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Developments in the Treatment of Multiple Myeloma Kenneth C. Anderson, M.D. Kraft Family Professor of Medicine Harvard Medical School Director, Jerome.

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Presentation on theme: "Developments in the Treatment of Multiple Myeloma Kenneth C. Anderson, M.D. Kraft Family Professor of Medicine Harvard Medical School Director, Jerome."— Presentation transcript:

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 Stewart AK, Richardson PG, San Miguel JF Blood 2009 Combinations in the Upfront Treatment of MM

7 Lenalidomide and Bortezomib/Lenalidomide-Based Consolidation Study detailsResponse data IFM Len consolidation (2 mos) Maintenance randomization: Len vs placebo IFM VRD induction ASCT VRD consolidation (2 cycles) Len maintenance 1 Attal et al. Haematologica 2011; 96 (s1): S23; oral presentation at IMW Roussel et al. ASH 2010 (Abstract 624), oral presentation n=572 Pre- consolidation Post- consolidation p CR (IF – )14%20%< ≥ VGPR58%67%< n=31 Post- induction Post- ASCT Post- consolidation sCR13%26%38% CR10% ≥ VGPR62%68%84% ≥PR94%91%94%

8 5 CALGB : CALGB :LEN Maintenance significantly prolonged PFS & OS vs. placebo 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: PFSOS

9 There was significant prolongation of both PFS (HR 0.49, 95% CI, 0.41–0.58, p<0.001) and OS (HR 0.77, 95% CI, 0.62–0.95, p=0.013) with LM vs. placebo/no maintenance Oral Abstract #407 - Lenalidomide Maintenance Therapy In Multiple Myeloma: A Meta-Analysis Of Randomized Trials Monday, December 9, 2013: 11:30 AM Lenalidomide Maintenance Therapy Meta- Analysis Singh M, et al. ASH Abstract 407.

10 Randomization NDMM, TE, sge 18–65 y CAD + GCSF 3 x VAD CAD + GCSF 3 x PAD MEL PBSCT In GMMG 2 nd MEL PBSCT In GMMG 2 nd MEL PBSCT Thalidomide maintenance 50 mg/day for 2 years Allogeneic Tx Bortezomib Maintenance 1.3 mg/m 2 / 2 weeks for 2 years Bortezomib induction and maintenance in ASCT Bortezomib1.3 mg/m2 i.v. Doxorubicin9 mg/m 2 Dexameth40 mg 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) Carfilzomib, 20/27 mg/m 2 Days 1,2,8,9,15,16 Dexamethasone, 40 mg Days 1,8,15,21 Thalidomide, 200 mg Days 1-28 Intensification* (1 cycle) Phase II open-label dose- escalation trial (N=70) *High-dose melphalan 200 mg/m 2 plus ASCT Sonneveld P, et al. ASH Abstract 688. Carfilzomib, 27 mg/m 2 Days 1,2,8,9,15,16 Dexamethasone, 40 mg Days 1,8,15,21 Thalidomide, 50 mg Days 1-28 Consolidation (4 28-day cycles) 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.

13 Carfilzomib/Thalidomide/ Dexamethasone: Response and AEs Patient Response, % High-risk* Patients Standard Risk Patients All Patients CR/sCR ≥VGPR PR90 96 *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 OS not reached N/A: not available 7 San Miguel et al. N Engl J Med 2008; 359(9): 906–917; 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) 1 Palumbo et al. Blood 2008; 112:3107– Facon et al. Lancet 2007; 370:1209– 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;86:16-22 Median PFS (mos)Median OS (mos) MP –2029.1–49.4 MPT –27.529–51.6 VMP 7,8, – % (3-yr OS)* MPR-R 9 31N/A VMP-VT/VP % (3-yr OS)* VMPT-VT % (3-yr OS)*

