Meletios A. Dimopoulos, MD Therapy Options for Transplant-Ineligible Patients with Multiple Myeloma Meletios A. Dimopoulos, MD Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece

What should be the goal of treatment in multiple myeloma? To search for an appropriate balance between treatment efficacy, toxicity & costs In fit elderly patients (65-80y) & young ones with severe co-morbidities ……… treatment goal should be to prolong survival and ensure QoL In very elderly patients (> 80-85y)…….to ensure QoL & avoid additional costs of expensive treatments

CR predicts long term outcome Analysis of 1175 elderly patients 25 50 75 100 10 20 30 40 60 70 80 PFS OS 100 CR 75 CR VGPR PR 50 VGPR PR 25 10 20 30 40 50 60 70 months months Gay et al. Blood 2011;117:3025-31 3 3

Approved Treatment Options of Patients Who Are Not Eligible for HDM and ASCT

MP vs. MPT: Meta-analysis of 1,682 individual patient data from 6 randomized clinical trials Hazard ratio P Median PFS 14.9 months 20.4 months 0.68 (0.61-0.76) <0.0001 Median OS 32.7 months 39.3 months 0.83 (0.73-0.94) 0.004 Fayers et al. Blood 2011;118:1239-1247

Myeloma IX: CTDa for elderly patients Median follow-up: 44 months ORR significantly higher with CTDa than MP (63.8% vs 32.6%; P < 0.0001) Higher rates of CR (13.1% vs 2.4%) and VGPR (16.9% vs 1.7%) Significantly longer OS for patients with favorable interphase FISH compared with those with adverse interphase FISH (P < 0.001) PFS OS Morgan et al. Blood 2011;118(5):1231-1238

VISTA: Final updated OS analysis (31% reduced risk of death with VMP) Median follow-up 60.1 months 100 90 80 70 60 50 40 30 20 10 Median OS benefit: 13.3 months 5-year OS rates: 46.0% vs. 34.4% Patients alive (%) Group N Event Median HR (95% CI) P-value MP 338 211 43.1 VMP 344 176 56.4 0.695 (0.567, 0.852) 0.0004 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Time (months) San Miguel et al. J Clin Oncol 2013;31:448-55

FIRST: Phase 3 trial of Lenalidomide + low-dose Dex vs FIRST: Phase 3 trial of Lenalidomide + low-dose Dex vs. MPT (IFM 07-01; MM-020) RANDOMIZATION Rd (28-day cycle; until disease progression) Lenalidomide 25 mg/day, days 1–21 Dexamethasone* 40 mg/day, days 1, 8, 15, and 22 Inclusion criteria N = 1,623 Previously untreated MM Age  65 years or not eligible for a transplant No neuropathy of grade > 2 Rd (28-day cycle; up to 18 cycles) Lenalidomide 25 mg/day, days 1–21 Dexamethasone* 40 mg/day, days 1, 8, 15, and 22 MPT (6-week cycle; up to 12 cycles ) Melphalan* 0.25 mg/kg/day, days 1–4 Prednisone 2.0 mg/kg/day, days 1–4 Thalidomide* 200 mg/day Primary end-point: PFS PFS: 28% reduction in the risk of DP/death for Rd (til DP) vs MPT OS: 22% reduction in the risk of death for Rd (til DP) vs MPT Len-dex will be a new standard of care for elderly newly diagnosed MM pts, or.... new backbone Benboubker L et al. N Engl J Med 2014; 371:906-17 8 8 8

FIRST Trial: Response endpoints (IMWG Criteria) Rd (n = 535) Rd18 (n = 541) MPT (n = 547) ORR (≥ PR) 75.1 73.4 62.3 CR 15.1 14.2 9.3 VGPR 28.4 28.5 18.8 PR 31.6 30.7 34.2 SD 18.9 20.5 26.5 VGPR or better 43.5 42.7 28.1 Median time to response (mos) 1.8 2.8 Duration of response (mos) 35.5 22.1 22.3 Benboubker L et al. N Engl J Med 2014; 371:906-17

