Disclosures for Alessandra Larocca, MD

Disclosures for Alessandra Larocca, MD Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare Celgene, Janssen-Cilag, BMS, Amgen Scientific Advisory Board No relevant conflicts of interest to declare Presentation includes discussion of the off-label use of a drug or drugs

Multiple Myeloma 2017 Highlights A post International Myeloma Workshop (IMW) Summary Paris, France April 21-22, 2017 Geriatric evaluation Alessandra Larocca, MD, PhD Division of Hematology University of Torino Torino, Italy

Myeloma is a disease of the elderly Incidence according to age In UK median age at diagnosis 73 (1990s) Latest USA SEER registry data: 55% are 75 years of age (1975-2010) 70% 43%

10-Year relative survival (%) Introduction of novel agents has improved overall survival in MM 50 45 40 35 30 25 20 15 10 5 0 < 50 50 59 60 69 70 79 80+ 1984 1986 1987 1989 1990 1992 1993 1995 1996 1998 1999 2001 2002 2004 Calendar period The major benefit was observed in younger patients Brenner H, et al. Blood. 2008;111:2521-6.

Age negatively affects survival In MM patients Meta-analysis of 1435 newly diagnosed MM patients treated with MP, MPT, VMP, VTP or VMPT-VT Age 3 year OS < 75 years 68% > 75 years 57% Bringhen S, et al. Haematologica 2013; 98 (6): 980-988

Grade 3/4 cardiac infective, GI AEs impact on survival of 1435 myeloma patients *At least one adverse event; Due to AEs, withdrawal of consent, patient compliance, unknown; progressive disease was excluded AE, adverse event; GI, gastrointestinal Bringhen S, et al. Haematologica. 2013;98:980 987; Larocca A, et al. Blood 2013;122: Abstract 687 and oral presentation at ASH 2013

CLARION STUDY Study Design Transplantineligible NDMM Randomization 1:1 N = 955 Stratification: ISS stage Route of bortezomib administration (if randomized to VMP) Region Age Maximum 9 cycles KMP Carfilzomib a 36 mg/m 2 IV Days 1, 2, 8, 9, 22, 23, 29, 30 (20 mg/m 2 days 1, 2, cycle 1 only) IV over 30 minutes Melphalan b 9 mg/m 2 and Prednisone 60 mg/m 2 Days 1 4 Maximum 9 cycles VMP Bortezomib 1.3 mg/m 2 Days 1, 4, 8, 11, 22, 25, 29, 32 (Days 4, 11, 25, 32 omitted for cycles 5+) IV or SC Melphalan b 9 mg/m 2 and Prednisone 60 mg/m 2 Days 1 4 Primary endpoint: PFS Secondary endpoints: OS, CRR, ORR, grade 2 PN rate, HRQoL, safety and tolerability Exploratory endpoint: MRD a Carfilzomib was administered for 2 weeks out of 3 twice per cycle b Melphalan dose was 7 mg/m 2 if age was > 75 years or CrCl was 30 to < 50 ml/min; 5 mg/m 2 if CrCl was 15 to < 30 ml/min. 1 CRR, complete response rate; CrCl, creatinine clearance; HRQoL, health-related quality of life; ISS, International Staging System; IV, intravenous; KMP, carfilzomib, melphalan, prednisone; MRD, minimal residual disease; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PN, peripheral neuropathy; SC, subcutaneous; VMP, bortezomib, melphalan, prednisone Facon T, et al. Presented at: 16th International Myeloma Workshop; New Delhi, India; March 1-4, 2017.

Proportion Event-Free CLARION STUDY Primary Endpoint: Progression-Free Survival 1.0 0.8 0.6 0.4 0.2 0 Number at risk: Median follow-up time: 22.2 months for KMP and 21.6 months for VMP The absence of PFS difference was consistent across subgroups 0 KMP VMP KMP (n = 478) 6 12 18 24 30 36 Months VMP (n = 477) Disease progression or death, n (%) 207 (43.3) 214 (44.9) Median PFS, months 22.3 22.1 HR for KMP vs VMP (95% CI) 0.91 (0.75 1.10) 1-sided P value 0.16 KMP 478 384 327 217 85 15 VMP 477 367 309 202 77 9 CI, confidence interval; HR, hazard ratio; KMP, carfilzomib, melphalan, prednisone; PFS, progression-free survival; VMP, bortezomib, melphalan, prednisone 0 0 Facon T, et al. Presented at: 16th International Myeloma Workshop; New Delhi, India; March 1-4, 2017.

