Myeloma update ASH 2014

Myeloma update ASH 2014

Updates in Newly Diagnosed Multiple Myeloma FIRST: effect of age on lenalidomide/dexamethasone vs MPT in transplantation-ineligible pts Phase III: MPT-T vs MPR-R in transplantation-ineligible pts Weekly vs twice weekly carfilzomib in combination with cyclophosphamide/dexamethasone

Updates in Relapsed/ Refractory 1 st and second relapse Multiple Myeloma ASPIRE: addition of carfilzomib to lenalidomide/dexamethasone Pomalidomide/bortezomib/dexamethasone Double relapsed/refractory setting Monoclonal antibodies in combination with lenalidomide/ dexamethasone SAR650984 (anti CD-38 mab) Daratumumab (anti CD-38 mab) Elotuzumab (anti-slamf7/cs1 mab)

Updates in Other Plasma Cell Disorders Phase III trial of melphalan/dexamethasone vs bortezomib/melphalan/dexamethasone for untreated AL amyloidosis Phase II trial of lenalidomide/dexamethasone in POEMS syndrome

FIRST Trial: Lenalidomide/Dexamethasone vs MPT in NDMM SCT-Ineligible Pts Randomized 1:1:1 Arm A Continuous Rd Arm B Rd18 Arm C MPT Active treatment + PFS follow-up phase Len + LoDex Continuously Lenalidomide 25 mg Days 1-21/28 LoDex 40 mg Days 1, 8, 15, 22/28 Len + LoDex 18 cycles (72 wks) Lenalidomide 25 mg Days 1-21/28 LoDex 40 mg Days 1, 8, 15, 22/28 Mel + Pred + Thal 12 cycles [2] (72 wks) Melphalan 0.25 mg/kg Days 1-4/42 Prednisone 2 mg/kg Days 1-4/42 Thalidomide 200 mg Days 1-42/42 PD or unacceptable toxicity Phase III (N = 1623) PD, OS, and subsequent anti-mm Tx Pts > 75 yrs: LoDex 20 mg Days 1, 8, 15, 22/28; Thal 100 mg Days 1-42/42; Mel 0.2 mg/kg Days 1-4. Stratification: age, country, and ISS stage. 1. Hulin C, et al. ASH 2014. Abstract 81. 2. Facon T, et al. Lancet. 2007;370:1209-1218. 3. Hulin C, et al. J Clin Oncol. 2009;27:3664-3670. 4. Benboubker L, et al. N Engl J Med. 2014;371:906-917

571 pts > 75 yrs FIRST Trial: PFS by Age Stratification Pts (%) 100 80 60 40 Aged 75 Yrs or Younger Rd Rd18 MPT HR (95% CI) Rd vs MPT: 0.68 (0.56-0.83) Rd vs Rd18: 0.68 (0.55-0.83) Rd18 vs MPT: 1.01 (0.84-1.21) 46% (Rd) Median, Mos 27.4 21.3 21.8 Pts (%) 100 80 60 40 Aged Older Than 75 Yrs Rd Rd18 MPT Median, Mos 21.2 19.4 19.2 HR (95% CI) Rd vs MPT: 0.81 (0.62-1.05) Rd vs Rd18: 0.75 (0.58-0.98) Rd18 vs MPT: 1.08 (0.83-1.39) 35% (Rd) 20 25% (Rd18) 23% (MPT) 20 19% (Rd18) 22% (MPT) 0 0 6 12 18 24 30 36 42 48 54 60 0 0 6 12 18 24 30 36 42 48 54 60 PFS (Mos) PFS (Mos) Hulin C, et al. ASH 2014. Abstract 81. Reproduced with permission.