FIRST Trial: PFS Continuous Rd reduced the risk of disease progression by 28% vs. MPT Hazard ratio Rd vs. MPT: 0.72; P = 0.0006 Rd vs. Rd18: 0.70; P = 0.0001 Rd18 vs. MPT: 1.03; P = 0.70349 Time (months) Patients (%) 100 80 60 40 20 6 12 18 24 30 36 42 48 54 72 wks Median PFS Rd (n= 535) 25.5 mos Rd18 (n= 541) 20.7 mos MPT (n= 547) 21.2 mos Rd 535 400 319 265 218 168 105 55 19 2 Rd18 541 391 167 108 56 30 7 MPT 547 380 304 244 170 116 58 28 6 1 mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, Lenalidomide plus low-dose dexamethasone. Benboubker L et al. N Engl J Med 2014; 371:906-17

FIRST Trial: Overall Survival Interim Analysis 574 deaths (35%) Overall survival (months) 100 80 60 40 20 6 12 18 24 30 36 42 48 54 Hazard ratio Rd vs. MPT: 0.78; P = 0.017 ( 22% risk of death with Rd) Rd vs. Rd18: 0.90; P = 0.307 Rd18 vs. MPT: 0.88; P = 0.184 4-year OS Rd (n= 535) 59.4% Rd18 (n= 541) 55.7% MPT (n= 547) 51.4% Patients (%) 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 Benboubker L et al. N Engl J Med 2014; 371:906-17

FIRST Trial: OS by Age Stratification Aged 75 Yrs or Younger Aged Older Than 75 Yrs 100 3-Yr OS, % 74 70 67 100 3-Yr OS, % 63 58 54 Rd Rd18 MPT Rd Rd18 MPT 80 80 60 60 Pts (%) Pts (%) 40 40 HR (95% CI) Rd vs MPT: 0.77 (0.59-1.01) Rd vs Rd18: 0.88 (0.67-1.16) Rd18 vs MPT: 0.88 (0.68-1.14) HR (95% CI) Rd vs MPT: 0.80 (0.59-1.09) Rd vs Rd18: 0.94 (0.69-1.29) Rd18 vs MPT: 0.85 (0.63-1.15) 20 20 6 12 18 24 30 36 42 48 54 60 6 12 18 24 30 36 42 48 54 60 OS (Mos) OS (Mos) Hulin C, et al. ASH 2014. Abstract 81.

FIRST Trial: Safety- Selected Gr3–4 TEAEs Rd (n=535) Rd 18 (n=541) MPT (n=545) Hematological (%) Anemia 18.2 15.7 18.9 Neutropenia 27.8 26.5 44.9 Thrombocytopenia 8.3 8.0 11.1 Febrile neutropenia 1.1 0.9 2.6 Non-hematological (%) Infections 28.9 21.9 17.2 Pneumonia 8.1 5.7 Diarrhea 3.9 3.3 1.5 Constipation 2.3 1.9 5.4 Peripheral sensory neuropathy 0.4 9.4 Rash 8.8 6.7 5.5 Deep vein thrombosis 3.7 Cataract 5.8 0.6 TEAEs: treatment emerging adverse events Benboubker L et al. N Engl J Med 2014; 371:906-17 13

