Relapsed/ Refractory Myeloma - update. Sep 2015

Transcription

1 Relapsed/ Refractory Myeloma - update Sep 2015

2 Natural History of MM Asymptomatic Symptomatic M Protein (g/l) MGUS or smoldering myeloma ACTIVE MYELOMA 1. RELAPSE Plateau remission 2. RELAPSE REFRACTORY RELAPSE First-line therapy Second-line Third-line

3 Relapsed/ Refractory Myeloma Definitions changing Double refractory Myeloma Challenges in management Treatment approach Treatment options

4 Definitions Primary refractory Myeloma - never achieved a minimal response or better with induction therapy Relapsed Myeloma - Relapsing disease after a period of remission to induction therapy Relapsed & Refractory Myeloma - disease that is not responsive to salvage therapy or progresses within 60 days of last therapy in patients who achieve MR Double refractory Myeloma - Disease refractory to lenalidomide and bortezomib therapy RajKumar et al Blood 2011;117(18):

5 Double refractory Myeloma Refractory to IMiD and Bortezomib Double-refractory disease, prognosis is poor, with a median overall survival (OS) and progressionfree survival (PFS) of 9 months and 5 months 1 Relatively frailer phenotype ( low counts, renal impairment, poor PS) and complex genotype ( clonal tides, enrichment of high risk genetic features) adds to the complexity Carfilzomib (FDA) and pomalidomide are approved agents in this setting S Kumar Leukemia. 2012;26(1):149 57

6 Case No 1 50 year old male presented with back pain and hip pain. No sig PMH IgA lambda paraprotein, Renal impairment creatinine 350 umol/l and anaemia, ISS 3 IgA kappa MM. No high risk genetic features Started on Velcade and dexamethasone, radiotherapy to hip and vertebroplasty to L2 compression fracture LC continue to rise, give VCD x 2 SD Ongoing pain and renal impairment started on BTD x 4 Minimal response

7 Case No 1 DTPACE with carboplatin x 2 PR and VTD x 2 Stem cells mobilised with plerixafor Pre transplant marrow 80% PC ASCT Reduced dose melphalan conditioning Achieved PR Started on cyclo/ Len/ Dex 2 months post transplant Now on Len maintenance almost 2 years out ECOG -1 back to work Primary refractory myeloma

8 Case No 2 58 year old lady diagnosed with MM 2006 IgA MM - ISS1. No significant PMH Treated with CTD followed by ASCT 2007 Biochemical relapse 2010 Treated on Myeloma X trial Received 4 x PAD chemo followed by Second ASCT Well until 2012

9 Case no 2 Relapse with rising paraprotein and bone pain March 2012 Started on Bisphosphonates and Cyclo/ Len? Dex Achieved Partial response Switched to Len monotherapy maintenance Dec 2012 Current in good partial response with ECOG 1 Biochemical relapse and eligible for second transplant

10 Case No 3 66 year old lady presented with anemia and bone pain, Jan 2013 IgA Kappa MM, ISS 1, Genetics failed CTD x 6 VGPR, tolerated therapy well apart form mild SOB Stem cells collected ASCT with HDM conditioning July 2013

11 Case No 3 Well apart form back pain Attends routine monitoring March 2014, MRI done Unremarkable in CR confirmed by marrow Admitted July 2014 with back pain anuria, creatinine 530 umol/l. Started on dialysis BM 60% PC, t(4:14) and del p53 on MM FISH Treated with VTD x 3 progressive disease

12 Case No 3 BTD x 2 Partial response Thalidomide related tremors, Thal held. Progressive disease. Switched to Lenalidomide / Dex - SD, poor QoL Palliated and RIP Nov 2014 Early relapse with high risk features

13 Assessment of relapsed MM Patient related factors * Age & Performance status * Frailty & Comorbidity * Marrow reserve, renal function, pre existing toxicity Disease/ Treatment related factors * Initial & subsequent therapy duration, response, tolerance * Remission period * Genetic features * Number of relapses

14 Questions at relapse 1. To treat or not to treat asymptomatic relapses. When treatment can be safely delayed? 2. When retreatment should be considered. What should be the response duration cutoff? 3. Can drugs be chosen based on disease biology? 4. How to use available drugs- Sequential approach? Multidrug combination approach? 5. For how long should a relapse treatment be continued?limited number of cycles? Indefinite? 6. When to consider a rescue second ASCT? What should be the minimal response duration from the first ASCT? 7. Is there a role for allogeneic transplantation? When should it be considered?

15 Current Treatment options Lenalidomide based therapy Bortezomib based therapy Bortezomib re treatment DRMM Pomalidomide based therapy, Bendamustine based therapy

16 Lenalidomide + dexamethasone: International multicentre clinical trials Lenalidomide Phase III study design 1,2 R A N D O M I S E Endpoints Primary endpoint: time to progression (TTP) Secondary endpoints Response rate, overall survival, safety * Study MM-009: 48 centres; U.S. and Canada (N=353) ** Study MM-010: 50 centres; Europe, Australia and Israel (N=351) 1.Weber DM, et al. N Engl J Med. 2007;357: Dimopoulos MA, et al. N Engl J Med. 2007;357:

17 Lenalidomide + dex delivers a significantly superior response compared with dex alone in relapsed/refractory multiple myeloma Pooled analysis from MM-009 and MM-010 shows statistically significant higher response rates for lenalidomide + dex compared with dex alone 1 Len= lenalidomide Len + dex = lenalidomide + dexamethasone CR = complete response VGPR = very good partial response PR = partial response References: 1.Dimopoulos MA, et al. Leukemia. 2009;23:

18 Lenalidomide + dex significantly improves TTP compared with dex alone 1 References: 1.Dimopoulos MA, et al. Leukemia. 2009;23:

19 Lenalidomide + dex increased overall survival compared with dex alone 1 At a median follow-up of 48 months for surviving patients, a significant benefit in overall survival (median of 38.0 vs 31.6 months, P=0.045) was retained in the lenalidomide + dex arm 1. This was achieved despite nearly half the patients in the control group receiving lenalidomide at the time of disease progression or study unblinding, which may have contributed to a greater than expected overall survival in the dex only patient group. Len= lenalidomide Len + dex = lenalidomide + dexamethasone dex - dexamethasone References: 1.Dimopoulos MA, et al. Leukemia. 2009;23:

20 Response rates with lenalidomide higher when patients are treated in earlier lines 1 CR = complete response VGPR = very good partial response PR = partial response References: 1.Stadtmauer EA, et al. Eur J Haematol. 2009;82(6):

21 Lenalidomide at first relapse References: 1.Stadtmauer EA, et al. Eur J Haematol. 2009;82(6):

22 Phase III APEX Trial: Bortezomib vs High-Dose Dexamethasone in Relapsed MM Induction Maintenance Treatment for 280 days Pts with relapsed MM following 1-3 therapies, not refractory to dexamethasone (N = 669) Dexamethasone 40 mg PO* Days 1-4, 9-12, and for four 5-wk cycles (n = 336) Bortezomib 1.3 mg/m 2 IV Days 1, 4, 8, 11 for eight 3-wk cycles (n = 333) Dexamethasone 40 mg PO Days 1-4 for four 5-wk cycles Bortezomib 1.3 mg/m 2 IV Days 1, 8, 15, 22 for three 5-wk cycles *Pts who progressed on dexamethasone allowed to cross over to receive bortezomib in a companion study. Richardson P, et al. N Engl J Med. 2005;352: Treatment for 273 days

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24 Time to progression APEX study

25 Phase III APEX Trial: OS (Extended Median OS Bortezomib: 29.8 months Follow-up) Dexamethasone: 23.7 months P =.027 > 62% of dexamethasone-treated pts crossed over to receive bortezomib 1-yr survival rate 80% for bortezomib vs 67% for dexamethasone (P =.001) Richardson P, et al. Blood. 2007;110:

26 Bortezomib retreatment - RETRIEVE study British Journal of Haematology, 2013, 160,

27 RETRIEVE study ORR 40%. In patients who achieved PR, median DOR and TTP were 6. 5 and 8. 4 months British Journal of Haematology, 2013, 160,

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29 DRMM TREATMENT OPTIONS

30 Date of Preparation 2 nd Feb 2014 Date UK-POM130017a prepared: June 2013 MM-003 Study Design: POM + LoDEX vs. HiDEX Objective: To compare the efficacy and safety of POM+LoDex vs. HiDEX in RRMM Primary endpoint: PFS Key secondary endpoints: OS, ORR ( PR), TTP, DoR, QoL and safety 28-day cycles RANDOMISATION 2:1 (n=455) (n = 302) POM: 4 mg/day D LoDEX: 40 mg ( 75 yrs) 20 mg (> 75 yrs) D1, 8, 15, 22 (n = 153) HiDEX: 40 mg ( 75 yrs) 20 mg (> 75 yrs) D1-4, 9-12, PD or intolerable AE PD Follow-Up for OS and SPM until 5 years postenrollment Companion trial MM-003C POM 21/28 days Thromboprophylaxis required for pts receiving POM or at high risk of DVT PD was independently adjudicated in real time. BORT: bortezomib; D: day; DoR: duration of response; DVT: deep vain thrombosis HiDEX: high-dose dexamethasone; LEN: lenalidomide; LoDEX: low-dose dexamethasone; ORR: overall response rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; POM: pomalidomide; PR: partial response; Qol: quality of life; RRMM: relapsed/refractory multiple myeloma; SPM: second primary malignancy; TTP: time to progression; Tx: treatment; yrs: years. San Miguel J, et al. Lancet Oncology 2013; 14(11) San Miguel et al: ASH 2013; Oral Presentation & Abstract 686.

