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Multiple Myeloma ASH 2013

Multiple Myeloma ASH 2013. Ashley Rosko MD Ashley.Rosko@osumc.edu . Check us out on www.OhioMyeloma.org www.cancer.osu.edu/go/myelomateam. 8 Take Homes Points: ASH 2013 Overview. Lay of the Land: therapeutics Newly Diagnosed MM Maintenance Supportive Care Relapsed/Refractory MM. 1.

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Multiple Myeloma ASH 2013

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  1. Multiple MyelomaASH 2013 Ashley Rosko MD Ashley.Rosko@osumc.edu Check us out on www.OhioMyeloma.org www.cancer.osu.edu/go/myelomateam

  2. 8 Take Homes Points: ASH 2013 Overview • Lay of the Land: therapeutics • Newly Diagnosed MM • Maintenance • Supportive Care • Relapsed/Refractory MM

  3. 1 MANY DRUGS IN THE PIPELINE FOR MYELOMA

  4. Immunology: Vaccine Engineered T cells Anti-PD-1 Anti-KIR

  5. 2 THE LARGEST STUDY IN MM: CONDUCTED IN OLDER ADULTS FIRST TRIAL

  6. FIRST Trial: Study Design Active Treatment + PFS Follow-up Phase Screening LT Follow-Up PD or Unacceptable Toxicity RANDOMIZATION 1:1:1 PD, OS and Subsequent anti-MM Tx LEN + Lo-DEX Continuously LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28 Arm A Continuous Rd LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28 Arm B Rd18 MEL + PRED + THAL 12 Cycles1 (72 wks) MELPHALAN 0.25mg/kg D1-4/42 PREDNISONE 2mg/kg D1-4/42 THALIDOMIDE 200mg D1-42/42 Arm C MPT Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 (100 mg D1-42/42); MEL2 0.2 mg/kg D1–4 • Stratification: age, country and ISS stage ISS, International Staging System; LT, long-term; PD, progressive disease; OS, overall survival 1Facon T, et al. Lancet 2007;370:1209-18; 2Hulin C, et al. JCO. 2009;27:3664-70. Facon T, et al. Blood. 2013;122:abstract 2. Slide Courtesy of Dr. Facon

  7. FIRST Trial: Study Endpoints Primary Endpoint Progression-free Survival (PFS)a Secondary Endpoints Overall Survival (OS) Responsea Duration of Response (DOR) Time to Response (TTR) Time to Treatment Failure (TTF) Time to 2nd Line Anti-MM Treatment (2nd AMT) Time to Progression (TTP) Safety Quality of Life (QoL) Primary comparison is between Arm A (Continuous Rd) vs. Arm C (MPT) aAssessed by independent response adjudication committee (IRAC). Slide Courtesy of Dr. Facon Facon T, et al. Blood. 2013;122:abstract 2.

  8. FIRST Trial: Baseline Characteristics aComplete cytogenetics profile for 762 pts (248 in Rd, 261 in Rd18 and 253 in MPT), High-risk including t(4;14), t(14;16), del(17p) • Patient characteristics were well balanced across all treatment arms Slide Courtesy of Dr. Facon CrCl , creatinine clearance; ECOG, Eastern Cooperative Oncology Group; ISS, international scoring system; PS, performance status; yrs, years Facon T, et al. Blood. 2013;122:abstract 2.

  9. 100 80 60 40 20 0 FIRST Trial: Final Progression-free Survival 28% reduced risk of disease progression Hazard ratio Rd vs. MPT: 0.72; P = 0.00006 Rd vs. Rd18: 0.70; P = 0.00001 Rd18 vs. MPT: 1.03; P = 0.70349 Patients (%) 72 wks 6 12 18 24 30 36 42 48 54 60 0 Time (months) mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone. Slide Courtesy of Dr. Facon/modified Facon T, et al. Blood. 2013;122:abstract 2.