FIRST Trial: OS by Age Stratification 100 80 Aged 75 Yrs or Younger 3-Yr OS, % Rd 74 Rd18 70 MPT 67 100 80 Aged Older Than 75 Yrs 3-Yr OS, % Rd 63 Rd18 58 MPT 54 Pts (%) 60 40 Pts (%) 60 40 20 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) 20 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) 0 0 6 12 18 24 30 36 42 48 54 60 0 0 6 12 18 24 30 36 42 48 54 60 OS (Mos) OS (Mos) Hulin C, et al. ASH 2014. Abstract 81. Reproduced with permission.

Phase III Trial Comparing MPT-T vs MPR-R in SCT-Ineligible Pts 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 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) 28-day cycles x 9 Randomization 1:1 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) Zweegman S, et al. ASH 2014. Abstract 179. R Maintenance Lenalidomide 10 mg on Days 1-21 q28d until PD T Maintenance Thalidomide 100 mg/day until PD Granulocyte-colony stimulating factor administered if absolute neutrophil count < 0.5 x 10 9 cells/l or in event of febrile neutropenia during a cycle.

Phase III Trial Comparing MPT-T vs MPR-R in SCT-Ineligible Pts with NDMM

MPT-T vs MPR-R: Safety Analysis Treatment Outcome, % MPR-R MPT-T *Primarily due to peripheral neuropathy in thalidomide arm, hematologic toxicity in lenalidomide arm Zweegman S, et al. ASH 2014. Abstract 179. 75 Yrs > 75 Yrs 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) 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

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) Zweegman S, et al. ASH 2014. Abstract 179. 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 NR 0.79 (0.61-1.03).08 2-yr OS, % 84 73 3-yr OS, % 69 64 4-yr OS, % 55 52

Weekly Carfilzomib + Cyclophosphamide/ Dex: Preliminary Efficacy MTD: 70mg/m2 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) Pts (%) 50 40 30 20 10 0 30 At Least ncr 41 24 47 100 At Least VGPR 89 0 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. Reproduced with permission. Pts (%) 80 60 40 20 57 91 77

ASPIRE: Phase III Trial Comparing Len/ Dexamethasone ± Carfilzomib in R/R MM Randomized, open-label, multicenter phase III trial Stratified by β 2 -microglobulin, prior bortezomib, and prior lenalidomide Pts with symptomatic R/R MM after 1-3 prior treatments with PR to 1 prior regimen (N = 792) KRd* (n = 396) Carfilzomib 27 mg/m 2 IV 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 Rd (n = 396) 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. Stewart AK, et al. ASH 2014. Abstract 79.

ASPIRE: Response Rates and PFS by Response Percentage of Pts 100 80 60 40 20 31.8 KRd Rd 9.3 69.9 40.4 87.1 66.7 Survival Probability 1.0 0.8 0.6 0.4 0.2 PFS by Response With KRd Tx scr CR VGPR PR MR SD PD 0 CR VGPR ORR ( PR) 0.0 0 10 20 30 40 50 Mos From Randomization AEs consistent with previous studies; no unexpected toxicities observed Stewart AK, et al. ASH 2014. Abstract 79. Reproduced with permission.

ASPIRE: PFS in ITT Population (Primary Endpoint) Proportion Surviving Without Progression 1.0 0.8 0.6 0.4 0.2 0.0 KRd Rd KRd Rd (n = 396) (n = 396) Median PFS, mos 26.3 17.6 HR (KRd/Rd) (95% CI) 0.69 (0.57-0.83) P value (1 sided) <.0001 0 6 12 18 24 30 36 42 48 Mos Since Randomization Risk Group by KRd (n = 396) Rd (n = 396) HR P Value FISH n Median PFS, Mos n Median PFS, Mos High 48 23.1 52 13.9 0.70.083 Standard 147 29.6 170 19.5 0.66.004 Stewart AK, et al. ASH 2014. Abstract 79. Reproduced with permission.