15 Facon T, et al. Blood. 2013;122:abstract 2. RANDOMIZATION 1:1:1 Arm B Rd18 Arm C MPT 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 0.25mg/kg D1-4/42 PREDNISONE 2mg/kg D1-4/42 THALIDOMIDE 200mg D1-42/42 PD, OS and Subsequent anti-MM Tx PD or Unacceptable Toxicity Active Treatment + PFS Follow-up Phase ScreeningLT Follow-Up Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL 2 (100 mg D1-42/42); MEL mg/kg D1–4 15 Stratification: age, country and ISS stage 1 Facon T, et al. Lancet 2007;370: ; 2 Hulin C, et al. JCO. 2009;27: FIRST Trial: Study Design LEN + Lo-DEX Continuously LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28 Arm A Continuous Rd ISS, International Staging System; LT, long-term; PD, progressive disease; OS, overall survival

16 Facon T, et al. Blood. 2013;122:abstract 2. Median PFS Rd (n=535)25.5 mos Rd18 (n=541)20.7 mos MPT (n=547)21.2 mos Rd Rd MPT Hazard ratio Rd vs. MPT: 0.72; P = Rd vs. Rd18: 0.70; P = Rd18 vs. MPT: 1.03; P = Time (months) Patients (%) % (Rd) 23% (Rd18) 23% (MPT) FIRST Trial: Final Progression-free Survival mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone.

17 FIRST Trial: Consistent PFS Benefit Across Subgroups ITT, intention to treat; ITT comparison for continuous Rd vs. MPT Facon T, et al. Blood. 2013;122:abstract 2. 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 30 – 50 ml/min CrCI 50 – 80 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% CIHR (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 MPT Favoring Rd 17 Cytogenetics high-risk included t(4;14), t(14;16), del(17p)

18 FIRST Trial: TTP and Time to 2 nd Anti-myeloma Therapy Facon T, et al. Blood. 2013;122:abstract 2. Rd Rd18 MPT TTP (months) Patients (%) Hazard ratio Rd vs. MPT: 0.68; P= Rd vs. Rd18: 0.62; P≤ Rd18 vs. MPT: 1.11; P= Time to Progression Time to 2 nd AMT Rd Rd18 MPT Time to 2 nd AMT (months) Hazard ratio Rd vs. MPT: 0.66; P< Rd vs. Rd18: 0.74; P= Rd18 vs. MPT: 0.88; P= Patients (%) Median TTP Rd (n=535)32.5 mos Rd18 (n=541)21.9 mos MPT (n=547)23.9 mos Median Time to 2 nd AMT Rd (n=535)39.1 mos Rd18 (n=541)28.5 mos MPT (n=547)26.7 mos 18

19 FIRST Trial: Conclusions 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. 19

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22 Larocca et al ASH 2013

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24 Larocca et al, ASH 2013

25 Bringhen et al ASH 2013

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27 Oral MLN 9708 Len Dex in Newly Diagnosed MM 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 MLN9708 maintenance Days 1, 4, 8, day cycles Induction: up to 16 x 21-day treatment cycles Maintenance MLN9708 Dex* Lenalidomide 25 mg, days 1–14 MLN9708 Dex* 411 *Dex 20/10 mg cycles 1–8 / 9–16 Thromboembolism prophylaxis with aspirin 81–325 mg QD or LMWH while receiving len-dex mandatory Richardson et al ASH 2013

28 Ixazomib lenalidomide dexamethasone in newly diagnosed multiple myeloma 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 –20 –40 –60 –80 –100 % decreases in M-protein –25% –50% –90% Subject identifier for the study Dose level (cohort):Ph 1, 3.0 mgPh 2, 3.0 mg 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 (n = 302) POM: 4 mg/day D LoDEX: 40 mg (≤ 75 yrs) 20 mg (> 75 yrs) D1, 8, 15, 22 RANDOMIZATION 2:1 Follow-Up for OS and SPM Until 5 Years Post Enrollment (n = 153) HiDEX: 40 mg (≤ 75 yrs) 20 mg (> 75 yrs) D1-4, 9-12, day cycles PD a or Unacceptable AE Companion trial MM-003C POM 21/28 days Stratification Age (≤ 75 vs. > 75 yrs) Number of prior Tx ( 2 vs. > 2) Disease population (primary refractory vs. relapsed/refractory vs. intolerance/failure) Thromboprophylaxis was required for those receiving POM or at high risk for DVT PD a or Unacceptable AE 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) 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]. ITT Population del(17p)/t(4;14) Standard-Risk Cytogenetics Subgroup POM + LoDEX a HiDEX a HR (95% CI) 0.49 ( ) 0.44 ( ) 0.55 ( ) 138/153 32/35 63/72 253/302 71/77 126/148 1 Favors POM + LoDEX 2 Favors HiDEX

