P, prednisone Larocca et al ASH 2013
23 Subgroup analysis: Age Progression-free Survival Overall Survival Patients (%) Age years Age <75 years Age 80 years Age years Age <75 years Age 80 years Time (months) Time (months) PFS, Age vs Age<75, HR=0.96 p=0.865 PFS, Age 80 vs Age<75, HR=0.80 p=0.449 OS, Age vs Age<75, HR=0.79 p=0.571 OS, Age 80 vs Age<75, HR=0.99 p=0.990
24 Conclusions The global population is rapidly aging. Aging is associated with an increased incidence of comorbidity, frailty, and disability. PFS and OS appeared similar between the 2- drug and the 3-drug combinations Melphalan seemed more toxic than cyclophosphamide Fit patients Unfit patients Frail patients Full dose therapy Reduced-dose therapy Further reduced-dose therapy Larocca et al, ASH 2013
25 Phase II Multicenter (10 centres) Study design CCd Induction Cycles 1-9 C Maintenance Until progression Response Assessments Cycle day Carfilzomib Dose (mg/m 2 ) Dosing CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 5 CYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCE Cyphosphamide 300 mg/m 2 orally Dexamethasone 40 mg orally Bringhen et al ASH 2013
26 Conclusions 1 CCd MPT VMP Rd Response rates VGPR 77% 36% 41% 40% ncr/cr/scr 47% 27% 30%* 14% Long-term outcomes 2-yr PFS 76% 47% ~47% ~47% 2-yr OS 87% 76% 79% 87% * CR only, ncr not reported Palumbo at al, Lancet, 2006 ;367: Fayers et al, Blood 2011; 118: ; San Miguel et al, N Eng J Med 2008;359:906-17; Rajkumar et al, Lancet Oncol 2010; 11:29-37 Bringhen et al ASH 2013
27 Oral MLN 9708 Len Dex in Newly Diagnosed MM Induction: up to 16 x 21-day treatment cycles MLN9708 MLN9708 MLN9708 MLN9708 Dex* Dex* Dex* Dex* Lenalidomide 25 mg, days 1 14 Maintenance MLN9708 maintenance Days 1, 4, 8, day cycles *Dex 20/10 mg cycles 1 8 / 9 16 Thromboembolism prophylaxis with aspirin mg QD or LMWH while receiving len-dex mandatory Phase 1: oral MLN9708 dose-escalation (dose of 3.0 and 3.7 mgs) Standard 3+3 schema, 33% dose increments, based on cycle 1 DLTs Phase 2: oral MLN9708 at the RP2D from phase 1 Stem cell collection allowed after cycle 4, with ASCT deferred until after 8 cycles MLN9708 maintenance continued at tolerated dose until progression or unacceptable toxicity Richardson et al ASH 2013
28 Ixazomib lenalidomide dexamethasone in newly diagnosed multiple myeloma 0 Dose level (cohort): Ph 1, 3.0 mg Ph 2, 3.0 mg % decreases in M-protein % 50% 90% Subject identifier for the study 56 pts treated at the RP2D were evaluable for response (7 phase 1, 49 phase 2) 61% of pts had 100% decreases in M-protein or serum free light chain from baseline Richardson et al ASH 2013
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30 Pomalidomide With Low-Dose Dexamethasone Relapsed and Refractory Multiple Myeloma POM was effective in heavily pretreated patients who had already received LEN and bortezomib and who progressed on their last line of therapy The combination of POM with LoDEX improves the ORR due to synergy between immunomodulatory agents and glucocorticoids POM + LoDEX, 34%; POM alone, 15% Response was durable with POM regardless of the addition of LoDEX POM + LoDEX, 8.3 months ; POM alone, 8.8 months POM is generally well tolerated, with low rates of discontinuations due to AEs Age had no impact on ORR, DoR, or safety Jagannath S, et al. ASH 2012 abstract 450.