Proportion Without PD CLARION STUDY Time to Progression 1.0 0.8 0.6 0.4 0.2 0 Number at risk: 0 KMP VMP KMP (n = 478) VMP (n = 477) Disease progression, n (%) 162 (33.9) 185 (38.8) Median TTP, months 27.5 23.5 HR for KMP vs VMP (95% CI) 0.84 (0.68 1.04) Nominal 1-sided P value 0.05 6 12 18 24 30 36 Months KMP VMP 478 477 380 367 326 308 216 202 84 77 15 9 0 0 CI, confidence interval; HR, hazard ratio; KMP, carfilzomib, melphalan, prednisone; PD, progressive disease; TTP, time to progression; VMP, bortezomib, melphalan, prednisone Facon T, et al. Presented at: 16th International Myeloma Workshop; New Delhi, India; March 1-4, 2017.

CLARION STUDY AEs of Interest AE, % KMP (n = 474) VMP (n = 470) All Grade Grade 3 All Grade Grade 3 Acute renal failure a 13.9 7.4 6.2 2.1 Cardiac failure a 10.8 8.2 4.3 2.8 Ischemic heart disease a 3.0 2.1 1.9 1.3 Hypertension a 24.7 10.1 8.1 3.6 Dyspnea b 18.1 3.6 8.5 0.6 Grade 5 AE 6.5 4.3 Leading to treatment discontinuation 17.5 15.5 a Standardized MedDRA Queries Narrow Search. b High-level term. AE, adverse event; KMP, carfilzomib, melphalan, prednisone; MedDRA, Medical Dictionary for Regulatory Activities; VMP, bortezomib, melphalan, prednisone Facon T, et al. Presented at: 16th International Myeloma Workshop; New Delhi, India; March 1-4, 2017.

All elderly are not equal Fit and Frail

Treatment goals in elderly MM patients FIT INTERMEDIATE FRAIL Co-morbidities, organ disfunction Life expectancy Impaired functional status Deep remission Balance efficacy/safety Do not harm Goal CR/MRD-negativity Good response QoL Priority Efficacy Combination of efficacy/safety Low toxicity

How to assess frailty? How to identify frail patients?

Geriatric Assessment (GA) ADVANTAGES LIMITATIONS Medical, psychosocial and Not routinely performed in functional capabilities hematology because it is complex and time-consuming. Impairment not identified in routine practice Multidimensional diagnostic process Predict severe treatment-related toxicity Predict OS in a variety of tumors Influence treatment choice and intensity The optimal tools for an appropriate GA need to be established. Wildiers H, et al. J Clin Oncol 2014: 32 (24):2595-2603.

GA or clinical judgement? GERIATRIC ASSESSMENT - age 80 years - ADL - comorbidity (CIRS-G) - geriatric syndromes Curative therapy GA 84 patients DLBC NHL Clinical judgement (blind to the result of GA) Palliative therapy 42 FIT patients by CGA received curative treatment by clinical judgment. 42 UNFIT patients by CGA: 20 received curative and 22 palliative therapy. UNFIT patients had similar outcome irrespectively of type of treatment. GA was an efficient method to identify elderly NHL patients who can benefit from a curative approach. Tucci A et al, Cancer 2009;115:4547 53.

GA or Performance Status (PS)? 363 elderly patients with solid or hematologic tumors (age 72 ys) Among patients with a good PS 13.0% had 2 or more comorbidities 9.3% and 37.7% had ADL or IADL limitation Association between PS, number of comorbidities, and CGA GA Performance Status Repetto L. et al, J Clin Oncol 2002

GA in older patients with cancer detect unknown geriatric problems All patients G8 screening CGA 71% Presence of geriatric profile 1967 cancer patients 67% Unknown geriatric problems* 29% Absence of geriatric profile FIT * Geriatric problems related mainly to: functional status, nutritional status, fatigue Kenis et al. Ann Oncol 2013;24(5):1306-12