31 Pomalidomide use in RRMM Retrospective audit UCL, Oxford, Kings, Southampton Aim: To assess the clinical efficacy of pomalidomide in a real-world setting in multiple UK centres Analysis: Toxicity, ORR, PFS, OS Rabin et al - Abstract IMW

32 Date of Preparation 2 nd Feb 2014 Date UK-POM130017a prepared: June 2013 MM-003: Baseline Characteristics and Prior Tx Characteristic POM + LoDEX (n = 302) HiDEX (n = 153) Median age, yrs (range) 64 (35-84) 65 (35-87) Median time from initial Dx (y) ECOG status 0/1/2/3 (%) 36/46/17 24/56/16 ISS I/II/III (%) 27/38/30 24/37/35 CrCL < 60 ml/min (%) Median number Prior Tx, n (range) 5 (2-14) 5 (2-17) Prior DEX (%) Prior THAL (%) Prior SCT (%) Prior LEN & BORT (%) Prior alkylator (%) LEN-refractory (%) BORT-refractory (%) LEN- and BORT-refractory (%) BORT: bortezomib; CrCl: creatinine clearance; DEX: dexamethasone; Dx: diagnosis; ECOG: Eastern Cooperative Oncology Group; HiDEX: high-dose dexamethasone; ISS: International Staging System; LEN: lenalidomide; LoDEX: low-dose dexamethasone; POM: pomalidomide; SCT: stem cell transplant; THAL: thalidomide; Tx: treatment. San Miguel J, et al. Lancet Oncology 2013; 14(11) San Miguel et al: ASH 2013; Oral Presentation & Abstract 686.

33 Median number of cycles was 4 (range 1-32), and median daily dose was 4 mg. Fifteen patients (19%) had dose reductions. In those with a GFR <45ml/min at baseline, 50% (7/14) started at a dose < 4mg

34 Date of Preparation 2 nd Feb 2014 Date UK-POM130017a prepared: June 2013 MM-003: Response (ITT) Response POM + LoDEX (N = 302) HiDEX a (N = 153) P Value ORR ( PR), n (%) 97 (32) 17 (11) <.001 VGPR 21 (7) 1 (1) scr/cr 4 (1) 0 (0) MR, n (%) 122 (40) 23 (15) SD, n (%) 247 (82) 94 (61) Median DOR, b mos (95% CI) a Pts (n = 11) who crossed over to receive POM were analysed per original randomised arm. b Kaplan-Meier estimate; patients with PR 7.5 ( ) 5.1 ( ).031 CI; confidence interval; CR, complete response; DOR, duration of response; HiDEX, high-dose dexamethasone; ITT, intent to treat; LoDEX, low-dose dexamethasone; MR, minimal response; ORR, overall response rate; POM, pomalidomide; PR, partial response; scr, stringent complete response; SD, stable disease; VGPR, very good partial response. San Miguel J, et al. Lancet Oncology 2013; 14(11) San Miguel et al: ASH 2013; Oral Presentation & Abstract 686.

35 Response & Toxicity Overall response ( PR) was 53%, VGPR 5%, and at least stable disease was achieved in 58/62 (94%). PFS was 4.3 months, and OS was 13.7 months. Impaired renal function (GFR <45ml/min, 14 patients) did not appear to influence PFS (4.0 months vs 4.5 months, p=0.44), or OS (10.8 vs 13.7 months, p=0.80). High risk FISH was present in 11/40 (28%) patients, who had comparable outcomes to standard risk patients: PFS 3.6 months vs 4.5 months, (p=0.70) and OS 11.3 vs not reached (p=0.19). Rabin et al - Abstract IMW

36 Date of Preparation 2 nd Feb 2014 Date UK-POM130017a prepared: June 2013 MM-003 Grade 3/4 Adverse Events: Event (%) Grade 3/4 haematologic AEs POM + LoDEX (n = 300) HiDEX* (n = 150) Neutropaenia Febrile neutropaenia 9 0 Anaemia Thrombocytopaenia Grade 3/4 non-haematologic AEs (> 5%) Infections Pneumonia 14 8 Bone Pain 7 5 Fatigue 5 6 Asthenia 4 7 Glucose intolerance 4 7 Grade 3/4 AEs of interest Rash 1 0 DVT/PE 1 0 Peripheral neuropathy a 1 1 Discontinuation due to AEs 9 10 a Peripheral neuropathy includes the preferred terms hyperaesthesia, neuropathy peripheral, peripheral sensory neuoropathy, paraesthesia, hypoaesthesia, and polyneuropathy. AE: adverse event; DVT: deep vein thrombosis; HiDEX: high-dose dexamethasone; LoDEX: low-dose dexamethasone; PE: pulmonary embolism; POM: pomalidomide. * Pts may have received POM + LoDEX following crossover. San Miguel J, et al. Lancet Oncology 2013; 14(11) San Miguel et al: ASH 2013; Oral Presentation & Abstract 686.

37 Response & Toxicity Inclusion of a third agent at start of therapy (14 patients) did not appear to confer benefit (PFS 4.3 vs 4.0 months, p=0.40) In eight patients with biochemical or clinical progression on pomalidomide/dexamethasone, a third agent was added, and 7 achieved SD/PR Grade 3/4 non-haematological toxicities occurred in 27/79 (34%) patients: pneumonia 15 patients (19%) and neutropaenic sepsis 9 patients (11.4%) being the commonest. Grade 3/4 neutropenia occurred in 28 patients (35%) and thrombocytopenia in 17 patients (22%) Rabin et al - abstract IMW

38 Progression free survival Rabin et al - abstract for IMW

39 Overall Survival Rabin et al - abstract IMW

40 Conclusions ORR of 53% is higher than observed in Phase III trial Renal impairment and patients with high risk cytogenetics fare comparably to standard risk and normal renal fn patients Addition of third agent should be explored prospectively to enhance effectiveness of this combination Is well tolerated in heavily pre treated and refractory MM patients