FIRST Trial - Renal Analysis: PFS Per Status PFS in normal (per IRAC assessment) PFS in mild RI (per IRAC assessment) 1.0 0.8 0.6 0.4 0.2 0.0 6 12 18 24 30 36 42 PFS (mos) 48 54 60 Survival probability Cont. Rd vs. MPT HR: 0.71, P = 0.05a Rd vs. Rd18 HR: 0.67, P = 0.02a Rd18 vs. MPT HR: 1.06, P = 0.76a 1.0 0.8 0.6 0.4 0.2 0.0 6 12 18 24 30 36 42 PFS (mos) 48 54 60 Survival probability Cont. Rd vs. MPT HR: 0.74, P = 0.02a Rd vs. Rd18 HR: 0.72, P < 0.01a Rd18 vs. MPT HR: 1.04, P = 0.76a Continuous Rd Rd18 MPT Continuous Rd Rd18 MPT PFS in moderate RI (per IRAC assessment) PFS in severe RI (per IRAC assessment) PFS (mos) 1.0 0.8 0.6 0.4 0.2 0.0 6 12 18 24 30 36 42 48 54 60 Survival probability Cont. Rd vs. MPT HR: 0.66, P < 0.01a Rd vs. Rd18 HR: 0.66, P < 0.01a Rd18 vs. MPT HR: 1.02, P = 0.89a 1.0 0.8 0.6 0.4 0.2 0.0 6 12 18 24 30 36 42 PFS (mos) 48 54 60 Survival probability Cont. Rd vs. MPT HR: 0.76, P = 0.31a Rd vs. Rd18 HR: 0.82, P = 0.48a Rd18 vs. MPT HR: 1.00, P = 1.00a Continuous Rd Rd18 MPT Continuous Rd Rd18 MPT aNominal P values are presented for multiplicity assessments which need to be taken into consideration before making clinical interpretations. HR, hazard ratio; mos, months; MPT, melphalan-prednisone-thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone; Rd18, Rd for 18 cycles; RI, renal impairment; IRAC, Independent Response Adjudication Committee Dimopoulos MA, et al. ASH 2014, abstract #2112.

Studies with Continuous Therapy for Patients Who Are Not Eligible for HDM and ASCT

Continuous Treatment in the non-Transplant Setting: Thalidomide Median follow-up (months) Median PFS (months) Median OS Reference MPT + T vs MP 38 21.8* 14.5 45.0 47.6 Palumbo et al. Blood 2008; 112(8):3107-14 39 13* 9 40* 31 Wijermans et al. JCO 2010; 28(19):3160-6 42 15 14 29 32 Waage et al. Blood 2010; 116(9):1405-12 CTDa/MP (CTD/CVAD) + T CTDa/MP (CTD/CVAD) 46 11* Morgan et al. Blood 2012; 119(1):7-15 Thal-IFN IFN† 35 27.7* 13.2 52.6 51.4 Ludwig et al. Haematologica 2010; 95(9):1548-54 †Thal/Dex vs MP induction *significant difference between arms

MM-015: MPR-R vs. MPR vs. MP RANDOMISATION Disease progression MPR-R Cycles (28-day) 1-9 Cycles 10+ RANDOMISATION MPR-R M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 R: 10 mg/day po, days 1-21 Lenalidomide Continued Tx Disease progression Lenalidomide (25 mg/day) +/- dexamethasone 10 mg/day, days 1-21 Primary Comparison MPR-R vs. MP MPR M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 R: 10 mg/day po, days 1-21 Placebo MP M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 PBO: days 1-21 Secondary Comparison MPR-R vs. MPR Addition of MPR arm per EMEA advice Placebo Double-Blind Treatment Phase Open-Label Extension/ Follow-Up Phase Stratified by age (≤ 75 vs. > 75 years) and stage (ISS 1,2 vs. 3) Palumbo et al. N Engl J Med 2012;366:1759-69

MPR-R vs. MPR vs. MP: PFS 58% Reduced Risk of Progression 65-75 Years of Age 2 2 - - Year PFS Year PFS Median PFS Median PFS 2 2 - - Year PFS Year PFS Median PFS Median PFS 5 10 15 20 25 30 35 40 50 75 100 100 100 100 100 100 MPR MPR - - R R 55% 55% Not reached Not reached MPR MPR - - R R 61% 61% Not reached Not reached MPR MPR 27% 27% 14.7 months 14.7 months 75 75 75 75 75 MP MP 16% 16% 13.0 months 13.0 months MP MP 10% 10% 12.4 months 12.4 months HR 0.315 HR 0.423 50 50 50 50 50 Log rank P < .001 Log rank P < .001 Patients (%) Patients (%) Patients (%) Patients (%) 25 25 25 25 25 HR 0.675 Log rank P = .031 5 5 10 10 15 15 20 20 25 25 30 30 35 35 40 40 5 5 5 10 10 10 15 15 15 20 20 20 25 25 25 30 30 30 35 35 35 40 40 40 Time (Months) Time (Months) Palumbo et al. N Engl J Med 2012;366:1759-69