39 factors 13 factors 3 factors Frailty Assessment in Myeloma IMWG Frailty Score 1 Revised Myeloma Co-morbidity Index 2 Mayo Frailty System 3 N 869 801 351 (172 no ASCT) Median Age 74 (46% 75) 63 (13% 75) 65 (33% 75) Population 6 study regimens Variable Len-based 63% BTZ-based 22% ASCT 39% Factors Access Age ADL IADL CCI www.myelomafrailtyscorecalcula tor.net/ Renal (Calc GFR) Lung (PFTs) KPS Fragility Age Cytogenetics www.myelomacomorbidityindex.o rg Age 70 ECOG PS 2 NT-ProBNP 300 ng/l 1 Palumbo et al, Blood 2015; 2 Engelhardt et al. Haematologica 2017; 3 Milani et al. Am J Hematol 2016

IMWG Frailty Score Study design 2 phase III and 1 phase II EMN trials for NDMM patients, ineligible for autologous stem cell transplantation EMN01- NCT01093136 N=659 Rd vs MPR vs CPR 26866138MMY2069 NCT01190787 N=152 VP vs VMP vs VCP Katz s Activity of Daily Living (ADL) Lawton s Instrumental Activity of Daily Living (IADL) Charlson Comorbidity Index (CCI) IST-CAR-506 NCT01346787 N=58 Carfilzomib-Cyclo-Dex 869 analyzed patients Palumbo A et al, Blood 25(13):2068-74, 2015

Charlson index Geriatric Assessment Total points 0-37 Charlson M, et al. J Chronic Dis. 1987;40(5):373-83. Instrumental activity of daily living (IADL) Activity of daily living (ADL) The maximum total score is 6; ; 0=completely dependent. Katz S, et al. JAMA 1963;185:914-919. The maximum total score is 8; 0=completely dependent. Lawton MP, et al. Gerontologist 1969;9:179-186.

IMWG Frailty Score Variable HR (CI 95%) P SCORE AGE Age <75 years 1-0 Age 75-80 years 1.13 (0.76-1.69) 0.549 1 Age >80 years 2.40 (1.56-3.71) <0.001 2 CHARLSON INDEX Charlson <1 1-0 Charlson >2 1.37 (0.92-2.05) 0.125 1 ADL SCORE ADL >4 1-0 ADL<4 1.67 (1.08-2.56) 0.02 1 IADL SCORE IADL >5 1-0 IADL<5 1.43 (0.96-2.14) 0.078 1 ADDITIVE TOTAL SCORE PATIENT STATUS 0 FIT 1 INTERMEDIATE >2 FRAIL Palumbo A et al, Blood 25(13):2068-74, 2015

1.00 IMWG Frailty Score: long-term outcome Overall Survival Progression-free Survival 1.00 0.75 0.50 0.25 0.00 1.00 0.75 0.50 @3 yrs P-value Fit 84% - Intermediate 76% 0.042 Frail 57% <0.001 0 6 12 18 24 30 36 42 48 Months Cumulative Incidence Non-hematologic AEs @12 mo P-value Fit 22% - Intermediate 26% 0.217 Frail 34% <0.001 0.75 0.50 0.25 0.00 1.00 0.75 0.50 @3 yrs P-value Fit 48% - Intermediate 41% 0.211 Frail 33% <0.001 0 6 12 18 24 30 36 42 48 Months Cumulative Incidence Drug Discontinuation @12 mo P-value Fit 16% - Intermediate 21% 0.026 Frail 31% <0.001 0.25 0.25 0.00 0 6 12 18 24 Months 0.00 0 6 12 18 24 Months Palumbo A et al, Blood 25(13):2068-74, 2015

Geriatric evaluation to select appropriate therapy in MM patients? Old chemotherapy (Melphalan) or Novel Drugs? Doublets or Triplets? ASCT? Continuous treatment? Newer drugs?

