New Agents in Multiple Myeloma. Saad Z Usmani, MD FACP

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1 New Agents in Multiple Myeloma Saad Z Usmani, MD FACP

2 The Context Advances in understanding myeloma biology has led to new therapeutic targets 100% 80% 60% TT3 OVERALL SURVIVAL Low-risk (42 / 363) Genomically defined Lowrisk patients make up ~85%, benefiting most from strategy combining novel agents and high dose melphalan. Management strategies are focusing on changing myeloma in to a curative and/or chronic illness for majority of patients. 40% 20% P <.0001 High-risk (30 / 77) 0% Years from start of treatment TT3 EVENT-FREE SURVIVAL 100% 80% 60% Low-risk (53 / 363) 40% 20% P <.0001 High-risk (35 / 77) 0% Years from start of treatment

3 Prognostic variables Tumor burden related: Serum b2 microglobulin levels Serum Albumin levels Elevated ESR or CRP levels (surrogate for IL6 ) > 3 lytic lesions on X-rays > 3 PET-avid focal lesions > 7 MRI focal lesions Serum calcium Percent BM plasmacytosis Tumor biology related: Having no CA is better than having any CA Still considered bad in year 2013: Translocation 14;16 (MAF overexpression) Translocation 14;20 (MAFB overexpression) Deletion 17p (p53 deletion) Amplification of chromosome 1q21 (overexpression of multiple genes, more prominently proteasome genes)? Translocation 4;14 GEP MyPRS High Risk (Arkansas 70-gene Signature) SKY-92 High Risk (HOVON 92-gene signature) Plasma cell labeling index, Bartl grade Clinical phenotypes Primary Plasma Cell Leukemia Extramedullary Disease Patient related: Age, Performance status, Comorbidities.

4 The Challenges Personalizing the right Total Therapy for individual patient with standard/low risk MM based on host factors, disease biology and disease burden. Identification of biologically defined high-risk MM (either asymptomatic or symptomatic) moving target. Better tools to judge depth of response and disease eradication. Different strategy needed for high-risk MM with investigational new drugs in Phase I/II clinical trial setting.

5 The Hope Robust pipeline of anti-myeloma novel drug classes are in development: Proteasome Inhibitors (parenteral and oral) Immunomodulatory drugs (IMiDs) Monoclonal antibodies Anti-CS1, Anti-DKK1, Anti-CD38, Anti-PD1, Anti-IL6, Anti- KIR, Anti-CD6 Kinesin spindle protein (KSP) Inhibitors Histone deacetylase (HDAC) Inhibitors Heat shock protein 90 (HSP90) Inhibitors Bruton's Tyrosine Kinase (BTK) Inhibitors Incorporation of MRD analyses and novel imaging in disease response assessment Presented by: Saad Z Usmani, MD FACP

6 ASCO 2013 #8512: Phase I/II dose-escalation study of daratumumab in patients with relapsed or refractory multiple myeloma. #8514: Weekly MLN9708, an investigational oral proteasome inhibitor (PI), in relapsed/refractory multiple myeloma (MM): Results from a phase I study after full enrollment. #8513: Effect of CMP, carfilzomib (CFZ) plus melphalanprednisone (MP), on response rates in elderly patients (pts) with newly diagnosed multiple myeloma (NDMM): Results of a phase (Ph) I/II trial. Presented by: Saad Z Usmani, MD FACP

7 DARATUMUMAB, A CD38 MONOCLONAL ANTIBODY IN PATIENTS WITH MULTIPLE MYELOMA Data from the dose-escalation (part I) and preliminary safety data from the extension part (part II) of the FIH study Abstract #8512 Henk Lokhorst, Torben Plesner, Peter Gimsing, Hareth Nahi, Monique Minnema, Ulrik Lassen, Jakub Krejcik, Jacob Laubach, Steen Lisby, Linda Basse, Paul Richardson University Medical Center Utrecht, Netherlands; Vejle Hospital, Denmark; Rigshospitalet, Copenhagen, Denmark; Karolinska Institutet, Stockholm, Sweden; Genmab A/S, Copenhagen, Denmark; Dana-Farber Cancer Institute, Boston, MA, USA

8 #8512: Daratumumab Trial Design PART 1 Doseescalation cohorts Open label, weekly i.v. infusion, 8 weeks Dose-escalation: 3+3 scheme* mg/kg PART 2 Expansion cohort Open label, single arm, i.v. infusion weekly: 8 weeks every other week: 16 weeks every fourth week: up to 96 weeks 8 mg/kg, 16 patients * - start with pre-dose at 10% of the full dose, max 10 mg - three weeks delay after first full dose - governed by independent data monitoring committee