MM-015: PFS & OS update in Patients 65-75 y Palumbo A, et al. IMW 2013;abstract P-227.

Phase III Trial Comparing MPT-T vs Phase III Trial Comparing MPT-T vs. MPR-R in SCT-Ineligible Patients with NDMM Joint study of the Dutch-Belgian Cooperative Trial Group for Hematology Oncology and the Nordic Myeloma Study Group Stratified by center and ISS Randomization 1:1 MPR Melphalan 0.18 mg/kg on Days 1-4 + Prednisone 2 mg/kg on Days 1-4 + Lenalidomide 10 mg on Days 1-21 (n = 319) R Maintenance Lenalidomide 10 mg on Days 1-21 q28d until PD 28-day cycles x 9 MPT Melphalan 0.18 mg/kg on Days 1-4 + Prednisone 2 mg/kg on Days 1-4 + Thalidomide 200 mg on Days 1-28 (n = 318) T Maintenance Thalidomide 100 mg/day until PD Granulocyte-colony stimulating factor administered if absolute neutrophil count < 0.5 x 109 cells/L or in event of febrile neutropenia during a cycle. Zweegman S, et al. ASH 2014. Abstract 179.

MPT-T vs. MPR-R: Efficacy Analysis Median follow-up: 33.6 mos ORR similar between arms: 81% MPT-T vs 83% MPR-R No significant difference in PFS or OS Outcome MPR-R (n = 319) MPT-T (n = 318) HR (95% CI) P Value ORR (on protocol), % 83 81 CR 13 10 VGPR 32 38 PR 39 33 Median PFS, mos 22 20 086 (0.72-1.04) .12 Median OS, mos NR 0.79 (0.61-1.03) .08 2-yr OS, % 84 73 3-yr OS, % 69 64 4-yr OS, % 55 52 Zweegman S, et al. ASH 2014. Abstract 179.

MPT-T vs. MPR-R: Safety Analysis Treatment Outcome, % MPR-R MPT-T ≤ 75 Yrs > 75 Yrs Completed 6 induction cycles 68 73 76 77 Initiated maintenance therapy 59 58 57 39 Discontinued maintenance 43 88 Due to AEs* 24 31 67 69 Median duration of maintenance, mos (range) 16 (0-53) 15 (1-52) 5 (0-49) 5 (0-44) *Primarily due to peripheral neuropathy in thalidomide arm, hematologic toxicity in lenalidomide arm MPT-T associated with significantly higher rate of grade ≥ 2 neuropathy (45% vs. 8%; P < .0001); higher rate of grade 3/4 hematologic AEs (including neutropenia [63% vs. 27%], thrombocytopenia [28% vs. 8%], and anemia [14% vs. 5%]) vs MPR-R Zweegman S, et al. ASH 2014. Abstract 179.

VMPT + VT versus VMP: Study design Patients (n=511): >65 years old; median age 71 years VMPT + VT VMP 9 x 5-wk cycles:* Bortezomib Melphalan Prednisone Thalidomide 9 x 5-wk cycles:* Bortezomib Melphalan Prednisone Maintenance (until relapse): Bortezomib (1.3 mg/m2 d 1, 15) + Thalidomide (50 mg continuously) No maintenance *Protocol amendment: from twice-weekly bortezomib dosing (d 1,4,8,11,22,25,29,32) to once-weekly bortezomib dosing (d 1,8,15,22); 61 patients in VMP arm and 70 patients in VMPT arm received twice-weekly bortezomib dosing. Palumbo et al. J Clin Oncol 2010;28:5101-9 Palumbo et al. J Clin Oncol 2014;32:634-40