41 BTD in DRMM Ann Hematol (2015) 94:

42 BTD in DRMM

43 FOCUS Study Design 43 Inclusion Criteria Measurable disease Relapsed and refractory multiple myeloma 3 prior regimens Mandatory prior treatment Bortezomib IMiDs Alkylating agent Corticosteroid Refractory to the most recent regimen Platelets Creatinine clearance 15 ml/min Carfilzomib Arm IV [10-min infusion] Days 1, 2, 8, 9, 15, and 16 of 28-day cycles for cycles mg/m 2 on days 1 and 2 of cycle 1 27 mg/m 2 thereafter Days 1, 2, 15, and 16 of 28-day cycles for cycles 10 Control Arm Corticosteroid (prednisone 30 mg PO, dexamethasone 6 mg PO, or equivalent) every other day) Optional cyclophosphamide (50 mg PO every day) 1:1 randomization Stratified by: Number of prior therapies Geographic region Multicenter (81 sites): Europe, Asia-Pacific

44 Patient and Disease Characteristics at Baseline Characteristic Carfilzomib (n=157) Median age, years (range) 63 (32 85) 65 years, % 47.8 ECOG performance status, % Cytogenetic risk category by FISH, % High 14.0 Standard 43.3 Unknown 42.7 ISS stage at baseline, % I II 49.7 III 48.4 Control (n=158) 66 (43 81) Measurable disease category, % Light chain proteinuria/ UPEP-positive ECOG, Eastern Cooperative Oncology Group; FISH, fluorescence in situ hybridization; ISS, International Staging System; UPEP, urine protein electrophoresis

45 Patient and Disease Characteristics at Baseline (continued) Characteristic Number of prior regimens, median (range) >6 prior regimens, % Carfilzomib (n=157) 5 (3 15) 28.7 Control (n=158) 5 (3 17) 27.8 Time from initial diagnosis to start of FOCUS, median years (range) Prior therapies, % Bortezomib/IMiD/alkylator/corticosteroid Transplant Anthracycline Refractory, % Bortezomib (any prior regimen) Bortezomib (last prior regimen) IMiD (any prior regimen) Bortezomib and IMiD (any prior regimen) Creatinine clearance, % <30 ml/min 30 <50 ml/min 45 IMiD, immunomodulatory agent 6 ( ) 5.4 ( )

46 Treatment Received Treatment Carfilzomib (n=157) Control (n=153) Median number of cycles (range) 5 (1 35) 3 (1 35) Median K relative dose intensity, % Median corticosteroid relative dose intensity, % Received optional cyclophosphamide, % Median cyclophosphamide dose received, mg/cycle** Relative dose intensity = actual dose intensity / planned dose intensity 46 *Maximal dexamethasone dose per cycle: 84 mg **Maximal cyclophosphamide dose per cycle: 1400 mg

47 Primary Endpoint: Overall Survival Proportion surviving Carfilzomib Control Deaths, n Median OS, mo HR (95% CI) ( ) One-sided P value No. at Risk Carfilzomib Control Carfilzomib Control Censored Time from randomization (months)

48 Secondary Endpoints: Response Response, n (%) Best overall response Carfilzomib (n=157) Control (n=158) One-sided P-value* VGPR 6 (3.8) 5 (3.2) - PR 24 (15.3) 13 (8.2) - MR 19 (12.1) 15 (9.5) - ORR 30 (19.1) 18 (11.4) 0.03 CBR 49 (31.2) 33 (20.9) 0.02 DCR 119 (75.8) 107 (67.7) 0.05 Median DOR, months (95% CI) 7.2 ( ) 9.5 (3.7 NE) - *Multiplicity unadjusted p-value 48 CI, confidence interval; DCR, disease control rate; DOR, duration of response; MR, minimal response; NE, not estimable; ORR, overall response rate; PR, partial response; VGPR, very good partial response

49 Secondary Endpoint: Progression-Free Survival Proportion progression-free No. at Risk Carfilzomib Control Carfilzomib Control Censored Time from randomization (months) Carfilzomib Control Events, n Median PFS, mo HR (95% CI) ( ) One-sided P value* 0.25 *Multiplicity unadjusted p-value More censoring due to non-protocol therapy in the control arm (32; 20.3%) compared with the K arm (12; 7.6%) in the PFS analysis

50 NOVEL THERAPEUTIC STRATEGIES

51 Relapsed MM Patient

52 Drugs tested in relapsed myeloma

53

54

55 Monoclonal antibodies in Myeloma

56 Carfilzomib, Lenalidomide, and Dexamethasone vs Lenalidomide and Dexamethasone in Patients with Relapsed Multiple Myeloma: Interim Results from ASPIRE, a Randomized, Open-Label, Multicenter Phase 3 Study A. Keith Stewart, S. Vincent Rajkumar, Meletios A. Dimopoulos, Tamás Masszi, Ivan Spicka, Albert Oriol, Roman Hájek, Laura Rosiñol, David S. Siegel, Georgi G. Mihaylov, Vesselina Goranova-Marinova, Péter Rajnics, Aleksandr Suvorov, Ruben Niesvizky, Andrzej Jakubowiak, Jesus F. San Miguel, Heinz Ludwig, Naseem Zojwalla, Margaret E. Tonda, Biao Xing, Philippe Moreau and Antonio Palumbo 56 NEJM, Jan 8 th, 2015