33 Forest Plot of OS Based on Prior Treatment a Number of events/number of pts. San Miguel JF, et al. ASH 2013 [abstract 686]. Subgroup HiDEX a HR (95% CI) 0.72 ( ) 0.56 ( ) 0.76 ( ) 0.75 ( ) 0.66 ( ) 0.70 ( ) 0.77 ( ) 0.77 ( ) 0.56 ( ) 0.92 ( ) 101/153 22/33 79/120 64/93 37/60 94/141 79/121 74/113 32/49 39/66 176/302 41/70 135/ /173 74/ / / /225 47/85 76/134 ITT Population ≤ 3 Prior Tx > 3 Prior Tx Prior THAL No Prior THAL LEN Ref BORT Ref LEN and BORT Ref LEN as Last Prior BORT as Last Prior POM + LoDEX a Favoring POM-LoDex Favoring HiDEX

34 MM-003: PFS and OS by M-Protein Reduction Patients Assigned to POM + LoDEX San Miguel JF, et al. ASH 2013 [abstract 686]. Median PFS was 4.0 mos and median OS was 13.1 mos overall for POM + LoDEX M-Protein Reduction Median PFS ≥ 25 % (n = 163)7.4 mos ≥ 50 % (n = 113)8.4 mos < 25% (n = 96)2.3 mos M-Protein Reduction Median OS ≥ 25 % (n = 163)17.2 mos ≥ 50 % (n = 113)19.9 mos < 25% (n = 96)7.5 mos PFS (mos) Proportion of Patients OS (mos)

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) 6 (67) sCR/CR00001 (11) VGPR1 (33)02 (67)1 (33)4 (44) PR1 (33) 2 (67)1 (11) SD1 (33)2 (67)003 (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 Improved antitumor activity with consecutive day dosing No neurotoxicity in animals 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; 67:6383Kirk et al, Blood 2008, 112: 2765 ; Siegel et al Blood 2012:120:2817. Epoxyketone Tetrapeptide

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 Response rates, PFS, and OS were preserved independent of FISH/cytogenetic risk status Well tolerated with no unexpected toxicities  ≥ VGPR27% ORR70% CBR83%  DOR (median)17.7 months  PFS (median)9.7 months  OS (median)> 18 months Shah et al ASH 2013

39 Antibody-dependent Cellular cytotoxicity (ADCC) ADCC Effector cells: MM FcR Complement-dependent Cytotoxicity (CDC) CDC MM C1q Apoptosis/growth arrest via targeting signaling pathways MM  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) MAb-Based Therapeutic Targeting of Myeloma Tai & Anderson Bone Marrow Research 2011

40 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 Elotuzumab Anti-CS MoAb in MM

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 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 2013

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 47 Lonial et al ASH 2013

48 Low AAG is Associated with Higher ORR patients did not have a baseline AAG measurement 2 4 patients did not have a baseline AAG measurement, including 1 responder Filanesib Single-agent Filanesib + Dex All Pts 1 AAG-HighAAG-LowAll Pts 2 AAG-HighAAG-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) Lonial et al ASH 2013

49 Protein protein aggregates (toxic) Ub 26S proteasome Ub Aggresome Panibinostat, Vorinostat, ACY1215 dynein Ub dynein Microtubule Autophagy Bortezomib, Carfilzomib, NPI0052, MLN9708, ONX 0912 Ub Lysosome HDAC6 Ub Development of Rationally-Based Combination Therapies (HDAC and Proteasome Inhibitors) 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 (6.9–8.4) versus 6.83 months (5.7–7.7) 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 All 3 patients treated 240 mg QD cohort had MR or better VGPR2 PR3 MR 1 2 SD5 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 11/16 pts (69%) had PR or better 16/16 pts (100%) had clinical benefit (including MR and SD) Yee, et al, Poster #3190, ASH M protein % change

53 PKB Akt Inhibitor: Dose Limiting Toxicities Afur / Bor / Dex dose (mg) nDLTComment 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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