Updated analysis on Survival Data PFS TNT OS OS post relapse Palumbo et al. J Clin Oncol 2014;32:634-40

Updated analysis on OS (advantage only for 65-75 years) Landmark analysis for OS Pts 65-75 years old: VMPT-VT vs VMP, P=0.0001 Pts > 75 years old: VMPT-VT vs VMP, P=0.25 Pts 65-75 years old Total Induction Maintenance Disc. for AEs Bortezomib dose intensity VMPT-VT 25% 81% 17% 89% 12% 77% VMP 15% - Pts > 75 years old Disc. for Aes 35% 58% 29% 53% 14% 49% 16% 80% Palumbo et al. IMW 2013 (Abstract P-134), poster presentation

Ixazomib Maintenance Following Induction With Ixazomib + Len/Dex in NDMM Phase I/II trial assessing weekly ixazomib plus lenalidomide/dexamethasone in pts with NDMM Ixazomib: the first oral proteasome inhibitor to be assessed in clinical trials Current analysis focused on efficacy and safety of maintenance ixazomib Maintenance population similar to overall phase II population Approximately 15% of pts with unfavorable characteristics in each group Kumar S, et al. Lancet Oncol 2014;15:1503-12.

Ixazomib Maintenance Improves Depth of Response 100 5 n = 2 16 19 19 n = 1 80 19 sCR CR nCR VGPR PR MR SD n = 5 33 60 8 48 Percent of Patients, % 16 n = 2 10 40 10 31 20 29 29 6 4 Best Response in Overall Population (n = 49) Best Response to Induction Best Response Overall In Pts Receiving Maintenance (n = 21) Kumar S, et al. Lancet Oncol 2014;15:1503-12.

Ixazomib Maintenance: PFS 1.0 0.8 0.6 0.4 0.2 Probability of PFS 3 6 9 12 15 18 21 24 27 30 33 Mos Phase II pts who received maintenance (n = 21) All phase II pts (n = 50) (pts who proceeded to ASCT [n = 14] were censored at last response assessment before ASCT) Median PFS among censored pts who received maintenance: not reached, 10 pts progressed; Estimated 2-yr PFS: 57% Median PFS among all phase II pts: 28.7 mos; Estimated 2-yr PFS: 50% Kumar S, et al. Lancet Oncol 2014;15:1503-12.

Ixazomib Maintenance: Efficacy and Safety Safety in maintenance period similar to induction period No grade 4 AEs, grade 3 drug-related AEs reported in 62% of pts 52% during induction; 14% during maintenance Limited new onset AEs during maintenance New onset AEs ≤ 10% except diarrhea (~ 45%), nausea (~ 20%), and pain in extremities (~ 15%) Serious AEs were reported in 4 pts during maintenance period but were considered not related to treatment Grade 3 acute myocardial infarction, grade 3 pneumonia, grade 3 orthostatic hypotension, and grade 2 ventricular extrasystoles No discontinuations due to AEs; 17 pts required dose reductions due to AEs during induction and 2 required dose reductions due to AEs during maintenance Kumar S, et al. Lancet Oncol 2014;15:1503-12.

Modified Lenalidomide/Bortezomib/ Dexamethasone in ASCT-Ineligible NDMM Phase II trial exploring utility of modified RVD (RVD lite); N = 30 Lenalidomide: single daily oral dose of 15 mg Days 1-21 Bortezomib: 1.3 mg/m2 SC once weekly Days 1, 8, 15, 22 Dexamethasone: 20 mg twice weekly if ≤ 75 yrs or once weekly if > 75 yrs RVD lite resulted in 90% ORR (≥ PR), ≥ VGPR: 53% 3 pts discontinued study after <1 cycle due to worsening adrenal insufficiency; rash attributed to lenalidomide; unrelated AEs manageable and well tolerated in an older population Grade 3 AEs in ≥ 5%: hypophosphatemia (32%), rash (12%), mood disorder (9%) Grade 4 AEs: hypoglycemia (3%), neutropenia (3%), corneal ulcer (3%) O’Donnell E, et al. ASH 2014. Abstract 3454.