Geriatric evaluation to select appropriate therapy in MM patients? Old chemotherapy (Melphalan) or Novel No evidence based medicine in frail Drugs? patients: Doublets or Triplets? No randomized phase 3 trials ASCT? No randomized phase 2 trials Continuous treatment? No meta-analysis

Proportion of patients Proportion of patients Melphalan or New Drugs? Doublets or Triplets? 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 PFS VD (N=168, 51% PFS events) VTD (N=167, 42% PFS events) VMP (N=167, 49% PFS events) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 OS VD (N=168, 27% OS events) VTD (N=167, 27% OS events) VMP (N=167, 25% OS events) 483 patients enrolled 50% patients with 1 co-morbidity 42% >75 years and 18% >80 years Median PFS 14.7, 15.4, and 17.3 months 40 42 44 46 Time (months) Median OS 49.8, 51.5, and 53.1 months 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 Time (months) VD, bortezomib-dexamethasone; VMP, V melphalan-prednisone; VTD, VD thalidomide Niesvizky R, et al. JCO 2015

1.00 0.75 0.50 0.25 0.00 CPR vs MPR vs Rd Melphalan or Novel Drugs? Progression-free survival Rd vs MPR: HR 1.189; CI 0.911-1.551; p=0.20 Rd vs CPR: HR 1.032; CI 0.799-1.332; p=0.81 Doublets Median follow-up or Triplets? 26 months Median PFS CPR 24 months MPR 27 months Rd 22 months 1.00 0.75 0.50 0.25 0.00 Overall survival 2-year OS CPR 84% MPR 81% Rd 80% Rd vs MPR: HR 0.954; CI 0.629-1.446; p=0.82 Rd vs CPR: HR 1.033; CI p=0.88 ; 0.680-1.570 0 10 20 30 40 50 months 0 10 20 30 40 50 months R, Lenalidomide; d, low dose dexamethasone; C, cyclophosphamide; M, melphalan; P, prednisone; PFS, progression-free survival; OS, overall survival; PFS, progression-free survival. Magarotto V, et al. Blood 2016

PAD ASCT? Phase 2 GIMEMA TRIAL 102 newly diagnosed myeloma patients Age 65-75 years or inelegible for Melphalan 200 mg/sqm PAD-MEL100-LP-L PBSC Mobilization (Cyclophosphamide+G-CSF) MEL-100 ASCT 4 cycles 2 cycles 2 cycles LP 4 cycles PAD = Bortezomib+Pegylated Doxorubicin+Dexamethasone; MEL100 = Melphalan100 mg/m2; LP = Lenalidomide + Prednisone; L= Lenalidomide L Gay F et al. Blood 2013;122:1376-1383

TTP Median 55 months 5-year 43% ASCT? PAD-MEL100-LP-L: Survival Median follow-up: 66 months PFS OS Median 48 months 5-year 43% Median not reached 5-year 63% TTP:time to progression, PFS: progression-free survival, OS: overall survival Gay F et al. Blood 2013;122:1376-1383

ASCT? Discontinuation or Deaths related to AEs Discontinuation or death related to AEs All patients (N=102) Patients <70 years (N=76) Patients >70 years (N=26) 30 (29%) 20 (26%) 10 (38%) AEs 22 (22%) 17 (22%) 5 (19%) Deaths 8 (8%) 3 (5%)* 5 (19%)* P value (Fisher exact test) 0.024 In pts >70 years during induction and transplant: Higher rate of infections (34% vs 21%) Higher treatment related deaths AEs: Adverce events, N: number Gay F et al. Blood 2013;122:1376-1383

Patients alive and progression-free (%) No. of patients at risk: Lenalidomide Observation CONTINUOUS TREATMENT? Myeloma XI study: Lenalidomide maintenance Transplant non-eligible Significant improvement in PFS from 11 to 24 months, HR=0.42 100 80 60 40 20 0 0 406 317 374 258 319 198 281 152 227 116 190 95 154 72 Time since randomisation (months) 133 59 102 46 84 27 74 22 62 16 51 12 42 9 29 8 24 4 13 4 10 2 Median PFS, months [95% CI] Lenalidomide (n=406) 24 [21, 30] Observation (n=317) 11 [9, 13] HR=0.42; 95% CI 0.35, 0.51 Log-rank p<0.0001 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 7 1 6 1 2 1 0 0 Jackson GH et al ASH 2016 Courtesy by Prof Gareth J. Morgan