9 #8512: Daratumumab Patients Characteristics (Part 1: N=32 Part 2: N=16) Cohort No subject Age a No of prior treatment Refractory to Len and Bort Len/Thal b Bort b Dex/Steroid other b Chemo b,c Auto/Allo b 1 mg/kg (42-76) 5 (2-8) e 88% / 71% 100% 88% / 41% 100% 65% / 12% 2 mg/kg 3 64 (60-71) 8 (6-10) e 100% / 100% 100% 100% / 100% 100% 100% / 0% 4 mg/kg 3 64 (62-66) 3 d (3-8) 67% f 100% / 33% 100% 100% / 33% 100% 67% / 33% 8 mg/kg 3 60 (56-68) 8 d (6-12) 100% f 100% / 67% 100% 100% / 67% 100% 100% / 33% 16 mg/kg 3 55 (54-59) 4 d (4-5) 67% f 100% / 67% 100% 100% / 33% 100% 100% / 67% 24 mg/kg 3 58 (50-69) 6 d (4-6) 67% f 100% / 67% 100% 100% / 33% 100% 67% / 0% PART mg/kg PART 2 8 mg/kg (50-69) 5.5 (3-12) 75% 100% / 58% 100% 100% / 42% 100% 83% / 33% (41-77) 4 (3-7) 69% 94% / 50% 100% 81% / 81% 100% 81% / 31% Allo: allogeneic stem cell transplantation, Auto: autologous stem cell transplantation, Bort: bortezomib, Chemo: chemotherapy, Len: lenalidomide, No: number, Thal: thalidomide a: median (range), b: number of patients exposed to the drug, c: vincristine, doxorubicin, cyclophosphamide, melphalan and others, d: revised after additional data collection, e: data not collected, f: data collected retrospectively

10 #8512: Daratumumab SAEs Assessed Related to Daratumumab Event Bronchospasm Anemia PART 1 N=32 1 patient: grade 3 (2 mg/kg) 1 patient: grade 2 (24 mg/kg) 1 patient: grade 3 (0.1 mg/kg) (DLT) PART 2 N= Thrombocytopenia 1 patient: grade 4 (0.1 mg/kg) 0 ASAT > 5.2 times upper limit of normal 1 patient: grade 3 (1.0 mg/kg) (DLT) 0 Cytokine release syndrome 1 patient: grade 2 (0.1 mg/kg) 0 Corticosteroids have been added as premedication: Prednisone 50 mg orally the day before infusion Dexamethasone 10 mg IV the day of infusion

11 #8512: Daratumumab Responses Progression Free Survival

12 #8512: Daratumumab Conclusion Daratumumab has shown a favorable safety profile as monotherapy in relapsed or relapsed and refractory Multiple Myeloma patients In part 1, where 15 of 32 (47%) heavily pre-treated evaluable Multiple Myeloma patients received 8 weeks of daratumumab as monotherapy in doses up to 24 mg/kg, a reduction in paraprotein was observed In 10 of these 32 patients (31%), this reduction qualified to a clinical response: 4 patients achieving PR (13%) 6 patients achieving MR (19%) Still in part 1, 8 of 12 patients (66%) at doses 4 mg/kg and above achieved a clinical response: 4 patients achieving PR (33%) 4 patients achieving MR (33%) Further studies to optimize both outcome and schedule are being planned No information reported on standard versus poor prognostic clinical or biologic features

13 Weekly MLN9708, an investigational oral proteasome inhibitor, in relapsed/refractory multiple myeloma: Results from a phase I study after full enrollment (Abstract #8514) Shaji K. Kumar, 1 William I. Bensinger, 2 Todd M. Zimmerman, 3 Craig B. Reeder, 4 James R. Berenson, 5 Deborah Berg, 6 Ai-Min Hui, 6 Neeraj Gupta, 6 Alessandra Di Bacco, 6 Jiang Yu, 6 Yaping Shou, 6 Ruben Niesvizky 7 1 Division of Hematology, Mayo Clinic, Rochester, MN; 2 Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, WA; 3 Department of Medicine, University of Chicago, Chicago, IL; 4 Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ; 5 Institute for Myeloma and Bone Cancer Research, West Hollywood, CA; 6 Millennium: The Takeda Oncology Company, Cambridge, MA; 7 Center of Excellence for Lymphoma and Myeloma, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY

14 #8514: Study design Oral single-agent MLN9708 administered on days 1, 8, and 15 of a 28-day cycle, for up to 12 cycles* Doseescalation cohorts Dose-escalation: 3+3 schema, based on cycle 1 DLTs (modified Fibonacci dose sequence) mg/m 2 MTD established Relapsed and refractory cohort Refractory to most recent therapy (PD while on therapy or within 60 days after last dose of therapy) Bortezomibrelapsed cohort Relapsed after previous bortezomib therapy but not refractory Expansion cohorts Proteasome inhibitor-naïve cohort Relapsed after 1 therapy, must include an IMiD and corticosteroids, no proteasome inhibitor DLT=dose-limiting toxicity; IMiD=immunomodulatory drug; PD=progressive disease. *Patients could receive prolonged treatment if benefitting from therapy Prior carfilzomib cohort Received prior carfilzomib and with relapsed or refractory disease

15 Patients Inclusion criteria: Age 18 years ECOG performance status of 0 2 For dose-escalation cohorts: relapsed or refractory MM after 2 prior therapies, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids For the four expansion cohorts: criteria per previous figure Measurable disease (serum M-protein 1 g/dl or urine M-protein 200 mg/24 hours) Exclusion criteria: Grade 2 peripheral neuropathy (PN) Grade >1 diarrhea No concomitant corticosteroid use at therapeutic dose

16 Patient characteristics Characteristics Dose-escalation cohorts (n=32) Median age, years (range) 64 (40 76) Expansion cohorts (n=31)* 65 (40 79) Total (N=60) 64 (40 79) Male, % White / African American / Other, % 78 / 22 / 0 94 / 0 / 6 85 / 12 / 3 Median time since MM diagnosis, years (range) Median no. prior lines of therapy (range) 4.9 ( ) 4.9 ( ) 4.9 ( ) 4 (1 13) 3 (1 12) 4 (1 13) Bortezomib, % Lenalidomide, % Thalidomide, % Carfilzomib/marizomib, % SCT, % Refractory to last therapy, % Bortezomib-refractory, # % *Includes 3 patients from MTD dose-escalation cohort. Persian. Protocol violation. # On last prior therapy.

17 Cytogenetics / FISH Patients with cytogenetic assessment, n Doseescalation cohorts (n=32) Expansion cohorts (n=31)* Total (N=60) Cytogenetics by FISH, n/n (%) 18/31 (58) 12/18 (67) 30/49 (61) Unfavorable abnormalities, n (%) t(4;14) 1 (6) 0 1 (3) t(14;16) 0 1 (8) 1 (3) 17p 3 (17) 0 3 (10) Hyperdiploidy 5 (28) 7 (58) 12 (40) *Includes 3 patients from MTD dose-escalation cohort.

18 Dose-limiting toxicity 3 patients experienced DLTs: 2 of 4 DLT-evaluable patients treated at 3.95 mg/m 2 Grade 3 nausea, grade 3 vomiting, and grade 3 diarrhea Grade 3 erythema multiforme rash 1 of 6 DLT-evaluable patients treated at 2.97 mg/m 2 Grade 3 nausea, grade 3 vomiting, and grade 3 diarrhea In all 3 cases, the DLTs resolved and patients continued on a lower dose of MLN9708 MTD of weekly oral MLN9708 was determined to be 2.97 mg/m 2 This dose level was therefore used for the treatment of patients in the four expansion cohorts

19 Conclusions Oral MLN9708 generally well tolerated AEs consisted mostly of hematologic and gastrointestinal events and were generally manageable, with a low rate of discontinuations Infrequent PN, with only 1 case of grade 3 PN observed Pharmacokinetic profile supports oral once a week dosing Phase 1 data suggest clinical activity in relapsed and/or refractory MM patients (median 4 prior lines of therapy) ORR ( PR) of 18%, plus 2% MR and 30% SD Exclusion of PN >grade 2 makes data less applicable to community practice population Low proportion of bortezomib resistant patients does MLN9708 really work in this patient population OR will it simply be an oral replacement for bortezomib? Low Proportion of High Risk Cyto/FISH Abnormalities In The Study Suggest looking at 1q21 amplification which has implications for PI resistance (Shaughnessy et al Blood 2011)