ASPIRE: Interim OS Analysis Median follow-up: 32 mos Median OS was not reached; results did not meet prespecified statistical boundary (P =.005) at interim analysis Proportion Surviving 1.0 0.8 0.6 0.4 0.2 0.0 KRd Rd 0 6 12 18 24 30 36 42 48 Mos Since Randomization Stewart AK, et al. ASH 2014. Abstract 79. Reproduced with permission. KRd Rd (n = 396) (n = 396) Median OS, mos NR NR HR (KRd/Rd) (95% CI) 0.79 (0.63-0.99) P value (1 sided).018

Pomalidomide/Bortezomib/Dexamethasone for Lenalidomide Refractory MM Phase I/II trial to determine MTD; assess safety and efficacy of pomalidomide/bortezomib/dexamethasone Included pts with relapsed MM who had 1-4 previous lines of therapy and were resistant/refractory to lenalidomide. 57% had prior bortezomib Accrual: 50 pts (phase I: 3 at dose level 1, 6 at dose level 2; phase II: 41) Current analysis: 47 pts treated at MTD (dose level 2 + phase II) 8 cycles Pomalidomide 4 mg/day on Days 1-21 Day 1 Day 8 Day 15 Day 22 Bortezomib 1.3 mg/m 2 (IV or SC) and dexamethasone 40 mg Lacy MQ, et al. ASH 2014. Abstract 304. Pomalidomide 4 mg/day until PD

Pomalidomide/Bortezomib/Dexamethas one: Summary of Efficacy Outcome Response, n (%) Pts Treated at MTD (N = 47) Std-Risk Pts (n = 28) Int-/High-Risk Pts (n = 19) ORR 40 (85) 24 (86) 16 (84) scr 3 (6) CR 6 (13) VGPR 12 (26) PR 19 (40) Median OS, mos NR NR NR Event free at 6 mos, % 100 100 100 Event free at 12 mos, % 94 95 92 Median PFS, mos (95% CI) 10.7 (9.4-18.5) 16.3 9.5 Median DoR, mos (95% CI) 13.7 (8.5-16.8) Lacy MQ, et al. ASH 2014. Abstract 304.

Pomalidomide/Bortezomib/Dexamethasone: Summary of Adverse Events Hematologic Toxicity 2% 2% Grade 3+ 70% 68% 81% All grades Anxiety Generalized muscle weakness Edema limbs Constipation Dyspnea Insomnia 89% 0 10 20 30 40 50 Pts (n) Dizziness Thromboembolic event Lung infection Vomiting Nausea Diarrhea Peripheral neuropathy Fatigue Lacy MQ, et al. ASH 2014. Abstract 304. Reproduced with permission. Nonhematologic Toxicity 0 5 10 15 20 35 25 30 Pts (n) 45% 64% 70%

Phase I Trial: SAR650984 in Combination With Len/Dex in Relapsed/Refractory MM Phase Ib trial of SAR650984 + len/dex in relapsed/refractory MM SAR650984 is a humanized IgG1 mab to the CD38 receptor widely expressed in many heme malignancies Dose escalation: SAR650984 3-10 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 SAR650984 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 2014. Abstract 83.

SAR650984 + Len/Dex: Efficacy Analysis DoR: 9.13 mo (range: 1.2-15.2) Response, % Total (N = 31) ORR 58 scr 6 VGPR 23 PR 29 CBR 65 MR 6 SD 19 PD 13 Not evaluable 3 Pts (%) 100 80 60 40 20 0 MR ORR 25% CBR 50% 25 25 3 (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) SAR650984 Dose Level, mg/kg q2w 8 29 scr 6 29 25 23 6 Martin TG, et al. ASH 2014. Abstract 83. Reproduced with permission.

SAR650984 + Len/Dex: PFS by Previous Lines of Therapy 100 90 1-2 prior lines (n = 7) Overall (N = 31) 3 prior lines (n = 24) 80 70 Median PFS: NR (95% CI: 6.2-NR) Probability 60 50 40 30 20 10 Median PFS: 6.2 mos (95% CI: 4.80-13.33) Median PFS: 5.8 mos (95% CI: 2.10-10.30) 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mos Martin TG, et al. ASH 2014. Abstract 83. Reproduced with permission.