31 MM-003 Design: POM + LoDEX vs. HiDEX 28-day cycles (n = 302) RANDOMIZATION 2:1 POM: 4 mg/day D LoDEX: 40 mg ( 75 yrs) 20 mg (> 75 yrs) D1, 8, 15, 22 HiDEX: (n = 153) 40 mg ( 75 yrs) 20 mg (> 75 yrs) D1-4, 9-12, PD a or Unacceptable AE PD a or Unacceptable AE Follow-Up for OS and SPM Until 5 Years Post Enrollment Companion trial MM-003C POM 21/28 days Stratification Age ( 75 vs. > 75 yrs) Thromboprophylaxis was required for those receiving POM or at high risk for DVT Number of prior Tx ( 2 vs. > 2) Disease population (primary refractory vs. relapsed/refractory vs. intolerance/failure) a Progression of disease was independently adjudicated in real time. Dimopoulos MA, et al. ASH 2013 [abstract 408].
32 PFS Based on Cytogenetic Profile POM + LoDEX significantly improved PFS vs. HiDEX regardless of the presence of del17p or t(4;14) Subgroup ITT Population POM + LoDEX a HiDEX a HR (95% CI) 253/ / ( ) del(17p)/t(4;14) 71/77 32/ ( ) Standard-Risk Cytogenetics 126/148 63/ ( ) Favors POM + LoDEX Favors HiDEX Note: Data shown only for pts with available cytogenetics; totals will not sum. a Number of events/number of patients. Dimopoulos MA, et al. ASH 2013 [abstract 408].
33 Forest Plot of OS Based on Prior Treatment Subgroup POM + LoDEX a HiDEX a HR (95% CI) ITT Population 176/ / ( ) 3 Prior Tx 41/70 22/ ( ) > 3 Prior Tx 135/232 79/ ( ) Prior THAL 102/173 64/ ( ) No Prior THAL 74/129 37/ ( ) LEN Ref 168/286 94/ ( ) BORT Ref 142/238 79/ ( ) LEN and BORT Ref 135/225 74/ ( ) LEN as Last Prior 47/85 32/ ( ) BORT as Last Prior 76/134 39/ ( ) a Number of events/number of pts. Favoring POM-LoDex Favoring HiDEX San Miguel JF, et al. ASH 2013 [abstract 686].
34 MM-003: PFS and OS by M-Protein Reduction Patients Assigned to POM + LoDEX 1.0 M-Protein Reduction 25 % (n = 163) Median PFS 7.4 mos 1.0 M-Protein Reduction 25 % (n = 163) Median OS 17.2 mos Proportion of Patients % (n = 113) 8.4 mos < 25% (n = 96) 2.3 mos % (n = 113) 19.9 mos < 25% (n = 96) 7.5 mos PFS (mos) OS (mos) Median PFS was 4.0 mos and median OS was 13.1 mos overall for POM + LoDEX San Miguel JF, et al. ASH 2013 [abstract 686].
35 Pom low dose dex and bortezomib in relapsed MM Table 4. Summary of Best Response (IMWG) in Intravenous BORT Cohorts Outcome Cohort 1 (n = 3) Cohort 2 (n = 3) Cohort 3 (n = 3) Cohort 4 (n = 3) Cohort 5 + Exp Cohort (n = 9) a Overall response, n (%) 2 (67) 1 (33) 3 (100) 3 (100) 6 (67) scr/cr (11) VGPR 1 (33) 0 2 (67) 1 (33) 4 (44) PR 1 (33) 1 (33) 1 (33) 2 (67) 1 (11) SD 1 (33) 2 (67) (33) Median cycles received (range) 5 (4-16) 6 (4-18) 16 (5-20) 10 (4-13) 11 (6-15) a 8 of 9 patients were evaluable for response; one patient discontinued study treatment in cycle 2 due to treatment-unrelated metastatic pancreatic cancer. CR, complete response; Exp, expansion; IMWG, International Myeloma Working Group; PR, partial response; SC, subcutaneous; scr, stringent complete response; SD, stable disease; VGPR, very good partial response. Richardson et al, ASH 2013
36 Carfilzomib: A Novel Proteasome (Chymotryptic) Inhibitor Novel chemical class with highly selective and irreversible proteasome binding Tetrapeptide Improved antitumor activity with consecutive day dosing O N O H N O N H O H N O N H O O No neurotoxicity in animals Epoxyketone 23% Responses lasting 7.8 months with survival 15.4 months in relapsed and relapsed/ refractory MM w/o Demo et al Cancer Res 2007; 67:6383 Kirk et al, Blood 2008, 112: 2765 ; Siegel et al Blood 2012:120:2817.
