Treatment Strategies for Transplant-ineligible NDMM Patients

1 Treatment Strategies for Transplant-ineligible NDMM Patients Thierry Facon, MD Professor of Hematology Service des Maladies du Sang University of Lille Lille, France

Multiple Myeloma affects primarily elderly patients 2 SEER: New MM Cases by Age Group Available from http://seer.cancer.gov/statfacts/html/mulmy.html. Accessed on 6/214.

Mean years of expected and observed survival and years of life lost Pooled analysis, 6996 patients : conventional CT, 3553 patients : transplant What means CURE for elderly and very elderly patients??? Ludwig H. et al, Journal of Clinical Oncology, 28, 1599-165, 21

Period estimates of 1-year survival of patients with MM by major age groups in defined calendar periods from 1984-1986 to 22-24 Brenner et al; Blood 28; 111:2521-26

Patients (%) Dexamethasone-based Regimens vs.mp for Elderly NDMM Patients (IFM 95-1) 1 8 6 4 2 12 24 36 48 6 72 84 96 18 Time (months) Treatment O/N Survival time median±se (month) MP 16/122 34. ± 3.6 M + DEX 97/118 39.6 ± 3.1 DEX 11/127 33.4 ± 2. DEX + IFN 12/121 32. ± 5.3 Facon T, et al. Blood. 26;17:1292-98.

Refresher on MPT and VMP data A journey back in time... MPT: melphalan, prednisone, thalidomide VMP: bortezomib, melphalan, prednisone

MPT becomes a standard of care Facon T, et al. Lancet. 27;37:129-18. Fayers PM, et al. Blood. 211;118: 1239-47.

VMP becomes a standard of care San Miguel JF, et al. N Engl J Med. 28;359: 96-17.

Both VMP and MPT are recognised standards of care in TNE NDMM patients 214: IMWG guidelines 1 Recommended treatments for patients not eligible for high-dose therapy, or in case the transplant procedure is not available, include MPT, MPV and CTD" 214: EMN guidelines 2 Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients" 214: NCCN guidelines 3 MPT and VMP are 2 of the five preferred primary regimens for nontransplant candidates with multiple myeloma 1. Ludwig H et al., Leukemia 213, in press. 2. Engelhardt M, et al. Haematologica. 214;99:232-42. 3. NCCN Guidelines Multiple Myeloma. Version 1.214.

MPT and VMP over time MPT: a stable standard of care thalidomide 1 (or 2 mg/day) MPV: an evolving standard of care from twice weekly to weekly 1,2 (21) from i.v. to s.c. 3 (212) subcutaneous weekly likely the current standard of care for VMP and other bortezomib-based regimens in the elderly 4 In case of renal impairment or extensive bone disease, twice weekly administration may be recommended 4 1. Palumbo A, et al. J Clin Oncol. 21;28:511-9. 2. Mateos MV, et al. Lancet Oncol. 21;11:934-41. 3. Moreau P, et al. Lancet Oncol. 211;12:431-4. 4 Ludwig H, et al. Oncologist 214 in press.

Patients (%) Patients (%) MMIX & XI Trials: Cyclo-DEX + THAL (CTDa) vs. MP Cyclo: 5 mg weekly; Thal: 2 mg daily; Dex: 2 mg days 1-4; 9-12 RR (CR) (%): 64(13) vs. 33(2) 1 PFS 1 OS 8 CTDa MP P =.1 8 CTDa MP P =.24 6 4 CTDa: 13m MP: 12.4m 6 4 2 2 CTDa: 33m MP: 3m CTDa MP 12 24 36 48 6 72 PFS (months) 428 227 96 48 22 7 423 219 81 28 12 3 CTDa MP 12 24 36 48 6 72 PFS (months) 428 38 233 136 62 22 423 315 235 12 55 19 CTDa was one of the standard of care in UK It may be improved switching Thal for Len CRDa Morgan G. Blood 211; 118(5): 1231-8;Pawlyn CH. ASH213: abstract 54.

UPFRONT Study: VD vs. VTD vs. VMP 12 PFS (intent-to-treat population) OS (intent-to-treat population) PFS, progression-free survival; OS, overall survival; VD, bortezomib-dexamethasone; VTD, bortezomib-thalidomide-dexamethasone; VMP, bortezomibmelphalan-prednisone Niesvizky R et al, Blood 213; 122;abstract 1966.