57 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 57

58 Secondary Endpoints: Response P< P< Percentage of Patients scr 14.1% vs 4.3% P< KRd Rd 0 CR VGPR ORR ( PR) Median duration of response was 28.6 months in the KRd group and 21.2 months in 58 the Rd group

59 Primary Endpoint: Progression-Free Survival ITT Population (N=792) Proportion Surviving Without Progression No. at Risk: KRd Rd KRd Rd KRd (n=396) Months Since Randomization Rd (n=396) Median PFS, mo HR (KRd/Rd) (95% CI) 0.69 ( ) P value (one-sided) <

60 Primary Endpoint: Progression-Free Survival ITT Population (N=792) Proportion Surviving Without Progression No. at Risk: KRd Rd KRd Rd KRd (n=396) Months Since Randomization Rd (n=396) Median PFS, mo HR (KRd/Rd) (95% CI) 0.69 ( ) P value (one-sided) <

61 PFS by Risk Group KRd (n=396) Rd (n=396) Risk Group by FISH N Median, months N Median, months HR P-value (one-sided) High

62 PFS by Risk Group KRd (n=396) Rd (n=396) Risk Group by FISH N Median, months N Median, months HR P-value (one-sided) High Standard

63 Secondary Endpoints: Interim Overall Survival Analysis Median Follow-Up 32 Months Proportion Surviving No. at Risk: KRd Rd KRd Rd Months Since Randomization KRd (n=396) Rd (n=396) Median OS, mo NE NE HR (KRd/Rd) (95% CI) 0.79 ( ) P value (one-sided) Median OS was not reached; results did not cross the prespecified stopping boundary (P=0.005) at the interim analysis 63

64 Conclusions PFS was significantly improved by 8.7 months with KRd (HR, 0.69; P<0.0001) An unprecedented median PFS of 26.3 months with KRd Interim OS analysis: trend in OS favoring the KRd group; Kaplan-Meier 24-month OS rates 73.3% (KRd) versus 65.0% (Rd) ORR was higher with KRd (87.1% vs 66.7%); significantly more patients achieved CR (31.8% vs 9.3%) 64 QoL Global Health Status improved

65 UK-REV Feb 2013 A Multi-Center Phase I/II Trial of Carfilzomib and Pomalidomide with Dexamethasone (Car-Pom-d) in Patients with Relapsed/Refractory Multiple Myeloma J.J. Shah, M.D. 1, E.A. Stadtmauer, MD 2, R. Abonour, MD 3, A.D. Cohen, MD 4, W.I. Bensinger, MD 5, C. Gasparetto, MD 6, J.L. Kaufman, MD 7, S. Lentzsch, MD 8, D.T. Vogl, MD, MSCE 2, R.Z. Orlowski, M.D., Ph.D 1, E.L. Kim, MPH 9, M.B. McKinley, BSN, MBA 9 and B.G.M. Durie, MD 10 1 M. D. Anderson Cancer Center, Houston, TX; 2 Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; 3 Indiana University Simon Cancer Center, Indianapolis, IN; 4 Fox Chase Cancer Center, Philadelphia, PA; 5 Fred Hutchinson Cancer Research Center, Seattle, WA; 6 Duke University Medical Center, Durham, NC; 7 Winship Cancer Institute of Emory University, Atlanta, GA; 8 Columbia University Herbert Irving Comprehensive Cancer Center, NY; 9 Academic Myeloma Consortium (AMyC), CORE Science Solutions, A Criterium Company, Culver City, CA; 10 Cedars-Sinai Samuel Oschin Cancer Center, Los Angeles, CA. Wang et al. ICML. 2011; Oral Presentation & Abstract 109 Shah et al: ASH 2012; Oral & Abstract 74.

66 Study objectives and design UK-REV Feb 2013 Primary objectives: MTD and tolerability of Car-Pom-dex in RRMM Secondary objectives: ORR, TTP, PFS, OS and TNT Phase I (n=12) 3+3 dose-escalation with dose expansion (n=20) at MTD: CAR POM DEX Cohort-1 27 mg/m 2 * 3 mg 40 mg ** Cohort 1 (initial dose level) 27 mg/m 2 * 4 mg 40 mg ** Cohort 2 36 mg/m 2 * 4 mg 40 mg ** Cohort 3 45 mg/m 2 * 4 mg 40 mg ** Cohort 4 56 mg/m 2 * 4 mg 40 mg ** Cycle 1 6 (28d cycle) CAR D1,2,8,9,15,16 POM D1 21 DEX Weekly Cycles: 7+ (28d cycle)*** CAR D1,2,15,16 POM D1 21 DEX Weekly MTD was determined as CAR 20/27 mg/m 2, POM 4 mg, DEX 40mg * CAR doses on days 1 and 2 of cycle 1 for all cohorts was 20 mg/m 2 ; subsequent dosing shown in table ** DEX reduced to 20 mg after cycle 1 *** Patients treated until progression / unacceptable toxicity MTD: maximum tolerated dose; ORR: overall response rate; TTP: time to progression; TNT: time to next therapy; PFS: progression free survival; OS: overall survival; Car: carfilzomib; POM: pomalidomide; DEX: dexamethasone Shah et al: ASH 2012; Oral & Abstract 74.