SAR650984 plus Len/Dex: Tx-Emergent AEs 100 Grade 1 Grade 2 Grade 3 Grade 4 Pts (n = 31) (%) 80 60 40 20 0 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 2014. Abstract 83. Reproduced with permission.

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 2014. Abstract 84.

Daratumumab in Combination With Len/Dex: Overall Best Response Overall Best Response VGPR or Better Response by Cycles of Treatment (Part 2) 100 80 100 86.7 CR 31% CR 6.7% 60 50.0 CR 6.7% 60 CR 8.0% 64.7 CR 11.8% PR VGPR Pats (%) 60 40 20 0 VGPR 46% PR 23% Part 1 VGPR 43% PR 37% Part 2 Pts (%) 40 20 0 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 2014. Abstract 84. Reproduced with permission.

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 100 100 100 Neutropenia 62 65 64 Muscle spasms 62 38 44 Diarrhea 54 18 31 Fatigue 62 16 29 Cough 31 28 29 Constipation 54 13 27 Nausea 38 19 24 Nasopharyngitis 62 3 20 Bone pain 31 13 18 Upper respiratory tract infection 46 3 16 Insomnia 31 6 16 Dyspnea 23 6 11 Anemia 31 19 11 Plesner T, et al. ASH 2014. Abstract 84.

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 (%) 40 20 20.0 20.0 Subsequent Infusion 33.3 38.1 4.8 0 8 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 2014. Abstract 84. Reproduced with permission.

Phase I Trial: Elotuzumab in Combination With Len/Dex in RR MM Phase Ib/II 1703 trial of elotuzumab + len/dex in relapsed/refractory MM Elotuzumab is a humanized IgG1 mab targeting SLAMF7, a glycoprotein highly expressed on myeloma and NK cells Elotuzumab 10 or 20 mg/kg on Days 1, 8, 15, 22 for cycles 1-2; Days 1, 15 for subsequent cycles Lenalidomide 25 mg on Days 1-21 of each 28-day cycle Dexamethasone 28 mg + 8 mg IV on elotuzumab dosing days, or 40 mg/wk for of each 28-day cycle Current analysis on phase II data to assess efficacy and safety of combination ~ 60% of pts received previous treatment with bortezomib and/or thalidomide and 20% to 30% were refractory to previous treatment Richardson PG, et al. ASH 2014. Abstract 302.

Elotuzumab in Combination With Len/Dex: Final Efficacy Results Response, % Elotuzumab 10 mg/kg (n = 36) Elotuzumab 20 mg/kg (n = 36) Total (N = 73) ORR 92 76 84 scr 6 3 4 CR 11 8 10 VGPR 47 38 43 PR 28 27 27 SD 8 19 14 Time to first response, mos 1.0 1.7 1.0 Median DoR, mos 23.0 18.0 20.8 Median PFS, mos 32.5 25.1 28.6 Richardson PG, et al. ASH 2014. Abstract 302.