13 Back to present day The benefits of continuous therapy in elderly patients

FIRST Trial: Study Design (Ph3 Pivotal Trial) RANDOMIZATION (N = 1,623) PD or unacceptable toxicity PD, OS and subsequent anti-mm Tx 14 Primary endpoint: PFS (Rd vs. MPT) Key secondary endpoints: OS, QoL, TTF, Time to 2 nd AMT, DOR, Safety Screening Arm A Continuous Rd (n = 535) Active Tx + PFS follow-up phase LEN + Lo-DEX continuously LENALIDOMIDE 25 mg D1-21/28 LoDEX 4 mg D1,8,15 & 22/28 Long-term follow-up Arm B Rd18 (n = 541) LEN + Lo-DEX 18 cycles (72 wks) LENALIDOMIDE 25 mg D1 21/28 LoDEX 4 mg D1,8,15 & 22/28 Arm C MPT (n = 547) MEL + PRED + THAL 12 cycles 1 (72 wks) MELPHALAN PREDNISONE THALIDOMIDE.25 mg/kg D1 4/42 2 mg/kg D1 4/42 2 mg D1 42/42 Pts > 75 yrs: LoDEX 2 mg D1, 8, 15 & 22/28; THAL 2 1 mg D1 42/42; MEL 2.2 mg/kg D1 4. AMT, anti-myeloma treatment; D, days; DOR, duration of response; LoDEX, low-dose dexamethasone; MM, multiple myeloma; OS, overall survival; PD, progressive disease; PFS, progression-free survival; pts, patients; QoL, quality of life; TTF, time to treatment failure, TX, treatment; wks, weeks. 1 Facon T, et al. Lancet. 27;37:129-18. 2 Hulin C, et al. J Clin Oncol. 29;27:3664-7 Facon T, et al. EHA 214: Abstract S643.

72 wks Patients (%) Patients (%) FIRST Trial: Final PFS and Interim OS 15 Final PFS Interim OS 1 Rd (n = 535) Rd18 (n = 541) Median PFS 25.5 mos 2.7 mos 1 4-year OS Rd (n = 535) 59.4% Rd18 (n = 541) 55.7% 8 6 MPT (n = 547) 21.2 mos Hazard ratio Rd vs. MPT:.72; P =.6 Rd vs. Rd18:.7; P =.1 Rd18 vs. MPT: 1.3; P =.7349 8 6 MPT (n = 547) 51.4% 4 4 2 2 Hazard ratio Rd vs. MPT:.78; P =.168 Rd vs. Rd18:.9; P =.37 Rd18 vs. MPT:.88; P =.184 6 12 18 24 3 36 42 48 54 6 PFS (mos) 6 12 18 24 3 36 42 48 54 6 OS (mos) Facon T, et al. EHA 214: Abstract S643.

Age Analysis 16

FIRST Trial - Age Analysis: Adjusted Starting Doses 17 Adjustment 75 yrs > 75 yrs Drugs/Regimens LEN (21/28 days) CrCl: < 3 ml/min 15 mg QOD 15 mg QOD CrCl: 3-5 ml/min 1 mg 1 mg CrCl: > 5 ml/min 25 mg 25 mg DEX (1, 8, 15, 22/28 days) MEL (1-4/42 days) PRED (1-4/42 days) THAL (28/28 days) N/A 4 mg 2 mg CrCl: < 5 ml/min ANC < 1,5/µL Platelet count: < 1,/µL.25 mg/kg.2 mg/kg.125 mg/kg.1 mg/kg N/A 2 mg/kg 2 mg/kg N/A 2 mg 1 mg ANC, absolute neutrophil count; CrCl, creatinine clearance; DEX, dexamethasone; LEN, lenalidomide; MEL, melphalan; N/A, not applicable; PRED, prednisone; QOD, once every 2 days; THAL, thalidomide. Hulin C, et al. FIRST Trial Effect of Age in NDMM patients. ASH 214, abstract #81.