37 CRd in Relapsed and Upfront MM Response to CRd therapy in RRMM was high, with an ORR of 78% 41% VGPR or better CRd well-tolerated with durable responses ASPIRE phase 3 open-label, international, multicenter trial comparing CRd to Rd in R/R MM fully enrolled. Remarkable extent and frequency of response to CRd upfront in ND MM (94% ORR, with 80% CR,nCR after 12 cycles in a subset of pts) Wang et al ASCO 2011; Jakubowiak et al, Blood 2012
38 Carfilzomib Pomalidomide Low dose Dex Median of 5 prior lines of therapy; 49% of patients had high/intermediate risk cytogenetics at baseline VGPR 27% ORR 70% CBR 83% DOR (median) 17.7 months PFS (median) 9.7 months OS (median) > 18 months Response rates, PFS, and OS were preserved independent of FISH/cytogenetic risk status Well tolerated with no unexpected toxicities Shah et al ASH 2013
39 MAb-Based Therapeutic Targeting of Myeloma Antibody-dependent Cellular cytotoxicity (ADCC) Complement-dependent Cytotoxicity (CDC) C1q Apoptosis/growth arrest via targeting signaling pathways Effector cells: CDC C1q ADCC FcR MM MM MM Daratumumab (CD38) Lucatumumab or Dacetuzumab (CD40) Elotuzumab (CS1) Daratumumab (CD38) XmAb 5592 (HM1.24) hun901-dm1 (CD56) nbt062-maytansinoid (CD138) 1339 (IL-6) BHQ880 (DKK1) RAP-011 (activin A) Daratumumab (CD38) Tai & Anderson Bone Marrow Research 2011
40 Elotuzumab Anti-CS MoAb in MM CS1 is highly and uniformly expressed on MM cells Elotuzumab (Elo) is a humanized monoclonal IgG1 antibody targeting CS1 Clinical trial of Elo in MM achieved SD Anti-MM activity of Elo enhanced by lenalidomide (len) in preclinical models Phase I/II trials: 80-90% response to len dex elo in relapsed MM with prolonged (> month 33 PFS) Phase III trial of len dex elo versus len dex in relapsed MM for new drug approval Hsi ED et al. Clin Cancer Res. 2008;14: ; Tai YT et al. Blood. 2008;112: ; Van Rhee F et al. Mol Cancer Ther. 2009;8: ; Lonial S et al. Blood. 2009;114:432; Richardson et al Blood 2010:864 Lonial et al, ASH 2012
41 Martin et al ASH 2013
42 Martin et al 2013
43 PHASE I/II STUDY OF DARATUMUMAB CD38 MONOCLONAL ANTIBODY IN RELAPSED/REFRACTORY MM Favorable safety profile as monotherapy In 15 of 32 (47%) showed benefit 4 patients achieving PR (13%) 6 patients achieving MR (19%) 5 patients achieving SD (16%) At doses 4mg/kg and above, 8 of the 12 patients had at least MR (66%) To be combined with lenalidomide dexamethasone Plesner et al ASH 2012
44 Daratumumab and lenalidomide dexamethasone in relapsed MM The best change in response paraprotein evaluated according to IMWG A: serum M-protein, B: urine-m-protein Plesner et al ASH
45 Kelley et al ASH 2013
46 Kelly et al ASH 2013
47 Background: Targeting KSP with ARRY-520 (Filanesib) Filanesib is a targeted Kinesin Spindle Protein (KSP) inhibitor KSP is a microtubule motor protein critical to the function of proliferating cells KSP inhibition induces aberrant mitotic arrest and rapid cell death Novel mechanism of action for MM Preferentially acts on MCL-1 dependent cells including MM Not expected to be cross-resistant with other drugs Lonial et al ASH
48 Lonial et al ASH 2013 Low AAG is Associated with Higher ORR Filanesib Single-agent Filanesib + Dex All Pts 1 AAG-High AAG-Low All Pts 2 AAG-High AAG-Low n ORR ( PR) 5 (16%) 0 (0%) 5 (24%) 8 (15%) 0 (0%) 7 (19%) CBR ( MR) 7 (22%) 0 (0%) 7 (33%) 11 (20%) 0 (0%) 10 (28%) Duration of Response (months) Time to Next Treatment (months) OS (months) patients did not have a baseline AAG measurement 2 4 patients did not have a baseline AAG measurement, including 1 responder 48