Elotuzumab in Combination With Len/Dex: Final Safety Results Preferred term, n (%) Elo 10 mg/kg (n = 36) Elo 20 mg/kg (n = 37) Any Grade Grade 3/4 Any Grade Grade 3/4 Diarrhea 24 (67) 5 (14) 25 (65) 2 (5) Muscle spasms 22 (61) 2 (6) 23 (62) 0 Fatigue 24 (67) 3 (8) 17 (46) 2 (5) Constipation 18 (50) 0 19 (51) 0 Nausea 18 (50) 0 17 (46) 1 (3) URI 19 (53) 1 (3) 15 (41) 1 (3) Pyrexia 14 (39) 1 (3) 17 (46) 1 (3) Back pain 17 (47) 3 (8) 13 (35) 1 (3) Anemia 17 (47) 6 (17) 12 (32) 5 (14) Insomnia 10 (28) 0 15 (41) 2 (5) Cough 12 (33) 0 12 (32) 0 Hyperglycemia 9 (25) 2 (6) 12 (32) 5 (14) Lymphopenia 13 (36) 10 (28) 8 (22) 5 (14) Pain in extremity 9 (25) 0 12 (32) 0 Dyspnea 10 (28) 3 (8) 10 (27) 1 (3) Peripheral edema 12 (33) 0 8 (22) 1 (3) Thrombocytopenia 13 (36) 7 (19) 7 (19) 6 (16) Asthenia 7 (19) 1 (3) 12 (32) 1 (3) Nasopharyngitis 10 (28) 0 9 (24) 0 Neutropenia 11 (31) 7 (19) 8 (22) 7 (19) Richardson PG, et al. ASH 2014. Abstract 302. Infusion reactions: if pts tolerated 2 ml/min, flow rate increased to 5 ml/ min 33% of infusions were at rate of 5 ml/min 11% experienced infusion reactions 7 at 2 ml/min rate 1 at 2 ml/min rate Most common events included pyrexia (3), nausea (1), rash (3)

Phase III Trial: Melphalan/Dexamethasone ± Bortezomib for Untreated AL Amyloidosis EMN-03: multicenter, randomized phase III trial comparing MDex and BMDex in newly diagnosed AL amyloidosis in Europe and Australia Continued until any of following: BMDex End of planned treatment Treatment-naive (9 or 8 cycles) pts with systemic (n = 40) CR after cycle 6 AL amyloidosis PR + organ response after (N = 80) MDex cycle 6 (n = 40) < PR after cycle 3 Progression of clonal Dosing in BMDex arm plasma cell disease Cycles 1, 2 (28 days): bortezomib 1.3 mg/m 2 on Days 1, 4, 8, 11; melphalan 0.22 mg/kg on Days 1-4; dexamethasone 40 mg on Days 1-4 Cycles 3-8 (35 days): bortezomib 1.3 mg/m 2 on Days 1, 8, 15, 22; melphalan 0.22 mg/kg on Days 1-4; dexamethasone 40 mg on Days 1-4 Dosing in MDex arm Cycles 1-9 (28 days): melphalan 0.22 mg/kg on Days 1-4; dexamethasone 40 mg on Days 1-4 Kastritis E, et al. ASH 2014. Abstract 35.

Melphalan/Dexamethasone ± Bortezomib in AL Amyloidosis: Efficacy Summary Response After Cycle 3, n (%) Response MDex (29 pts) BMDex (30 pts) P Overall Hem 15 (52) 22 (73).086 CR 1 (3) 4 (13).173 VGPR 9 (31) 11 (37).648 PR 4 (14) 7 (23).347 Cardiac 5/23 (22) 4/17 (23).893 Renal 6/15 (40) 3/16 (19).193 Best Response (Median 5 Cycles), n (%) Response MDex (29 pts) BMDex (30 pts) P Overall Hem 15 (52) 23 (77).045 CR 6 (21) 7 (23).807 VGPR 6 (21) 11 (37).176 PR 3 (10) 5 (17).478 Cardiac 5/23 (22) 4/17 (23).893 0 Renal 7/15 (47) 5/16 (31).378 0 12 24 36 40 Kastritis E, et al. ASH 2014. Abstract 35. Reproduced with permission. Mos Survival Probability (%) Survival Probability (%) 100 80 60 40 20 0 100 80 60 40 20 PFS P =.109 BMDex MDex 0 12 24 36 40 Mos OS P =.504 BMDex MDex