FIRST Trial - Age Analysis: Baseline Characteristics 18 Pt characteristics were well balanced across all Tx arms Characteristic Median age, yrs (range) Continuous Rd (N= 349) 7 (44 75) Age 75 yrs Rd18 (N= 348) 7 (4 75) MPT (N= 359) 7 (51 75) Continuous Rd (N= 186) 79 (76 91) Age > 75 yrs Rd18 (N= 193) 79 (76 89) MPT (N= 188) 79 (76 92) Male (%) 54 53 54 57 46 5 ECOG PS 2 (%) 21 2 18 25 23 24 ISS stage III (%) 37 37 36 47 47 5 CrCl (%) < 3 ml/min 6 8 8 13 11 15 3 and < 5 ml/min 5 and < 8 ml/min 16 14 17 39 37 35 48 48 42 4 45 39 CrCl, creatinine clearance; ECOG, Eastern Cooperative Oncology Group; ISS, international staging system; MPT, melphalan-prednisone-thalidomide; PS, performance status; pt, patient; Rd, lenalidomide and low-dose dexamethasone; Rd18, Rd for 18 cycles; tx, treatment; yrs, years. Hulin C, et al. FIRST Trial Effect of Age in NDMM patients. ASH 214, abstract #81.

Pts (%) Pts (%) FIRST Trial - Age Analysis: PFS 19 Age 75 yrs Median (mos) Age > 75 yrs Median (mos) 1 Rd 27.4 Rd18 21.3 1 Rd 21.2 Rd18 19.4 MPT 21.8 MPT 19.2 8 8 6 Hazard ratio (95% CI) Rd vs. MPT:.68 (.56.83) Rd vs. Rd18:.68 (.55.83) Rd18 vs. MPT: 1.1 (.84 1.21) 6 Hazard ratio (95% CI) Rd vs. MPT:.81 (.62 1.5) Rd vs. Rd18:.75 (.58.98) Rd18 vs. MPT: 1.8 (.83 1.39) 4 46% (Rd) 4 35% (Rd) 2 25% (Rd18) 23% (MPT) 2 19% (Rd18) 22% (MPT) 6 12 18 24 3 36 42 48 54 6 PFS (mos) 6 12 18 24 3 36 42 48 54 6 PFS (mos) Rd 349 267 211 18 149 114 78 44 18 2 Rd 186 133 18 85 69 54 27 11 1 Rd18 348 268 22 186 119 79 39 2 5 2 Rd18 193 123 99 79 48 29 17 1 2 MPT 359 257 213 173 119 8 39 2 5 1 MPT 188 123 91 71 51 36 19 8 1 mos, months; MPT, melphalan-prednisone-thalidomide; PFS, progression-free survival; pts, patients; Rd, lenalidomide and low-dose dexamethasone; Rd18, Rd for 18 cycles; yrs, years. Hulin C, et al. FIRST Trial Effect of Age in NDMM patients. ASH 214, abstract #81.

Pts (%) Pts (%) FIRST Trial - Age Analysis: OS Interim Analysis 2 Age 75 yrs Age > 75 yrs 1 3-yr OS Rd 74% 1 3-yr OS Rd 63% Rd18 7% Rd18 58% 8 MPT 67% 8 MPT 54% 6 6 4 4 Rd Rd18 MPT 2 6 12 18 24 3 36 42 48 54 6 OS (mos) 349 348 359 Hazard ratio (95% CI) Rd vs. MPT:.77 (.59 1.1) Rd vs. Rd18:.88 (.67 1.16) Rd18 vs. MPT:.88 (.68 1.14) 329 328 33 311 39 36 295 287 291 272 264 262 226 216 214 154 14 139 85 82 71 31 31 21 5 5 2 2 Rd Rd18 MPT 6 12 18 24 3 36 42 48 54 6 OS (mos) 186 193 188 Hazard ratio (95% CI) Rd vs. MPT:.8 (.59 1.9) Rd vs. Rd18:.94 (.69 1.29) Rd18 vs. MPT:.85 (.63 1.15) 159 177 154 146 156 142 138 138 127 131 129 113 112 18 98 7 69 66 36 42 35 12 13 9 1 1 1 mos, months; MPT, melphalan-prednisone-thalidomide; OS, overall survival; pts, patients; Rd, lenalidomide and low-dose dexamethasone; Rd18, Rd for 18 cycles; yrs, years. Hulin C, et al. FIRST Trial Effect of Age in NDMM patients. ASH 214, abstract #81.