Weekly Carfilzomib in Combination With Cyclophosphamide/Dex in NDMM Phase I/II trial to assess feasibility of reduction of carfilzomib dosing from twice weekly to once weekly when used in combination with cyclophosphamide/dexamethasone in elderly pts with NDMM Carfilzomib given weekly using standard 3+3 phase I dose-escalation (starting at 45 mg/m2, increasing to 56 or 70 mg/m2) Phase I data (n = 12) identified MTD as 70 mg/m2 3 of 12 pts in phase I portion received MTD Phase II cohort currently enrolling 18 pts included in current analysis Similar baseline characteristics across all pts in phase I and II cohorts, with 30% of pts aged ≥ 75 yrs and 33% with unfavorable cytogenetics Palumbo A, et al. ASH 2014. Abstract 175.

Weekly Carfilzomib + Cyclophosphamide/ Dex: Preliminary Efficacy Outcome Phase I (n = 12) MTD (n = 19) Total (N = 28) Median cycles received, n (range) 9 (1-9) 4 (1-9) 8 (1-9) ORR (≥ PR), n (%) 11 (92) 15 (79) 24 (86) ≥ VGPR 9 (75) 11 (58) 18 (64) sCR + CR + nCR 4 (33) 4 (21) 7(25) At Least nCR At Least VGPR 47 50 100 89 91 41 77 40 80 30 57 30 24 60 Pts (%) Pts (%) 20 40 10 20 Cycle 4 Cycle 9 Cycle 4 Cycle 9 Once weekly[1] Twice weekly[2] 1. Palumbo A, et al. ASH 2014. Abstract 175. 2. Bringhen S, et al. Blood. 2014;124:63-69.

Weekly Carfilzomib + Cyclophosphamide/ Dex: Safety and Tolerability Outcome,[1] n (%) Phase I (n = 12) MTD (n = 21) Total (N = 30) Any SAE* 1 (8) 4 (19) 5 (17) Any drug-related SAE† 4 (13) Dose reduction due to AE 3 (25) 3 (10) Discontinuation due to AE 2 (17) 2 (9) Median cycles, n (range) 9 (1-9) 4 (1-9) 8 (1-9) Outcome, % Once-Weekly Carfilzomib[1] Twice-Weekly Carfilzomib[2] Grade 3/4 hematologic AEs 23 27 Grade 3/4 nonhematologic AEs 30 29 Median carfilzomib dose, mg 3534 2904 Carfilzomib dose adjustments Reductions 10 21 Discontinuations 13 14 *AEs graded using NCI-CTCAE v4.02. †Drug-related defined as related to any drug in the combination. 1. Palumbo A, et al. ASH 2014. Abstract 175. 2. Bringhen S, et al. Blood. 2014;124:63-69.

The elderly patient population – a highly heterogeneous group Aging – a complex, multifactorial process Associated with substantial physiological, cognitive and functional changes Definition of the elderly population complex  A highly heterogeneous population Chronological versus biological age Fit / independent versus frail / dependent on help Disability Comorbidities …… Nigam et al. Journal of Aging Research 2012;Article ID 468469 Ludwig et al. J Clin Oncol 2010;28:1599-1605

Age and organ damage correlate with poor OS: Meta-analysis of 4 randomized trials Bringhen et al. Haematologica 2013;98(6):980-987

General considerations when treating the elderly We cannot treat all elderly patients the same Importance of assessing comorbidity, frailty …. Challenge: No formalized assessment recommended, but a range of options available Activity of Daily Living Instrumental Activity of Daily Living Charlson Comorbidity Score ….