49 Development of Rationally-Based Combination Therapies (HDAC and Proteasome Inhibitors) Protein Ub Ub protein aggregates (toxic) Ub Ub Ub Ub 26S proteasome HDAC6 Panibinostat, Vorinostat, ACY1215 HDAC6 Ub Ub Bortezomib, Carfilzomib, NPI0052, MLN9708, ONX 0912 dynein Ub HDAC6 Ub Aggresome Lysosome dynein Ub Ub Ub Ub Ub Ub Microtubule Autophagy Hideshima et al. Clin Cancer Res. 2005;11:8530.Catley et al. Blood. 2006;108:
50 VANTAGE 088: An International, Multicenter, Randomized, Double-Blind Study of Vorinostat or Placebo with Bortezomib in Relapsed MM The combination of vorinostat + bortezomib is active in patients with relapsed and refractory MM Significant improvement in response rate ORR 54% vs 41% (P<0.0001); CBR 71% vs 53% (P<0.0001) PFS and TTP were prolonged in the combination arm compared with bortezomib alone PFS hazard ratio reduction of 23% (P=0.01); 7.63 months ( ) versus 6.83 months ( ) Diarrhea, fatigue, and thrombocytopenia limited tolerability. Dimopoulos et al Lancet Oncol 2013; 14:
51 Ricolinostat (HDAC 6 inhibitor) alone and in combination with bortezomib in relapsed refractory MM Monotherapy 6/15 patients had stable disease (SD) as their best response. Combination with bortezomib and dexamethasone 20/22 were evaluable for response assessment in six combination cohorts Overall response rate ( PR): 25% in heavily pretreated patients 5 patients withdrew after one cycle and 3 had progressive disease after 2 cycles Clinical benefit rate ( SD): 60% 6/10 patients refractory to bortezomib had SD (1 VGPR, 1 MR, 4 SD) Responding patients have been on study 2 to 16 cycles VGPR PR 2 3 All 3 patients treated 240 mg QD cohort had MR or better MR 1 2 SD 5 51 Monotherapy response data from Final CSR. Combination response data pulled from live database Nov 8, One patient had a 26% decrease in M Protein after Cycle 2 and withdrew after two subsequent cycles with SD
52 Ricolinostat (HDAC 6 inhibitor) lenalidomide dexamethasone in relapsed refractory MM M protein % change CR 1 VGPR 3 PR 1 7 MR 2 SD 3 11/16 pts (69%) had PR or better 16/16 pts (100%) had clinical benefit (including MR and SD) 52 Yee, et al, Poster #3190, ASH 2013
53 PKB Akt Inhibitor: Dose Limiting Toxicities Afur / Bor / Dex dose (mg) n DLT Comment None /6 LFT elevation G /6 Erythema Multiforme G None /6 Rash G3 Rash G3 / Diarrhea G3 /Thrombocytopenia G NA - MTD / RP2D: Afuresertib 150 mg PO daily Bortezomib 1.3 mg/m 2 IV/SC on days: 1,4,8,11 Dexamethasone 40 mg PO on days: 1,4,8,11 All DLTs were reversible Voorhees et al ASH 2013
54 Maximum % change in M-protein or FLC from baseline Voorhees et al ASH 2013
55 Treatment of Multiple Myeloma: Conclusions In newly diagnosed transplant candidates, three drug regimens incorporating immunomodulatory drugs and proteasome inhibitors before and after transplant can prolong PFS and OS. Lenalidomide dex until progression is standard of care for non transplant patients with newly diagnosed myeloma. Lenalidomide maintenance until progression prolongs PFS and OS, with an increased risk of secondary cancers in patients who have received MP or high dose therapy and ASCT.
56 Treatment of Multiple Myeloma: Conclusions Pomalidomide low dose dex is active in relapsed refractory MM, (including 17p deletion) Bortezomib or Carfilzomib and pomalidomide low dose dex increases response and is tolerated in relapsed refractory MM Novel agents including oral proteasome inhibitor ixazomib, monoclonal antibodies SAR and daratumumab, immunotoxin indatuximab, KSP inhibitor filanesib, Akt inhibitor afuresertib, and HDAC6 inhibitor ricolinostat demonstrate promising activity in relapsed refractory MM Incorporation of novel therapies at all stages of disease is further improving patient outcome in MM
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