FIRST Trial - Renal Analysis: Characteristics 21 Patients: Of the 1,623 pts enrolled in the FIRST trial: 389 (24%) had normal renal function 715 (44%) had mild RI 372 (23%) had moderate RI 147 (9%) had severe RI Outcomes by Renal Subgroup: A significant benefit was seen with continuous Rd vs. Rd18 or MPT in pts with mild or moderate RI Continuous Rd vs. MPT, mild RI: HR =.74; P =.2 Continuous Rd vs. MPT, moderate RI: HR =.66; P <.1 At 36 mos a higher percentage of pts are still progression free in continuous Rd vs. Rd18 and MPT PFS, progression free survival; Rd, lenalidomide plus low-dose dexamethasone; Rd18, Rd for 18 cycles; MPT, melphalan-prednisone-thalidomide; pts, patients; RI, renal impairment; HR, hazard ratio; mos, months Dimopoulos MA, et al. FIRST trial: Impact of Renal Impairment in NDMM pts. ASH 214, abstract #2112.

FIRST Trial - Renal Analysis: PFS Per Status Survival probability Survival probability Survival probability Survival probability 22 PFS in normal (per IRAC assessment) PFS in mild RI (per IRAC assessment) 1..8 Continuous Rd Rd18 MPT 1..8 Continuous Rd Rd18 MPT.6.6.4.4.2 Cont. Rd vs. MPT HR:.71, P =.5 a Rd vs. Rd18 HR:.67, P =.2 a Rd18 vs. MPT HR: 1.6, P =.76 a. 6 12 18 24 3 36 42 PFS (mos) 1..8.6 48 54 6 PFS in moderate RI (per IRAC assessment) Continuous Rd Rd18 MPT.2 Cont. Rd vs. MPT HR:.74, P =.2 a Rd vs. Rd18 HR:.72, P <.1 a Rd18 vs. MPT HR: 1.4, P =.76 a. 6 12 18 24 3 36 42 PFS (mos) 1..8.6 PFS in severe RI (per IRAC assessment) 48 54 6 Continuous Rd Rd18 MPT.4.4.2 Cont. Rd vs. MPT HR:.66, P <.1 a Rd vs. Rd18 HR:.66, P <.1 a Rd18 vs. MPT HR: 1.2, P =.89 a. 6 12 18 24 3 36 42 48 54 6 PFS (mos) a Nominal 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. FIRST trial: Impact of Renal Impairment in NDMM pts. ASH 214, abstract #2112..2 Cont. Rd vs. MPT HR:.76, P =.31 a Rd vs. Rd18 HR:.82, P =.48 a Rd18 vs. MPT HR: 1., P = 1. a. 6 12 18 24 3 36 42 PFS (mos) 48 54 6

Change From Baseline FIRST Trial: EORTC QLQ-MY2 Results 23 Rd resulted in a significant reduction in patient-reported Side Effects of Tx vs. MPT at most time points More side effects 2 15 Side Effects of Tx Rd MPT Fewer side effects 1 5 5 * * * P.5 vs. baseline (1-sample t-test). P.5 Rd vs. MPT (2-sample t-test). * * * * * * * C2D1 Mo 3 Mo 6 Mo 12 Mo 18 Visit EORTC, European Organisation for Research and Treatment of Cancer; Mo, month; MPT, melphalan, prednisone, thalidomide; Rd, lenalidomide plus low-dose dexamethasone; Tx, treatment. Facon T, et al. EHA 214: Abstract S643.