VP vs. VMP vs. VCP in the elderly (>75 years) 23/11/2018 150 patients (> 75 years) randomized from 3 countries Patients: Symptomatic disease, organ damage, measurable disease 1° R A N D O M I Z T VP Nine 35-day courses Vsc: 1.3 mg/sqm, d 1,8,15,22 P: 50 mg, 3 times wk MAINTENANCE 28- day course until relpase Vsc: 1.3 mg/sqm, d 1, 15 P: 25 mg; 3 times wk VMP Nine 35-day courses Vsc: 1.3 mg/sqm, d 1,8,15,22 M: 2 mg, 3 times wk P: 50 mg, 3 times wk MAINTENANCE 28- day course until relpase Vsc: 1.3 mg/sqm, d 1, 15 P: 25 mg; 3 times wk VCP Nine 35-day courses Vsc: 1.3 mg/sqm, d 1,8,15,22 C: 50 mg, 3 times wk P: 50 mg, 3 times wk MAINTENANCE 28- day course until relpase Vsc: 1.3 mg/sqm, d 1, 15 P: 25 mg; 3 times wk Vsc, subcutaneous bortezomib, cyclophosphamide; M, melphalan; P, prednisone Larocca et al. Blood 2013;122 (ASH abstracts):539 37

VP vs. VMP vs. VCP: Subgroup analysis Fit vs Unfit vs Frail* Progression-free Survival Overall Survival 0.00 0.25 0.50 0.75 1.00 5 10 15 20 25 0.00 0.25 0.50 0.75 1.00 5 10 15 20 25 Patients (%) PFS, Fit versus Frail, p=0.02 PFS , Fit versus Unfit, p=0.2 OS, Fit versus Frail, p=0.001 OS , Fit versus Unfit, p=0.02 Time (months) Time (months) *Unfit defined as: ADL 5 or IADL 6-7 or Charlson 1 or fit patient >80 yr Frail defined as: ADL <4 or IADL <5 or Charlson >2 or unfit patient >80 yr Larocca et al. Blood 2013;122 (ASH abstracts):539

VP vs. VMP vs. VCP: Subgroup analysis Progression-free Survival Median follow-up 17 months Overall Survival 0.00 0.25 0.50 0.75 1.00 5 10 15 20 25 0.00 0.25 0.50 0.75 1.00 5 10 15 20 25 Patients (%) VP VCP VMP VP VCP VMP OS, VMP versus VP, p=0.29 OS , VCP versus VP, p=0.20 OS, VMP versus VCP, p=0.70 Time (months) Time (months) PFS, VMP versus VP, p=0.15 PFS , VCP versus VP, p=0.28 PFS, VMP versus VCP, p=0.69 Larocca et al. Blood 2013;122 (ASH abstracts):539

Dose adjustment recommendations for the treatment of frail elderly patients Agent Dose level 0 Dose level – 1 Dose level – 2 Bortezomib 1.3 mg/m2 twice / week d 1,4,8,11 / 3 wks 1.3 mg/m2 once / week d 1,8,15,22 / 5 weeks 1.0 mg/m2 once / week Thalidomide 100 mg/d 50 mg/d 50 mg qod Lenalidomide 25 mg/d d 1-21 / 4 weeks 15 mg/d 10 mg/d Dexamethasone 40 mg/d d 1,8,15,22 / 4 week 20 mg/d Melphalan 0.25 mg/kg d 1-4 / 4-6 weeks 0.18 mg/kg 0.13 mg/kg Prednisone 25 mg qod 12.5 mg qod Cyclophosphamide Palumbo et al. N Engl J Med 2011;364:1046-60

Conclusions for NDMM patients not eligible for HDM Approved treatment for patients who are not eligible for transplant include: MPT, VMP, CTD and Rd continuous Continuous treatment with PIs or IMiDs gives promising results in this setting Novel combinations, i.e. modified VRD, may be also a treatment option in the near future Caution is needed for frail patients-weekly schedule of bortezomib and dose modifications are necessary

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