Novel Treatment Advances and Approaches in Management of Relapsed/Refractory Multiple Myeloma

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1 Novel Treatment Advances and Approaches in Management of Relapsed/Refractory Multiple Myeloma Ravi Vij, MD MBA Professor of Medicine Washington University School of Medicine Section of Stem Cell Transplant and Leukemia St. Louis, Missouri Disclosures Research Funding: Takeda, Onyx Honoraria: Celgene, Onyx, Millennium, BMS, Janssen, Sanofi, Merck, Seattle Genetics 1

2 Upfront Treatment of MM Clearly not a transplant candidate based on age, performance status, and comorbidity Potential transplant candidate Conventional Therapy Non-alkylator based induction x 4 cycles Stem cell harvest Rajkumar SV, et al. Mayo Clin Proc. 2009;84: Relapsed/Refractory Multiple Myeloma 2

3 When to Consider Retreatment? Clinical relapse Based on direct indicators of increasing disease and/or end organ dysfunction Biochemical relapse Patients with asymptomatic rise in M protein can be observed to determine the rate of rise and nature of relapse Caveat: Patients with known aggressive or high risk disease should be considered for salvage, even in the setting of biochemical relapse?a significant paraprotein relapse (defined as doubling of the M component in 2 consecutive measurements separated by less < 2 months or an increase in the absolute levels of serum M protein by more than or equal to 1 g/dl Factors to Consider in Treatment Selection DISEASE-RELATED DOR to initial therapy FISH/cytogenetics/genomics profile PRIOR TREATMENT-RELATED Prior drug exposure Toxicity of regimen Mode of administration Previous SCT PATIENT-RELATED Pre-existing toxicity Presence of other conditions Age General health Personal lifestyle and preferences DOR, duration of response; FISH, fluorescence in situ hybridization; SCT, stem cell transplant Lonial S. Hematology Am Soc Hematol Educ Program. 2010;303. 3

4 Options for Relapsed/Refractory Disease How long from initial therapy? 6 months >6 months Repeat initial therapy Different therapy Different therapy Stem cell transplant Stem cell transplant Clinical trial Recent Trials X Rd vs Rd 4

5 ASPIRE Study Design 28-day cycles KRd Randomization N=792 Stratification: β 2 -microglobulin Prior bortezomib Prior lenalidomide Carfilzomib 27 mg/m 2 IV (10 min) Days 1, 2, 8, 9, 15, 16 (20 mg/m 2 days 1, 2, cycle 1 only) Lenalidomide 25 mg Days 1 21 Dexamethasone 40 mg Days 1, 8, 15, 22 After cycle 12, carfilzomib given on days 1, 2, 15, 16 After cycle 18, carfilzomib discontinued Rd Lenalidomide 25 mg Days 1 21 Dexamethasone 40 mg Days 1, 8, 15, 22 9 Primary Endpoint: Progression-Free Survival ITT Population (N=792) Proportion Surviving Without Progression No. at Risk: KRd Rd KRd Rd KRd Rd (n=396) (n=396) Median PFS, mo HR (KRd/Rd) (95% CI) 0.69 ( ) P value (one sided) < Months Since Randomization

6 Secondary Endpoints: Response Percentage of Patients scr 14.1% vs 4.3% P< P< P< KRd Rd 0 CR VGPR ORR ( PR) 11 Median duration of response was 28.6 months in the KRd group and 21.2 months in the Rd group TOURMALINE MM1: Study Design Randomized, double-blind, placebo-controlled phase III trial [1] Stratified by prior therapy (1 vs 2-3), ISS stage (I-II vs III), and prior PI exposure (yes vs no) R/R MM pts with measurable disease; 1-3 prior treatments; CrCl 30 ml/min; not refractory to PIs or lenalidomide (N = 722) Primary endpoint: PFS by IRC per IMWG criteria [2] Secondary endpoints (data not yet mature): OS, OS in del(17p) pts 1. Moreau P, et al. ASH Abstract Rajkumar SV, et al. Blood. 2011;117: Ixazomib 4 mg PO D1,8,15 + Lenalidomide 25 mg* D Dexamethasone 40 mg D1,8,15,22 (n = 360) Placebo D1,8,15 + Lenalidomide 25 mg* D Dexamethasone 40 mg D1,8,15,22 (n = 362) *10 mg for pts with CrCl 60 or 50 ml/min. 28-day cycles until PD or unacceptable toxicity 6

7 TOURMALINE MM1: Efficacy Characteristic PFS benefit with ixazomib seen in all prespecified subgroups, including cytogenetic high risk, PI and IMiD exposed Moreau P, et al. ASH Abstract 727. Ixazomib + Rd (n = 360) Placebo + Rd (n = 362) P Value Median PFS, mos * ORR, % CR VGPR PR Median time to response, mos Median DoR, mos Median TTP, mos *HR: HR: ELOQUENT 2: Study Design Randomized, open label, multicenter phase III trial Pts with R/R MM and 1-3 prior treatments Elotuzumab 10 mg/kg IV QW cycles 1, 2 then Q2W + Lenalidomide 25 mg PO D Dexamethasone 40 mg PO QW (n = 321) (N = 646) Lenalidomide 25 mg PO D Dexamethasone 40 mg PO QW (n = 325) Primary endpoints: PFS, ORR Secondary endpoints: OS, safety, 28-day DoR, cycles health related QoL Threshold for interim OS significance Until PD or unacceptable toxicity Dimopoulos MA, et al. ASH Abstract 28. 7