67 Patient demographics UK-REV Feb 2013 Eligibility criteria: R/R MM; prior Tx with and refractory to LEN Characteristic N = 32 Gender Male: 20 (62.5%) Female: 12 (37.5%) Age, median (range) 63.5 years (44 78) N prior regimens, median (range) 6 (1 15) ECOG PS 0: 16 (50%) 1: 14 (44%) 2: 2 (6%) Years since initial DEX, median (range) 5.0 years ( ) Prior stem cell transplant 21 (65.6%) Prior BORT 31 (97%)* Prior LEN 32 (100%) * All but two patients refractory R/R: relapsed and/or refractory; Tx: treatment; LEN: lenalidomide; N: number; DEX: dexamethasone; BORT: bortezomib ; MM: multiple myeloma; ECOG: Eastern Cooperative Oncology Group. Shah et al: ASH 2012; Oral & Abstract 74.

68 Results: Efficacy UK-REV Feb 2013 Clinical benefit rate ( MR) = 67% Responses observed in high-risk cytogenetic patients Responses & OS were sustain & durable independent of risk status Percentage response ALL (n=30) High / Int Risk (n=11) SD MR PR VGPR All Patients N = 30 Median PFS 7.4 months 1 year OS 90% * High / Int Risk defined as 17p-positive, t(4:14), t(14:16), hypodiploid by msmart risk classification ORR: overall response rate; VGPR: very good partial response; PR: partial response; MR: minimal response; SD: stable disease; PFS: progression free survival; OS: overall survival; Int: intermediate. Shah et al: ASH 2012; Oral & Abstract 74.

69 UK-REV Feb 2013 Results: Tolerability Grade 3 / 4 Haematological AEs 20% patients All Grades n(%) Grade 3/4 n(%) Anaemia 20 (62) 12 (37) Neutropenia 18 (56) 9 (28) Thrombocytopenia 27 (84) 18 (56) Febrile neutropenia 2 (6) 2 (6) Grade 3 / 4 Non Haematological AEs 20% patients All Grades n(%) Grade 3/4 n(%) Diarrhoea 10 (31) 0 (0) Fatigue 18 (56) 1 (3) Dyspnoea 9 (28) 0 (0) Hypocalcaemia 11 (34) 0 (0) No grade 3 / 4 Peripheral neuropathy AEs: adverse events. Shah et al: ASH 2012; Oral & Abstract 74.

70 UK-REV Feb 2013

71 UK-REV Feb 2013 Authors conclusions MTD was CAR 20/27 mg/m 2, POM 4 mg, DEX 40mg in RRMM Limited grade 3/4 non haematological toxicities, the regimen was well tolerated and highly active in heavily pre-treated, refractory patients Enrolment on-going for an 82-patient phase II trial in the Mayo Clinic MTD: maximum tolerated dose; CAR: carfilzomib; POM: pomalidomide; DEX: dexamethasone Shah et al: ASH 2012; Oral & Abstract 74.

72 S471 ELOQUENT-2: a phase 3, randomized, open-label study of lenalidomide/dexamethasone with/without elotuzumab in patients with relapsed/refractory multiple myeloma Meletios Dimopoulos* 1, Sagar Lonial 2, Antonio Palumbo 3, Darrell White 4, Sebastian Grosicki 5, Ivan Spicka 6, Adam Walter-Croneck 7, Philippe Moreau 8, Maria-Victoria Mateos 9, Hila Magen 10, Andrew Belch 11, Donna Reece 12, Meral Beksac 13, Andrew Spencer 14, Heather Oakervee 15, Masafumi Taniwaki 16, Christoph Röllig 17, Ka Lung Wu 18, Anil Singhal 19, Jesus San Miguel 20, Morio Matsumoto 21, Jessica Katz 22, Eric Bleickardt 23, Valerie Poulart 24 and Paul Richardson 25 on behalf of the ELOQUENT-2 Investigators 1 National and Kapodistrian University of Athens, Athens, Greece; 2 Winship Cancer Institute, Emory University School of Medicine, Atlanta, USA; 3 A.O.U. San Giovanni Battista di Torino - Ospedale Molinette, Torino, Italy; 4 QEII Health Science Center and Dalhousie University, Halifax, Canada; 5 Silesian Medical University, Katowice, Poland; 6 Charles University Hospital, Prague, Czech Republic; 7 Medical University of Lublin, Lublin, Poland; 8 University Hospital, Nantes, France; 9 University Hospital of Salamanca-IBSAL, Salamanca, Spain; 10 Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, and Tel Aviv University, Ramat Aviv, Israel; 11 Cross Cancer Institute and University of Alberta, Edmonton, Canada; 12 Princess Margaret Hospital, Toronto, Canada; 13 Ankara University, Ankara, Turkey; 14 Alfred Health-Monash University, Melbourne, Australia; 15 Barts and the London NHS Trust, London, UK; 16 Kyoto Prefectural University of Medicine, Kyoto, Japan; 17 Universitatsklinikum der TU, Dresden, Germany; 18 ZNA Stuivenberg, Antwerp, Belgium; 19 AbbVie Biotherapeutics Inc. (ABR), Redwood City, USA; 20 Clinical Universidad de Navarra, Pamplona, Spain; 21 Nishigunma National Hospital, Shibukawa, Japan; 22 Bristol-Myers Squibb, Princeton, USA; 23 Bristol-Myers Squibb, Wallingford, USA; 24 Bristol- Myers Squibb, Braine-l'Alleud, Belgium; 25 Dana-Farber Cancer Institute, Boston, USA Presented at the European Hematology Association (EHA) 20th Congress; Vienna, Austria; June 11 14,