  10. FIRST Trial: Overall Survival Interim Analysis574 deaths (35% of ITT) 100 80 60 40 20 0 6 12 18 24 30 36 42 48 54 60 0 Rd Rd18 MPT 535 541 547 488 505 484 457 465 448 433 425 418 403 393 375 338 324 312 224 209 205 121 124 106 43 44 30 5 6 3 0 0 0 Patients (%) Hazard ratio Rd vs. MPT: 0.78; P = 0.0168 Rd vs. Rd18: 0.90; P = 0.307 Rd18 vs. MPT: 0.88; P = 0.184 Overall survival (months) Facon T, et al. Blood. 2013;122:abstract 2. Slide Courtesy of Dr. Facon

  11. FIRST Trial: Response Endpoints aIMWG Criteria; CR, complete response; mos, months ORR, overall response rate; PR, partial response; SD, stable disease; VGPR, very good PR. bResponse assessment for Rd obtained every 4 wks and for MPT every 6 wks; Response and progression rate based on IRAC assessment. aDurieet al. Leukemia 2006; 20:1467–1473. Facon T, et al. Blood. 2013;122:abstract 2. Slide Courtesy of Dr. Facon/Modifed

  12. FIRST Trial: Safety – Selected Grade 3–4 TEAEs Severity of AEs graded according to NCI CTCAE v3.0. DVT, deep-vein thrombosis; PE, pulmonary embolism; TEAEs, treatment-emerging adverse events. Slide Courtesy of Dr. Facon/Modified Facon T, et al. Blood. 2013;122:abstract 2.

  13. FIRST Trial: Second Primary Malignancy AML, acute myeloid leukemia; MDS, myelodysplastic syndromes; MPT, melphalan, prednisolone, thalidomide; NMSC; nonmelanoma skin cancer; Rd, lenalidomide plus low-dose dexamethasone; SPM, second primary malignancy. Facon T, et al. Blood. 2013;122:abstract 2. Slide Courtesy of Dr. Facon/Modified

  14. FIRST Trial: [Author] Conclusions Continuous Rd significantly extended PFS, with an OS benefit vs. MPT PFS: HR= 0.72 (P= 0.00006) Consistent benefit across most subgroups Rd better than Rd18 (HR= 0.70, P= 0.00001) 3 yr PFS: 42% Rd vs 23% Rd18 and MPT Planned interim OS: HR= 0.78 (P= 0.0168) 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. Slide Courtesy of Dr. Facon

  15. 3 IDENTIFYING VULNERABILITY in MM PATIENTS is IMPORTANT for OS Vulnerability: Occult Geriatric Factors that affect treatment outcomes

  16. Take Home #3: Heterogeneity Older Adult • Oncologist: Disease focused • Global Approach to Older Adult with MM

  17. 4 MAINTENANCE THERAPY IMPROVES PFS: At a PRICE

  18. (#406) Lenalidomide Maintenance After Stem-Cell Transplantation For MM: Follow-Up Analysis Of The IFM 2005-02 Trial • 614 Patients <65 yo Len vs. Placebo • Study stopped due to increase of SPM • Median duration of tx: 2 years • 5 year PFS42% vs. 18% with placebo (p<0.0001) • 5-year post randomization OSwas similar in the 2 groups: 68% in the LEN group versus 67% in the placebo group (HR=1).

  19. Lenalidomide Maintenance After Stem-Cell Transplantation For MM: Follow-Up Analysis Of The IFM 2005-02 Trial • SPM • LEN group: 44 SPMs / 35 patients • hematologic: 20 • non-hematologic: 24 • Placebo group: 28 SPMs / 20 patients • hematologic: 6 • non-hematologic: 22

  20. Take Home: Maintenance post AHSCT • Generally give maintenance therapy in post-ASCT • Wait for platelet recovery, delay past 3 months • Customized for high risk Cytogenetics • Maintenance in Elderly • Improves PFS, OS and has toxicities

  21. 5 SKELTAL RELATED EVENTS (SRE)in the ERA of NOVEL AGENTS Still a Problem

  22. (#3090) SRE in Era of Novel Agents • Retrospective 400 MM: osteolyticdisease in 284 (71%) • 223 MRI: diffuse>focal>normal>variegated • SREs were observed in 167 (41.7%) • Treatment: IMiD and/or PI + Bisphosphonates • SRE incidence: 21.6% at relapse • Bortezomib-only-based regimens had lower SRE rate (2/20, 10%) vs. all others (36/156, 22%, p=0.173)

  23. SRE in Era of Novel Therapy • Limited studies: bortezomib has been shown to produce an anabolic bone effect (increase bone ALP and osteocalcin)1 • (#3204)Low-dose bortezomib on bone remodeling and on disease progression in SMM • (# 3182) Zoledronic Acid improves overall survival compared To Pamidronate In MM Mohty M, Malard F, Mohty B, Savani B, Moreau P, Terpos E. The effects of bortezomib on bone disease in patients with multiple myeloma. Cancer. 2013 Nov 18.