8 ELOQUENT 2: Efficacy Outcome PFS Median, mos 1 yr, % 2 yrs, % 3 yrs, % Elotuzumab + Len/Dex (n = 321) Len/Dex (n = 325) PFS benefit seen with elotuzumab in all predefined subgroups HR (95% CI) 0.73 ( ; P =.0014) Median time to next treatment, mos ( ) ORR, % Interim OS, mos ( ; P =.0257) Dimopoulos MA, et al. ASH Abstract 28. Pollux: Study Design Key eligibility criteria RRMM 1 prior line of therapy Prior lenalidomide exposure, but not refractory Creatinine clearance 30 ml/min Stratification factors No. of prior lines of therapy ISS stage at study entry R A N D O M I Z E 1:1 DRd (n = 286) Daratumumab 16 mg/kg IV Qw in Cycles 1 to 2, q2w in Cycles 3 to 6, then q4w until PD R 25 mg PO Days 1 to 21 of each cycle until PD d 40 mg PO 40 mg weekly until PD Rd (n = 283) R 25 mg PO Days 1 to 21 of each cycle until PD d 40 mg PO 40 mg weekly until PD Primary endpoint PFS Secondary endpoints TTP OS ORR, VGPR, CR MRD Time to response Duration of response Statistical analyses Primary analysis: ~177 PFS events Prior lenalidomide Cycles: 28 days ISS, international staging system; DRd, daratumumab/lenalidomide/dexamethasone; IV, intravenous; qw, weekly; q2w, every 2 weeks; q4w, every 4 weeks; PD, progressive disease; R, lenalidomide; PO, oral; d, dexamethasone; Rd, lenalidomide/dexamethasone; PFS, progression-free survival; TTP, time to progression; OS, overall survival; ORR, overall response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual disease. a On daratumumab dosing days, dexamethasone 20 mg was administered as pre-medication on Day 1 and Day

9 Recent Trials vs Vd 9

10 PANORAMA1: Study Design Randomized, multicenter, placebo controlled, double blind phase III trial Stratified by prior lines of therapy and prior bortezomib Pts with symptomatic RRMM after 1-3 prior treatments (bortezomibrefractory excluded) (N = 768) Phase I: Eight 3-wk cycles Panobinostat 20 mg Days 1, 3, 5 of Wks 1, 2 Bortezomib 1.3 mg/m 2 IV Days 1, 4 of Wks 1, 2 Dexamethasone 20 mg Days 1, 2, 4, 5 of Wks 1, 2 (n = 387) Placebo Days 1, 3, 5 of Wks 1,2 Bortezomib 1.3 mg/m 2 IV Days 1, 4 of Wks 1, 2 Dexamethasone 20 mg Days 1, 2, 4, 5 of Wks 1, 2 (n = 381) SD SD Phase II: Four 6-wk cycles Panobinostat 20 mg Days 1, 3, 5 of Wks 1, 2, 4, 5 Bortezomib 1.3 mg/m 2 IV Day 1 of Wks 1, 2, 4, 5 Dexamethasone 20 mg Days 1, 2 of Wks 1, 2, 4, 5 Placebo Days 1,3,5 of Wks 1, 2, 4, 5 Bortezomib 1.3 mg/m 2 IV Day 1 of Wks 1, 2, 4, 5 Dexamethasone 20 mg Day 1 of Wks 1, 2, 4, 5 San-Miguel JF, et al. Lancet Oncol. 2014;15: PANORAMA1: PFS Significant improvement in PFS with addition of panobinostat to bortezomib and dexamethasone PFS (%) Panobinostat, bortezomib, and dexamethasone Placebo, bortezomib, and dexamethasone HR: 0.63 (95% CI: ; P <.0001) Mos San-Miguel JF, et al. Lancet Oncol. 2014;15:

11 PANORAMA1: Safety AE, % San-Miguel JF, et al. Lancet Oncol. 2014;15: Panobinostat (n = 381) Placebo (n = 377) Any grade 3/4 AE Grade 3/4 nonhematologic AEs Diarrhea 25 8 Asthenia or fatigue Peripheral neuropathy Pneumonia Grade 3/4 hemorrhage 4 2 Grade 3/4 hematologic AEs (new or worsening) Thrombocytopenia Lymphopenia Neutropenia Serious AE Discontinuation due to treatment-related AE ENDEAVOR Study Design Presented By Meletios Dimopoulos at 2015 ASCO Annual Meeting 11