73 From N Engl J Med, Lonial S et al, Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. Copyright (2015) Massachusetts Medical Society. Reprinted with permission

74 ELOQUENT-2 Study Design Open-label, international, randomized, multicenter, phase 3 trial (168 global sites) Key inclusion criteria RRMM 1 3 prior lines of therapy Prior Len exposure permitted in 10% of study population (patients not refractory to Len) Elo plus Len/Dex (E-Ld) schedule (n=321) Elo (10 mg/kg IV): Cycle 1 and 2: weekly; Cycles 3+: every other week Len (25 mg PO): Days 1 21 Dex: weekly equivalent, 40 mg Len/Dex (Ld) schedule (n=325) Len (25 mg PO): Days 1 21; Dex: 40 mg PO Days 1, 8, 15, 22 Assessment Tumor response: every 4 weeks until progressive disease Survival: every 12 weeks after disease progression Endpoints: Co-primary: PFS and ORR Repeat every 28 days Other: overall survival (data not yet mature), duration of response, quality of life, safety All patients received premedication to mitigate infusion reactions prior to elotuzumab administration Elotuzumab IV infusion administered ~ 2 3 hours

75 Baseline Demographics and Disease Characteristics Characteristic E-Ld (n=321) Ld (n=325) Age (years), median (range) 67 (37 88) 66(38 91) 65 years 187 (58) 183 (56) Region, % Europe North America Rest of the world International Staging System disease stage, n (%) I II III Not reported 4 14 Cytogenetics (FISH) del(17p) Yes No Not reported 2 1 t(4;14) Yes 9 10 No Not reported 2 1 1q21 Yes No Not reported 2 1 FISH = fluorescence in situ hybridization

76 Baseline Demographics and Disease Characteristics Characteristic E-Ld (n=321) Ld (n=325) Prior regimens, median (range) 2 (1 4) 2 (1 4) Prior therapies, % Bortezomib Melphalan * Thalidomide Lenalidomide 5 7 Response to most recent line of therapy, % Refractory Bortezomib refractory Thalidomide refractory 9 11 Relapsed Prior stem cell transplantation, % * Oral or intravenous. Prior lenalidomide was permitted if best response was partial response and patients were not refractory to prior lenalidomide treatment; patients could not receive more than 9 cycles of lenalidomide and had at least 9 months between the last dose of lenalidomide and progression. One patient in the elotuzumab group had an unknown response to the most recent line of therapy

77 Treatment Summary E-Ld (n=321) Ld (n=325) Number of treatment cycles, median (range) 19 (1 42) 14 (1 40) Patients on treatment, n (%)* 113 (35) 66 (21) Duration of treatment, median (wk) Full dose intensity (i.e. 90%), n (%) Elotuzumab 264 (83) Lenalidomide 163 (51) 161 (51) Dexamethasone 146 (46) 148 (47) *At the time of the cut-off date for the interim analysis

78 Co-primary Endpoint: Progression-Free Survival Probability progression free year PFS 68% 57% 2-year PFS 41% 27% Median PFS (95% CI) E-Ld HR 0.70 (95% CI 0.57, 0.85); p= mo (16.6, 22.2) Ld E-Ld Ld 14.9 mo (12.1, 17.2) 0.0 No. of patients at risk: E-Ld Ld PFS (months) From N Engl J Med, Lonial S et al, Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. Copyright (2015) Massachusetts Medical Society. Reprinted with permission E-Ld treated patients had a 30% reduction in the risk of disease progression or death; treatment difference at 1 and 2 years was 11% and 14%, respectively PFS analysis used the primary definition of PFS

79 Co-primary Endpoint: Overall Response Rate 100 p= E-Ld Ld Response rate (%) Overall response rate* Combined response (scr + CR + VGPR) 4 7 Complete response (scr + CR) Very good partial response Partial response *Defined as partial response or better. Complete response rates in the E-Ld group may be underestimated due to interference from therapeutic antibody in immunofixation and serum protein electrophoresis assay

80 Phase I Trial: Daratumumab in Combination With Len/Dex in Rel/Ref MM Phase I/II dose-escalation trial of daratumumab in combination with len/dex in rel/ref MM (safety cohort: n =45; efficacy cohort: n = 43) Daratumumab is a human mab targeting CD38-expressing cells Dose escalation: daratumumab 2-16 mg/kg/wk for 8 wks, twice monthly for 16 wks, then once monthly for 24 mos in total or until PD, unmanageable AE Lenalidomide 25 mg on Days 1-21 of each 28-day cycle Dexamethasone 40 mg/wk for of each 28-day cycle Median prior lines of therapy: 2 (range: 1-4); most with prior exposure to IMiDs and/or a proteasome inhibitor; 3 pts refractory to len MTD: daratumumab 16 mg/kg + len 25 mg and dex 40 mg/wk Plesner T, et al. ASH Abstract 84.