Treatment improved HRQoL HRQoL decreased significantly in all domains upon progression Global Health Status: Higher Score = Better Global Health Status Mean value Mean value FIRST Trial: Impact of Disease Progression Mean value Mean value 8 7 6 5 4 3 2 1 Fatigue: Higher Score = Worse Fatigue 5 4 3 2 1 *** Rd *** +++ +++ *** MPT *** +++ +++ Score Baseline Best prior to PD PD *** above Best Prior to PD: P.5 vs. baseline. +++ above PD: P.5 vs. Best Score Prior to PD. Physical Functioning: Higher Score = Better Physical Functioning 8 7 6 5 4 3 2 1 Pain: Higher Score = Worse Pain Rd MPT Rd MPT 5 4 3 2 1 *** Rd *** +++ +++ *** MPT *** +++ +++ 24 HRQoL, health-related quality of life; MPT, melphalan, prednisone, thalidomide; PD, progressive disease; Rd, lenalidomide plus low-dose dexamethasone. Delforge M, et al. Health-Related Quality of Life in Transplant-Ineligible Patients With NDMM- Results From the FIRST Trial. ASCO 214, Abstract 8516.

Why is IFM 27-1/MM2/FIRST an important trial? (among others) Design: Continuous (CT) vs. Fixed Duration Therapy (FDT) - the FIRST trial compared the same regimen (Rd) given either as CT or FDT Alkylator-free vs. Alkylator-containing - without being designed to assess the role of alkylating agents Result: Continuous Rd > MPT Conclusion: A dual paradigm changing study - in a disease where alkylators and FDT have been the standard of care for decades A practice changing study - establishing continuous Rd as a new standard of care

Maintenance treatment with bortezomib in elderly patients with MM Median follow-up (months) Median PFS (months) 5-year OS VMP- VT/VP 1 46 35 58% VMPT-VT 2 54 35.3* 61%* *significant difference versus no maintenance 1 Mateos et al. Blood 212; 12: 2581-2588 2 Palumbo et al. JCO 214, Epub 21 January

What is the next step forward?

Treatment of NDMM in Elderly Patients Landscape and Perspectives < VMP # Vd? Alternating regimens 6? VMP-Daratumumab 1 MP < MPT < Rd Rd-MLN 978 2 Rd-Elotuzumab 3 Rd-Daratumumab 4 < MPR-R MPT-T MP-Carfilzomib 5 1 MMY37; 2 Tourmaline 2, clinical trial.gov ref: NCT185524. Accessed June 214; 3 Eloquent 1, clinical trial.gov ref: NCT1335399. Accessed June 214; 4 MMY38; 5 Clarion, clinical trial.gov ref: NCT1818752. Accessed June 214; 6 Mateos et al. ASH 213, abs 43.

The fresh wind of Alternating regimens 1. Are they truly innovative? 2. The right way to manage multiple novel agents? Or a good idea only at first sight? 3. A way to avoid the VMP vs Rd debate? 4. Will they be really transformative?

Bersagel et al. NEJM. 1979;31:743-49

Alternating regimens as a way to manage multiple novel agents From financially acceptable to financially lethal VMP Rd VMP Rd VD Rd VD Rd VD ixazomib Rd VD ixazomib Rd anti CD38 VD ixazomib Rd VD ixazomib Rd anti CD38/Elotuzumab VD ixazomib Rd VD ixazomib Rd

Patients (%) Challenges and perspectives with transplantineligible patients Conclusion 1 During the past 1 years significant progress has been made in the management of transplant-ineligible MM patients Median PFS has increased from 1 15 to 25 3 months Median OS has increased from 3 to approx. 6 months 1 8 6 4 2 12 24 36 48 6 72 84 96 18 OS (months) Treatment O/N Survival time median ± Standard Error (month) MP 16/122 34. ± 3.6 M + DEX 97/118 39.6 ± 3.1 DEX 11/127 33.4 ± 2. DEX + IFN 12/121 32. ± 5.3 Facon T, et al. Blood. 26;17:1292-98; Facon T et al. Blood. 213; 122:abstract 2.

Patients (%) Challenges and perspectives with transplantineligible patients Conclusion 1 During the past 1 years significant progress has been made in the management of transplant-ineligible MM patients Median PFS has increased from 1 15 to 25 3 months Median OS has increased from 3 to approx. 6 months 1 First Trial: 8 6 4 4-year OS Rd (n= 535) 59.4% Rd18 (n= 541) 55.7% MPT (n= 547) 51.4% 2 12 24 36 48 6 72 84 96 18 OS (months) Treatment O/N Survival time median ± Standard Error (month) MP 16/122 34. ± 3.6 M + DEX 97/118 39.6 ± 3.1 DEX 11/127 33.4 ± 2. DEX + IFN 12/121 32. ± 5.3 Facon T, et al. Blood. 26;17:1292-98; Facon T et al. Blood. 213; 122:abstract 2.