  24. SRE: Preventing Falls and Fractures • The optimal dose of Ca and Vitamin D is not known • Vitamin D supplementation prevents falls and fractures (40% MM Vit D deficient) Badros A, et al. Prevalence and significance of vitamin D deficiency in multiple myeloma patients. Br J Haematol. 2008 Jul;142(3 Bischoff-Ferrari HA, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med. 2012 Jul 5;367(1):40-9.

  25. 6 CD38 ANTIBODIES ARE UP AND COMING…

  26. CD38 Targeting • (#1986) Preliminary Safety and Efficacy Data Of Daratumumab In Combination With Lenalidomide and Dexamethasone In Relapsed Or Refractory MM • (#284) SAR650984, a CD38 Monoclonal Antibody In Patients With Selected CD38+ Hematological Malignancies- Data From a Dose-Escalation Phase I Study

  27. (#284) SAR650984, a CD38 Monoclonal Antibody In Patients With Selected CD38+ Hematological Malignancies- Data From a Dose-Escalation Phase I Study • 32 patients / 27 MM • Primary Objective: MTD • Secondary Objectives: safety, PK/PD, disease response, immunogenicity • Median = 6 (2 – 14) • Administered every 2 weeks (Q2W) or weekly (QW)

  28. SAR650984: Grade 3-4 Drug-Related TEAEs and Drug-Related SAEs (All Treated Patients) Slide Courtesy of Dr. Martin No Grade 3-4 drug-related TEAEs / drug-related SAEs below 3mg/kg (N=16)

  29. SAR650984: Maximal Change in ParaproteinMyeloma Patients Treated at Doses of 1 mg/kg Q2W or Higher 150 1 mg/kg Q2W 3 mg/kg Q2W 125 5 mg/kg Q2W 10 mg/kg Q2W 100 10 mg/kg QW 20 mg/kg Q2W 75 50 25 % Change in Paraprotein 0 -25 -50 -75 -100 One patient at 3.0 mg/kg and 20 mg/kg with 0% change; One patient at 20 mg/kg not evaluable Slide Courtesy of Dr. Martin

  30. SAR650984: Phase 1 Response Summary CBR:38.5% ORR: 30.8% Slide Courtesy of Dr. Martin

  31. 7 COMPLETELY ORAL REGIMENS FOR MM

  32. Twice-weekly Oral MLN9708, an Investigational Proteasome Inhibitor, in Combination with Lenalidomide (Len) and Dexamethasone (Dex) in Patients (Pts) with Newly Diagnosed Multiple Myeloma (MM): Final Phase 1 Results and Phase 2 Data Paul G. Richardson,1 Craig C. Hofmeister,2 Cara A. Rosenbaum,3Myo Htut,4 David H. Vesole,5 Jesus G. Berdeja,6 Michaela Liedtke,7Ajai Chari,8 Stephen D. Smith,9 Daniel Lebovic,10 Deborah Berg,11Eileen Liao,11 Neeraj Gupta,11 Alessandra Di Bacco,11 Jose Estevam,11Ai-Min Hui,11Rachid Baz12 1Dana-Farber Cancer Institute, Boston, MA; 2The Ohio State University, Columbus, OH; 3University of Chicago, Chicago, IL; 4City of Hope National Medical Center, Duarte, CA;5The John Theurer Cancer Center at Hackensack UMC, Hackensack, NJ; 6Sarah Cannon Research Institute, Nashville, TN; 7Stanford Cancer Institute, Stanford, CA; 8Mount Sinai School of Medicine, New York, NY; 9Oregon Health & Science University / now University of Washington Fred Hutchinson Cancer Research Center, Seattle, WA; 10University of Michigan, Ann Arbor, MI; 11Takeda Pharmaceuticals International Co., Cambridge, MA;12H. Lee Moffitt Cancer Center, Tampa, FL