81 Daratumumab in Combination With Len/Dex: Overall Best Response Overall Best Response VGPR or Better Response by Cycles of Treatment (Part 2) CR 31% CR 6.7% CR 6.7% 60 CR 8.0% 64.7 CR 11.8% PR VGPR Pats (%) VGPR 46% PR 23% Part 1 VGPR 43% PR 37% Part 2 Pts (%) VGPR 43.3% 2 Cycles (n = 30) VGPR 52% 4 Cycles (n = 25) VGPR 52.9% 6 Cycles (n = 7) CR Mean follow-up: 12.9 mos (Part 1); 5.6 mos (Part 2) Median time to response: 1 mo for 16 mg/kg in Part 2; median time to CR: 4.9 mos in Part 2 Plesner T, et al. ASH Abstract 84. Reproduced with permission.

82 Daratumumab in Combination With Len/Dex: Adverse Events Most Common (Incidence in > 10% Pts) AEs, % Part 1 (n = 13) Part 2 (n = 32) Total (N = 45) Total number of pts with AEs Neutropenia Muscle spasms Diarrhea Fatigue Cough Constipation Nausea Nasopharyngitis Bone pain Upper respiratory tract infection Insomnia Dyspnea Anemia Plesner T, et al. ASH Abstract 84.

83 Daratumumab in Combination With Len/Dex: Safety Daratumumab related serious AEs Pneumonia, neutropenia, diarrhea (1 pt each receiving 16 mg/kg, early infusion program) Laryngeal edema (1 pt receiving 16 mg/kg, accelerated infusion program) 60 First Infusion Infusion-Related Reactions 63.6 Pts (%) Subsequent Infusion mg/kg Part 1 (n = 10) 16 mg/kg Part 1 (n = 3) 16 mg/kg Part 2 Current Infusion Program (n = 21) 16 mg/kg Part 2 Accelerated Infusion Program (n = 11) 19/45 pts reported infusion-related reactions; mostly grade 1-2 Plesner T, et al. ASH Abstract 84. Reproduced with permission.

84 Phase I Trial: SAR in Combination With Len/Dex in Relapsed/Refractory MM Phase Ib trial of SAR len/dex in relapsed/refractory MM SAR is a humanized IgG1 mab to the CD38 receptor widely expressed in many heme malignancies Dose escalation: SAR mg/kg on Days 1 and 15 of each 28- day cycle + lenalidomide 25 mg on Days 1-21 of each 28-day cycle and dexamethasone 40 mg/wk during each 28-day cycle Previous MM Treatment SAR Dose, mg/kg q2w 3 (n = 4) 5 (n = 3) 10 (n = 24) Overall (N = 31) Median prior regimens, n (range) 10 (3-14) 7 (6-7) 6 (2-12) 7 (2-14) Median prior lines, n (range) 6 (2-11) 6 (4-6) 4 (1-9) 4 (1-11) Median time on last Len, mos (range) 7 (3-17) 3 (3-10) 10 (1-54) 9 (1-54) Relapsed/refractory to IMiD 3 (75) 2 (67) 21 (88) 26 (84) Martin TG, et al. ASH Abstract 83.

85 SAR Len/Dex: Efficacy Analysis DoR: 9.13 mo (range: ) Response, % Total (N = 31) ORR 58 scr 6 VGPR 23 PR 29 CBR 65 MR 6 SD 19 PD 13 Not evaluable 3 Pts (%) MR ORR 25% CBR 50% (n = 4) PR ORR 67% CBR 67% 67 5 (n = 3) VGPR ORR 63% CBR 67% 4 10 (n = 24) ORR 58% CBR 65% Overall (n = 31) SAR Dose Level, mg/kg q2w 8 29 scr Martin TG, et al. ASH Abstract 83. Reproduced with permission.

86 SAR Len/Dex: PFS by Previous Lines of Therapy prior lines (n = 7) Overall (N = 31) 3 prior lines (n = 24) Median PFS: NR (95% CI: 6.2-NR) Probability Median PFS: 6.2 mos (95% CI: ) Median PFS: 5.8 mos (95% CI: ) Mos Martin TG, et al. ASH Abstract 83. Reproduced with permission.

87 SAR plus Len/Dex: Tx-Emergent AEs 100 Grade 1 Grade 2 Grade 3 Grade 4 Pts (n = 31) (%) There were 15 incidences of infusion reaction, all occurring in the first 2 cycles 2 pts discontinued treatment: 1 serious grade 3 anaphylactic reaction in cycle 1 and 1 nonserious grade 3 maculopapular rash in cycle 2 (AEs resolved in both pts) Remaining incidents were grade 1/2 and did not lead to treatment discontinuation Martin TG, et al. ASH Abstract 83. Reproduced with permission.

88 Agents under Investigation Ixazomib combinaion Panorama 1 Bortezomib/ Panobinostat/ Dexamethasone CD19 CAR -N Engl J Med 2015;373: NYESO ex vivo TCR engineered T cells ( Nature pre pub July 2015) ARRY-520, Kinesin spindle protein inhibitor

89 Conclusion Relapse MM patients required detailed clinical assessment Discussion at MDT recommended Consider clinical trials where appropriate Second ASCT is treatment of choice for selected cohort of 1 st relapse MM patients Combination of PI/Mab + IMiD + Dex DRMM management remains challenging with OS less than a year