72 wks Patients (%) Patients (%) PFS: FIRST and MM-15 Trials 35 FIRST Trial: PFS (Median follow-up 37 mos) MM-15: PFS (Median follow-up 3 mos) Median PFS Median PFS 1 Rd (n = 535) Rd18 (n = 541) 25.5 mos 2.7 mos 1 MPR-R (n = 152) MPR (n = 153) 31 mos 14 mos MPT (n = 547) 21.2 mos MP (n = 154) 13 mos 8 6 Hazard ratio Rd vs. MPT:.72; P =.6 Rd vs. Rd18:.7; P =.1 Rd18 vs. MPT: 1.3; P =.7349 8 6 Hazard ratio MPR-R vs. MPR:.49; P <.1 MPR-R vs. MP:.4; P <.1 4 4 2 2 6 12 18 24 3 36 42 48 54 6 PFS (mos) 5 1 15 2 25 3 35 4 PFS (mos) Facon T, et al. Blood. 213;122:abstract 2. Dimopoulos MA, et al. Blood. 213;122:abstract 45.

Thalidomide enters the treatment of multiple myeloma Miami, December 4 8, 1998 Full publication in: Singhal S, et al. N Engl J Med. 1999;341:1565-71.

MPT vs MP for elderly NDMM patients: Meta-analysis of 1685 individual-patient data from 6 trials Survival proportion..2.4.6.8 1. PFS HR=.67 in favor of MPT, p<.1 Median 14.9 mos (14.-16.6) Median 2.3 mos (18.8-21.6) MPT MP 12 24 36 48 months..2.4.6.8 1. OS HR=.83 in favor of MPT, p=.5* Median 39.3 mos (35.6-44.6) Median 32.7 mos (3.5-36.6) MPT MP 12 24 36 48 months *Cox model for treatment, with analysis stratified by study using a random effects (frailty) model Fayers et al. Blood 211;118:1239-1247

Patients without event (%) Patients without event (%) VISTA Trial: MP + Bortezomib (VMP) vs. MP Bortezomib twice a week x 4 cycles + weekly x 5 cycles RR (CR) (%): 71(3) vs. 35(4) TTP OS 1 1 8 VMP MP 8 6 6 4 4 2 VMP: 24. months MP: 16.6 months, P <.1 3 6 9 12 15 18 21 24 27 2 Median follow-up 6 months Median OS: VMP: 56m MP: 43m, P =.8 6 12 18 24 3 36 42 48 54 6 66 72 78 Time (months) Time (months) San Miguel et al. JCO 213; 31(4):448-55.

Change From Baseline Change From Baseline Change From Baseline Change From Baseline FIRST Trial: EORTC QLQ-C3 Results Scores improved significantly from baseline at most time points across Tx groups 39 Improved 2 Global Health Status 2 Physical Functioning 1 * * * * * * * * 1 * * * * * * * 1 Rd MPT 1 Rd MPT Decreased 2 C2D1 Mo 3 Mo 6 Mo 12 Mo 18 Visit 2 C2D1 Mo 3 Mo 6 Mo 12 Mo 18 Visit Increased Decreased 2 1 ** * P.5 vs. baseline (1-sample t-test). 1 2 * Fatigue * Visit * C2D1 Mo 3 Mo 6 Mo 12 Mo 18 Rd MPT 2 1 1 2 ** * Pain * * * ** C2D1 Mo 3 Mo 6 Mo 12 Mo 18 Visit Rd MPT EORTC, European Organisation for Research and Treatment of Cancer; MPT, melphalan, prednisone, thalidomide; Rd, lenalidomide, low-dose dexamethasone; Tx, treatment. Delforge M, et al. Health-Related Quality of Life in Transplant-Ineligible Patients With NDMM- Results From the FIRST Trial. ASCO 214, Abstract 8516.