20 Randomization Future directions Other single-agent and combination trials initiated/ongoing, including: Phase 3 trial of weekly oral MLN9708 plus lenalidomide and low-dose dexamethasone versus placebo, lenalidomide, and low-dose dexamethasone in patients with relapsed and/or refractory MM (NCT ; TOURMALINE-MM1) Patient population: Approximately 703 patients with relapsed and/or refractory MM following 1 3 prior lines of therapy, who are not refractory to prior lenalidomide or proteasome inhibitor-based therapy MLN mg, days 1, 8, 15 Lenalidomide 25 mg, days 1 21 Dexamethasone 40 mg, days 1, 8, 15, 22 Repeat every 28 days until disease progression, unacceptable toxicity, or subsequent therapy Oral placebo, days 1, 8, 15 Lenalidomide 25 mg, days 1 21 Dexamethasone 40 mg, days 1, 8, 15, 22 Repeat every 28 days until disease progression, unacceptable toxicity, or subsequent therapy Endpoints: Primary: PFS Key secondary: OS, OS in patients with del(17) Other secondary: ORR, CR+VGPR rate, TTP, safety, PFS/OS in highrisk patients, change in global health status Phase 3 trial of weekly oral MLN9708 plus lenalidomide and low-dose dexamethasone versus placebo, lenalidomide, and low-dose dexamethasone in previously untreated transplant-ineligible MM patients (NCT )

21 Effect of CMP, Carfilzomib (CFZ) plus Melphalan Prednisone (MP), on response rates in elderly patients with newly diagnosed multiple myeloma: results of a phase I/II trial Cyrille Touzeau, Brigitte Kolb, Cyrille Hulin, Denis Caillot, Lofti Benboubker, Mourad Tiab, Xavier Leleu, Murielle Roussel, Carine Chateleix, Michel Attal, Thierry Facon, Philippe Moreau Abstract # 8513

22 Options for Transplant-Ineligible Patients Regimen ORR >VGPR ncr/cr AE-related Discontinuations MPT 76% 36% 27% 35% VMP 71% 41% 30% 33% MPR 80% 45% 33% 24% VMPT-VT - 59% 38% 22% Rd 70% 40% CR-4% 19% Presented by: Saad Z Usmani MD FACP

23 PATIENTS CHARACTERISTICS (n=68) Phase 1 + Phase 2: 68 patients enrolled Median age (range) 72 (61-86) Male / Female (%) 51 / 49 Isotype (%) IgG IgA Light chain Karnofsky PS (%) >90% 70-90% 60-70% Creatinine > 150 µmol/l (%) 10 ISS (%) t(4;14) or t(14;16) or 17p del (%) 17

24 PHASE 1 RESULTS Cohort 1: CFZ 20 mg/m 2 + MP oct 10, > dec 8, patients, 1 DLT: DVT Cohort 2: CFZ 27 mg/m 2 + MP jan 31, > feb 4, patients, 1 DLT: grade 3 febrile neutropenia Cohort 3: CFZ 36 mg/m 2 + MP apr 07, 2011 apr 28, patients, 1 DLT: grade 3 febrile neutropenia Cohort 4: CFZ 45 mg/m 2 + MP may 07, 2011 july 25, patients, 2 DLT, fever + hypotension -> MTD defined at 36 mg/m 2

25 RESPONSE RATES (66 patients) Best Response Patients n (%) CR 4 (6%) VGPR 33 (50%) PR 23 (35%) SD 6 (9%) PD 0 -> ORR : 91% -> At least VGPR : 56%

26 SAFETY All grades n (%) Grade 3-4 n (%) anemia 36 (54%) 14 (21%) thrombopenia 24 (35%) 5 (7%) neutropenia 24 (35%) 15 (22%) DVT 5 (7%) 1 (1.5%) Conges ve Heart Failure 4 (6%) 3 (4.5%) Atrial Fibrila on 3 (4.5%) 1 (1.5%) Peripheral oedema 15 (22%) 0 (0%) Hypertension 2 (3%) 2 (3%) Peripheral Neuropathy 16 (23.5%) 1 (1.5%) Nausea 21 (31%) 3 (4.5%) Diarrhea 12 (17.5%) 0 (0%) Infec on 35 (52%) 6 (9%) Fa gue 27 (40%) 1 (1.5%) Insomnia 6 (9%) 3 (4.5%) Elevated liver enzymes 20 (29%) 3 (4.5%) Renal failure 14 (21%) 2 (3%) 8 patients (11%) discontinued CMP due to AE

27 Options for Transplant-Ineligible Patients Regimen ORR >VGPR ncr/cr AE-related Discontinuations MPT 76% 36% 27% 35% VMP 71% 41% 30% 33% MPR 80% 45% 33% 24% VMPT-VT - 59% 38% 22% Rd 70% 40% CR-4% 19% CMP 91% 56% CR-6% 8% CMP A Reasonable Choice for Upfront Transplant Ineligible MM. Concerns in Patients over 75 years with/without Cardiovascular Comorbidities Presented by: Saad Z Usmani MD FACP