Melphalan/Dexamethasone ± Bortezomib in AL Amyloidosis: Safety Grade 3 AE, n (%) MDex (n = 40, 163 cycles) BMDex (n = 40, 144 cycles) P Value Overall 19 (12) 39 (27) <.001 Cytopenia 9 (5) 15 (10).111 Fluid retention 4 (2) 3 (2).828 Fatigue 2 (1) 1 (0.5) -- ctn increase 1 (0.5) 1 (0.5) -- Diarrhea 1 (0.5) 0 -- Renal failure 1 (0.5) 3 (2) -- Insomnia 0 2 (1) -- Peripheral neuropathy 0 3 (2) -- Injection-site reaction 0 1 (0.5) -- 14 pts(35%) experienced at least 1 grade 3 AE in each group There were 4 (cardiac) deaths in the first 100 days, 1 in the MDex arm and 3 in the BMDex arm (P =.307) Kastritis E, et al. ASH 2014. Abstract 35.

Phase II: Lenalidomide/Dexamethasone in POEMS Syndrome Prospective phase II trial of lenalidomide/dexamethasone in pts with newly diagnosed or relapsing POEMS syndrome All eligible pts Group 1: Pts eligible for irradiation or ASCT 2 cycles Len/Dex Irradiation ASCT Group 2: all other pts 9 cycles Len/Dex 1 yr low-dose Len only Lenalidomide: 25 mg 21 days/28 (10 mg if creatinine clearance < 50 ml/min) Dexamethasone: 40 mg/wk (20 mg if older than 75 yrs of age or frail) Low-dose Lenalidomide: 10 mg 28 days/28 for 12 cycles Aspirin or low molecular weight heparin given as venous thromboembolic event prophylaxis Jaccard A, et al. ASH 2014. Abstract 36.

Serum VEGF, pg/ml 2000 1800 1600 1400 1200 1000 800 600 400 200 0 Lenalidomide/Dexamethasone in POEMS Syndrome: Efficacy Serum VEGF Summary Inclusion Post cycle 1 350 Post cycle 2 300 Normal value VEGF normal at inclusion: serum 1 pt, plasma 7 pts Plasma VEGF After 2 cycles, VEGF normal: serum 10 pts, plasma 20 pts VEGF level with > 50% drop: serum 17 pts, plasma 20 pts Plasma VEGF, pg/ml 250 200 150 100 50 0 Jaccard A, et al. ASH 2014. Abstract 36. Reproduced with permission.

Lenalidomide/Dexamethasone in POEMS Syndrome: Efficacy Summary Hematologic responses in assessable pts after 2 cycles Measurable IgG M-spike (n = 9): VGPR (n = 5); PR (n = 1); stable (n = 3) IgA (n = 12): CR (n = 1); PR (n = 3); stable (n = 9) FLC λ (n = 21): normalized (n = 9); > 50% reduction (n = 3) Neurologic responses after 2 cycles Improvement with ONLS: n = 11 Improvement with NIS score: n = 10 Improvement based on clinical judgment of investigator: n = 16 10-meter walking test improved in 5 of 8 evaluable pts Jaccard A, et al. ASH 2014. Abstract 36.

Lenalidomide/Dexamethasone in POEMS Syndrome: Efficacy Last Follow-up Parameter Group 1: ASCT (n = 8) Group 1: Radiation (n = 9) Clinical status No relapses 1 relapse at 6 mos (in pt with BM involvement) Group 2 (n = 9) 1 PD after 9 cycles 3 pts on therapy 3 pts on maintenance 2 pts off tx Median VEGF level at baseline, pg/ml (range) Serum 5237 (1544-8640) 1423 (705-3560) 1606 (162-12,000) Plasma 384 (17-924) 232 (48-1025) 254 (33-1794) Median VEGF level at last follow-up, pg/ml (range) Serum 530 (294-1951) 457 (170-472) 870 (115-6980) Plasma 75 (19-91) 66 (12-145) 42 (19-844) In group 1, ASCT feasible after 2 cycles (8 of 9 pts received ASCT, median follow-up: 10.5 mos) No collection failures, engraftment syndrome; 1 death following ASCT (cerebral bleeding after falling) Jaccard A, et al. ASH 2014. Abstract 36.