FIRST Trial - Age Analysis: Adjusted Starting Doses 4 Drugs/Regimens LEN (21/28 days) Adjustment 75 yrs > 75 yrs CrCl: < 3 ml/min CrCl: 3-5 ml/min CrCl: > 5 ml/min DEX (1, 8, 15, 22/28 days) MEL (1-4/42 days) PRED (1-4/42 days) THAL (28/28 days) N/A CrCl: < 5 ml/min ANC < 1,5/µl Platelet count: < 1,/µL N/A N/A ANC, absolute neutrophil count; CrCl, creatinine clearance; DEX, dexamethasone; LEN, lenalidomide; MEL, melphalan; N/A, not applicable; PRED, prednisone; QOD, once every 2 days; THAL, thalidomide. Hulin C, et al. FIRST Trial Effect of Age in NDMM patients. ASH 214, abstract #81.

FIRST Trial - Age Analysis: Adjusted Starting Doses 41 Adjustment 75 yrs > 75 yrs Drugs/Regimens LEN (21/28 days) CrCl: < 3 ml/min 15 mg QOD 15 mg QOD CrCl: 3-5 ml/min 1 mg 1 mg CrCl: > 5 ml/min 25 mg 25 mg DEX (1, 8, 15, 22/28 days) MEL (1-4/42 days) PRED (1-4/42 days) THAL (28/28 days) N/A CrCl: < 5 ml/min ANC < 1,5/µl Platelet count: < 1,/µL N/A N/A ANC, absolute neutrophil count; CrCl, creatinine clearance; DEX, dexamethasone; LEN, lenalidomide; MEL, melphalan; N/A, not applicable; PRED, prednisone; QOD, once every 2 days; THAL, thalidomide. Hulin C, et al. FIRST Trial Effect of Age in NDMM patients. ASH 214, abstract #81.

Challenges and perspectives with transplantineligible patients Conclusion 2 High-risk patients still have a very poor outcome with first generation novel agents There is a need for adequate risk assessment and innovative therapy Frail patients remain a challenge Assessment of organ function, comorbidities, frailty, and disability should be considered Additional progress is anticipated with 2 nd /3 rd generation PIs, IMiDs, monoclonal Abs, and innovative treatment regimens

What are the most important challenges? Discussion on cytogenetics and frailty

Probability of OS Probability of OS Cytogenetic abnormalities are a major prognostic factor in elderly patients with MM the IFM experience 1,89 patients (median age 72, range 66 94), including 1,95 patients with updated data on treatment modalities and survival 1. OS according to t(4:14) 1. OS according to del(17p).75 p < 1.4 p < 1.6.75.5.5.25. t(4:14) neg t(4:14) pos 1 2 3 4 5 Time (years) Whatever the treatment, t(4;14) and del(17p) were associated with shorter PFS and OS; similar results were achieved in the subgroup of 335 patients > 75 years.25. del(17p) < 6 del(17p) 6 1 2 3 4 5 Time (years) Avet-Loiseau H, et al. J Clin Oncol. 213;31:286-9

The challenge of high-risk CA [t(4;14), del(17p), t(14;16)] in NDMM elderly patients Study No of patients with high-risk CA Outcome of high-risk CA patients MPT/MP 1 NR NR CTDa/MP 1 (MRC Myeloma IX) NR CTDa does not overcome the effect of high-risk CA and not significantly better than MP in highrisk CA RD/Rd 2 (E4A3) 21 2y OS=76% for high-risk CA vs 91% VMP/MP 3 (VISTA) VMP/VTP VT/VP 4 (GEM-5) 46 44 Absence of OS benefit, median OS 44.1mo. VMP vs 5.6 mo., MP Adverse prognosis of both t(4;14) and del (17p) regardless of induction and maintenance. Median OS t(4;14)=29 mo., del(17p) = 27mo. First generation novel agents do not overcome the negative prognosis of high-risk CA in newly diagnosed elderly patients with MM 1. Bergsagel PL, et al. Blood 213;121:884-91. 2. Rajkumar SV, et al. Lancet Oncology 21;11:29-37. 3. San Miguel J, et al. JCO 213;31:448-55. 4. Mateos MV, et al. Blood 211; 118:4547-53.