12 Secondary End Point: Response Rates Presented By Meletios Dimopoulos at 2015 ASCO Annual Meeting Primary End Point: Progression-Free Survival<br />Intent-to-Treat Population (N=929) Presented By Meletios Dimopoulos at 2015 ASCO Annual Meeting 12

13 CASTOR: Study Design Phase III study Pts with relapsed/refractory MM who received 1 prior regimen including bortezomib (but not refractory to bortezomib) (N = 498) Daratumumab 16 mg/kg Cycles 1-3 Q7D, 4-8 Q21D, 9+ Q28D Bortezomib 1.3 mg/m 2 SC Cycles 1-8, Days 1, 4, 8, 11 Dexamethasone 20 mg Cycles 1-8, Days 1, 2, 4, 5, 8, 9, 11, 12 (n = 251) Bortezomib 1.3 mg/m 2 SC Cycles 1-8, Day 1, 4, 8, 11 Dexamethasone 20 mg Cycles 1-8, Day 1, 2, 4, 5, 8, 9, 11, 12 (n = 247) Median follow-up: 7.4 mos Primary endpoint: PFS Secondary endpoints: TTP, OS, ORR, VGPR, CR, MRD, time to response; DoR Palumbo A, et al. ASCO Abstract LBA4. 13

14 Myeloma X Study Schema Cook G, et al. ASH Abstract 394. Overall Survival Median overall survival ASCT2 67 months (95% CI 55, ) NTC 52 months (95% CI 42,60) Log Rank p=0.022 Cook G, et al. ASH Abstract

15 Watch This Space! Small molecules Venetoclax Selinexor Immunotherapies Check point inhibitors (pembrolizumab,nivolumumab) Antibody drug conjugates, BiTEs CAR T cells Will 1+0=2? Protosome inhibitor + dug X Immunomodulation + drug X 15

16 Don t Forget the Neighbourhood Coming soon?: value based care From Guidelines to Pathways 16

17 The next leap:understanding of biology Empericism still rules 17

18 New strategies to win the war The genetics do matter High risk Intermediate risk * Standard risk * FISH Del 17p t (14; 16) t (14; 20) GEP High risk signature OS 2 YR FISH t (4; 14) Cytogenetic Deletion 13 or hypodiploidy PCLI 3% OS 3.5 YR All others including: Hyperdiploid t (11; 14) ** t (6; 14) OS 5 YR *Note that a subset of patients with these factors will be classified as high risk GEP. LDH>ULN and beta 2M > 5.5 may indicate worse prognosis. Prognosis is worse when associated with high beta 2 M and anemia. **t (11; 14) may be associated with plasma cell leukemia. msmart = Mayo Stratification of Myeloma and Risk-adapted therapy; FISH = fluorescence in situ hybridization; GEP =gene expression profelling; ULN = upper limite of normal. PCCLL = plasma cell labeling index; LDG = lactate deydrogenase. Dispenzieri A et al. Mayo Clin Proc 2007;82: ; Kumar SK et al. Mayo Clin Proc :

19 What is the critical event? Adapted with permission from XXX. MGUS: monoclonal gammopathy of undetermined significance Palumbo A et al. N Engl J Med. 2011;364(11): Is it time to surrender our AK47s and becoming snipers? Lohr et al Cancer Cell 2014; 25:

20 Nowell Dogma to Darwinian Evolution n=28 Keats J et al. Blood.2012; 120 (5): ) Tiding Clones Keats J et al. Blood.2012; 120 (5): ) 20

21 Lohr et al Cancer Cell 2014; 25: Compass Study 21

22 Big data and patient centricity TOP 10 INVESTIGATORS Dr. Jagannath (n= Mt. Sinai affiliate site patients = 89) Dr. Siegel (n= RCCA patient = 83) Dr. Vij (n=62) Dr. Lonial (n=54) Dr. Zimmerman (n=36) Dr. Orloff (n=34) Dr. Niesvizky (n=24) Dr. Walker (n=21) Dr. Rifkin (n=20) Dr. Fay (n=18) Dr. Berdeja (n=18) In Silico Engineering: Creating Avatars Doudican Naet al J. Transl Med

23 3D Tissue Engineering Pluente et al (submitted for publication) Perhaps we have to take the next leap? 23

24 From blockbusters to orphans? Today Tomorrow? Biomarker driven Bayesian trials N of 1 Trials Novel Trial Designs 24

25 It certainly has potential Conclusions Most advances in treatment of myeloma to date have targeted normal plasma cell biology and have been the result of an empirical paradigm of drug development. However, the future of advances in myeloma therapy lies in precision/personalized medicine. Tools to make this possible are starting to emerge. This will also require novel clinical trial designs. 25

26 The Goal: Cure?* Ineffective treatment Dexamethasone Tumor Volume Alkylators High-Dose Therapy Limit of detection Time *So Far Possible in Infection and Cancer From plasma cell biology to biology of myeloma? Questions? 26