  33. Study design Maintenance Induction: up to 16 x 21-day treatment cycles 1 2 4 5 8 9 11 12 15 21 MLN9708 maintenance Days 1, 4, 8, 11 21-day cycles MLN9708 MLN9708 MLN9708 MLN9708 Dex* Dex* Dex* Dex* Lenalidomide 25 mg, days 1–14 *Dex 20/10 mg cycles 1–8 / 9–16 All patients required thromboembolism prophylaxis with aspirin 81–325 mg QD or LMWH while receiving len-dex • Phase 1: oral MLN9708 dose-escalation • Standard 3+3 schema, 33% dose increments, based on cycle 1 DLTs • Phase 2: oral MLN9708 at the RP2D from phase 1 (3mg) • MLN9708 maintenance continued at the last tolerated dose until progression or unacceptable toxicity Slide Courtesy of Dr. Richardson

  34. Preliminary response data • 62 of 64 pts were evaluable for response (2 patients did not have post-baseline response assessments thus were not evaluable) • Median follow-up is 10.9 months • Slide Courtesy of Dr. Richardson *Best confirmed/unconfirmed response by investigator assessment using IMWG uniform response criteria; †Includes 7 phase 1 pts treated at MLN9708 3.0 mg

  35. Individual best M-protein or serum FLC response to treatment (pts treated at RP2D) Dose level (cohort): Ph 1, 3.0 mg Ph 2, 3.0 mg 0 –20 –25% –40 –50% % decreases in M-protein –60 –80 –90% –100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 Subject identifier for the study • 56 patients 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 • Slide Courtesy of Dr. Richardson

  36. Drug-related* AEs, grade 3 (≥5% of total) *Drug-related defined as related to any drug in the combination; †Includes 7 phase 1 pts treated at MLN9708 3.0 mg;#Any rash-related AE within the MedDRA System Organ Class, includes rash maculo-papular, rash papular (n=3), dermatitis exfoliative, erythemamultiforme, rash macular, Stevens-Johnson syndrome (n=1); ‡Includes peripheral neuropathy and peripheral sensory neuropathy There were no drug-related grade 4 AEs

  37. An All Oral Regimen: Double Edge Sword • 3 phase 3 trials using MLN9708 alone… • Overall non-adherence rate ranging from 24% to 47% • No difference found in adherence for medications taken for prevention or treatment1 • Dx: Cancer slightly better • Patient Beliefs: disease severity, poor health and life threatening diseases actually had lower adherence2 1. DiMatteo MR. Variations in patients' adherence to medical recommendations : a quantitative review of 50 years of research. Med Care. 2004 Mar;42(3):200-9. PubMed PMID: 15076819. • 2. DiMatteoMR, Haskard KB, Williams SL. (2007). Health beliefs, disease severity, and patient adherence: • A meta-analysis. Medical Care, 45(6), 521-528.

  38. 8 MY ASSESSMENT of OLDER ADULTS with NDMM

  39. DYNAMIC

  40. Clinical Trials • 8 open clinical trials in MM and amyloidosis: • NDMM: non-ASCT eligible Phase III study of Elotuzumab/Len/Dex • Molecular Profiles of NDMM • RRMM: Ph I  Lenalidomide + Anti-PD-1 monoclonal antibody • RRMM: Ph 1/2 Pom/Car/Dex (pomalidomide/Carfilzomib - provided) • RRMM: Ph 2 ARRY-520 +/- Carfilzomib • RRMM: Ph 1 TGO2 + Carfilzomib

  41. 8 ASH 2013: TakeHome Points • Many drugs: mechanism of action and expected toxicities • FIRST: Continuous Rev/Dex compared to MPT improves PFS, OS • Fitness matters • Role for Maintenance Therapy • SRE continue to lead to morbidity • Targeted therapy CD38: single agent activity • Completely oral regimens: double edge sword • Comprehensive approach to older adult

  42. Thank you. Yvonne EfeberaMD Craig Hofmeister MD MPH Don Benson MD PhD Ashley Rosko MD

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