Higher risk of mortality in patients 75 years of age Retrospective meta-analysis of 4 EU phase III trials (N = 1,435) with MP, MPT, VMP, and VMPT Median follow up 33 months Median OS in total population 5 months Estimated 3-year OS 68% in patients < 75 years of age vs 57% in patients 75 years of age (HR 1.44, CI 1.2-1.72, p <.1) HR (95% CI) p value All 1.44 (1.2.72) <.1 MP 1.21 (.9 1.64).21 MPT 1.12 (.81 1.56).49 VMP 1.62 (1.4 2.52).3 VTP/VMPT 3.2 (1.86 4.9) <.1.1 Higher mortality in patients < 75 years of age 1 1 Higher mortality in patients 75 years of age Bringhen S, et al. Haematologica. 213; 98:98

Factors associated with shorter survival Advanced age, renal failure, severe cardiac/infective AEs and drug discontinuation were associated with shorter OS PN was associated with longer OS HR (95% CI) p value Male 1.13 (.95 1.35).17 Age 75 years 1.36 (1.14 1.63).1 Serum creatinine 2 mg/dl 1.59 (1.18 2.16).3 Grade 3/4 haem AEs 1.24 (.88 1.75).21 Grade 3/4 non-haem AEs 1.72 (1.19 2.47).4 cardiac 2.61 (1.49 4.6).1 infections 2.46 (1.58 3.82) <.1 GI 1.89 (.92 3.89).8 VTE 1.14 (.42 3.1).79 PN.29 (.7 1.18).8 Drug discontinuation 1.61 (1.3 2.5).3.1.1 Lower mortality 1 1 Higher mortality Bringhen S, et al. Haematologica. 213; 98:98

Patients (%) Frailty is Stronger Predictor of Overall Survival than ISS or FISH (GIMEMA) 1..75.5.25 1-yr OS Fit 96% Unfit 93% Frail 78% Unfit vs Fit, HR = 1.61 P =.42 Frail vs Fit, HR = 3.57 P <.1 6 12 18 24 3 Months Multivariate Analysis Unfit vs. Fit 1.24 (.74, 2.8) Frail vs. Fit 3.11 (1.97, 4.9) ISS 3 vs. ISS 1-2 1.77 (1.23, 2.54) HR vs. SR FISH 1.83 (1.26, 2.63) ECOG 2-3 vs. -1 1.19 (.81, 1.76) Lower risk Death FIT ISS 1-2 FISH neg.24 1 4.9 Higher risk Death FRAIL ISS 3 FISH pos Fit defined as: score = ; Unfit defined as: score = 1; Frail defined as: score > 2. Mina R, et al. EHA 19 th Congress; June 12-15, 214: abstract P354.

IMWG consensus statement on the treatment of Transplant-ineligible NDMM patients Newly diagnosed, symptomatic MM patients NOT eligible for high dose therapy (MEL2) and SCT Assessment of patient status: Presence of comorbidities and/or limits in mental or mobility functions Specific index and scores can be used Very fit Fit Unfit Reducedintensity ASCT (MEL 1) MPT MPV/VMPT-VT VCD/VRD MPR-R/Rd Low-dose MPT/MPV Vd/Rd MPR-R, melphalan, prednisone, lenalidomide followed by lenalidomide maintenance; MPT, melphalan, prednisone, thalidomide; MPV, bortezomib, melphalan, prednisone; Rd, lenalidomide, low-dose dexamethasone; Vd, bortezomib, low-dose dexamethasone; VMPT-VT, bortezomib, melphalan, prednisone, thalidomide followed by bortezomib plus thalidomide maintenance Palumbo A, et al. J Clin Oncol. 214;32:587-6

Patients surviving (%) Continued Improvement in Survival Since the Introduction of Novel Agents 1,56 patients grouped into 21 25 and 26 21 cohorts Survival improved over time, particularly in patients aged > 65 years (P =.1) 1 8 Diagnosed 26 21 Survival 21 25 26 21 P Median OS, years 4.6 NR.1 6 1-year survival, % 83 9 4 Diagnosed 21 25 5-year estimated OS, % 2 Overall 48 66 > 65 years 31 56.1 1 2 3 4 5 < 65 years 63 73 NS Follow-up from diagnosis (years) Kumar SK, et al. Leukemia. 214;28(5):1122-8.

Refresher on MPT and VMP data A journey back in time... MPT: melphalan, prednisone, thalidomide VMP: bortezomib, melphalan, prednisone