CONTINUOUS TREATMENT? FIRST trial: Frailty Analysis Progression-free survival HR, hazard ratio; MPT, melphalan, prednisone, and thalidomide; NR, not reached; PFS, progression-free survival; pt, patient; Rd, lenalidomide and low-dose dexamethasone; Tx, treatment. Facon T. A Frailty Scale Predicts Outcomes in Patients With Newly Diagnosed Multiple Myeloma Who Are Ineligible for Transplant Treated With Continuous Lenalidomide Plus Low-Dose Dexamethasone in the FIRST Trial. ASH 2015, abstract 4239 Facon T, et al. Abstract 4239, ASH 2015

RANDOMIZATION 1:1 A phase III, multicentre, randomized study to determine the efficacy and safety of standard schedule versus a new algorithim of dose reductions in ELDERLY INTERMEDIATE newly diagnosed myeloma patients Event-free survival* PD, OS and Subsequent anti-mm Tx Screening Arm A Continuous Rd Arm B Rd9-R Active Treatment + PFS Follow-up Phase LEN + Lo-DEX: 9 Cycles LENALIDOMIDE 25mg D1-21/28 Lo-DEX 20mg D1,8,15 & 22/28 LEN + Lo-DEX Continuously LENALIDOMIDE 25mg D1-21/28 Lo-DEX 20mg D1,8,15 & 22/28 Lo-LEN Continuously Lo-LEN 10mg D1-21/28 *Event-free survival defined as: Progression Death for any cause Discontinuation of lenalidomide therapy Occurrence of any haematological grade 4 or non-haematological grade 3-4 adverse events (AES), including Secondary Primary Malignancies (SPMs) LT Follow-Up LT, long-term; PD, progressive disease; OS, overall survival

NEWER DRUGS? Summary of key studies in RRMM Progression-free survival by Age ELOQUENT-2: ERd vs Rd ASPIRE: KRd vs Rd POLLUX: DRd vs Rd TOURMALINE-MM1: IRd vs Rd Stewart K, NEJM 2015. Lonial S NEJM 2015. Moreau P, NEJM 2016, Dimopoulus et al. EHA 2016

Conclusions 34

1. Treatment goals based on frailty Life expectancy PATIENT STATUS ASSESSMENT Age (score 0 1 2) Charlson (score 0 1) ADL (score 0 1) IADL (score 0 1) FIT INTERMEDIATE FRAIL Co-morbidities, organ function Impaired functional status Deep remission Balance efficacy/safety Do not harm Goal CR/MRD-negativity Good response QoL Priority Efficacy Combination of efficacy/safety Low toxicity

2. Treatment algorithm based on balancing safety and efficacy PATIENT STATUS ASSESSMENT Age (score 0 1 2) Charlson (score 0 1) ADL (score 0 1) IADL (score 0 1) FIT INTERMEDIATE FRAIL Additive total score = 0 Additive total score = 1 Additive total score 2 Full-dose Full-dose/Reduced Reduced dose TRIPLET REGIMENS DOUBLET REGIMENS Doublet regimens VMP Rd -> R? rd MPT Vd Vd Rd Palliative VRD ASCT Palumbo A et al, Blood 25(13):2068-74, 2015

Patients ADL IADL 3. Treatment Decision Process Comorbidities Hospitalization Medications Social Support Goals of Care CR vs Disease Control Expectations Multiple Myeloma Cytogenetics Stage Tumor burden Newer Drugs Comorbidities: cardiovascular Karf! pulmonary functions MoAb! Compliance +Ixazomib Toxicities Neuropathy + Karf DVT/PE +MoAb Cardiac toxicity +MoAb

Conclusion Elderly patients live on the borderline of a precariously balanced physiological state. It is more important to know what sort of person has a disease than to know what sort of disease a person has [Hippocrates]

Acknowledgments Divisione di Ematologia U Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino Prof. Mario Boccadoro Dr. Sara Bringhen Dr. Francesca Gay Dr. Chiara Cerrato Dr. Mariella Genuardi Dr. Roberto Mina Dr. Stefania Oliva Dr. Mattia D Agostino Dr. Marco Salvini Dr. Giusy Cetani Dr. Paola Omedé & Laboratory Staff Dr. Benedetto Bruno & Transplant Unit Nurses Data Managing Staff Dr. Gianni Ciccone and CPO