Multiple Myeloma: Relapsed/Refractory. Sagar Lonial, MD Emory University School of Medicine Atlanta, Georgia

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1 Multiple Myeloma: Relapsed/Refractory Sagar Lonial, MD Emory University School of Medicine Atlanta, Georgia

2 Topics Dara Updates IPD CPD Selinexor Venatoclax Pembro BCMA

3 Efficacy of Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Relapsed or Refractory Myeloma Based on Prior Lines of Therapy: Updated Analysis of CASTOR Abstract 115 Mateos M-V, Estell J, Barreto W, Corradini P, Min C-K, Medvedova E, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Casneuf T, Chiu C, Sasser AK, Nooka A

$Study Design Multicenter, randomized, open-label, active-controlled, phase III study Key eligibility criteria RRMM 1 prior line of therapy Prior bortezomib exposure, but not refractory Stratification$ 3 weeks: Cycles 4-8 V: 1.3 mg/m 2 SC on Days 1, 4, 8, and 11 of Cycles 1-8 d: 2 mg PO-IV on Days 1, 2, 4, 5, 8, 9, 11, and 12 of Cycles 1-8 Vd (n = 247) V: 1.

3 weeks: Cycles 4-8 V: 1.3 mg/m 2 SC on Days 1, 4, 8, and 11 of Cycles 1-8 d: 2 mg PO-IV on Days 1, 2, 4, 5, 8, 9, 11, and 12 of Cycles 1-8 Vd (n = 247) V: 1.

4 Study Design Multicenter, randomized, open-label, active-controlled, phase III study Key eligibility criteria RRMM 1 prior line of therapy Prior bortezomib exposure, but not refractory Stratification factors ISS (I, II, and III) Number of prior lines (1 vs 2 or 3 vs >3) Prior bortezomib (no vs yes) R A N D O M I Z E 1:1 N = 498 DVd (n = 251) Daratumumab (16 mg/kg IV) Every week: Cycles 1-3 Every 3 weeks: Cycles 4-8 V: 1.3 mg/m 2 SC on Days 1, 4, 8, and 11 of Cycles 1-8 d: 2 mg PO-IV on Days 1, 2, 4, 5, 8, 9, 11, and 12 of Cycles 1-8 Vd (n = 247) V: 1.3 mg/m 2 SC on Days 1, 4, 8, and 11 of Cycles 1-8 d: 2 mg PO-IV on Days 1, 2, 4, 5, 8, 9, 11, and 12 of Cycles 1-8 Cycles 1-8: repeat every 21 days Cycles 9+: repeat every 28 days D only Every 4 weeks: Cycles 9+ Obs only Premedication for the DVd treatment group consisted of dexamethasone 2 mg, acetaminophen, and an antihistamine Primary endpoint PFS Secondary endpoints TTP OS ORR, VGPR, CR MRD Statistical analyses Planned to enroll 48 patients Primary analysis: ~177 PFS events CR, complete response; d, dexamethasone; D, daratumumab; DVd, daratumumab, bortezomib and dexamethasone; ISS, International Staging System; IV, intravenous; MRD, minimal residual disease; Obs, observation; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PO, orally; RRMM, relapsed/refractory multiple myeloma; SC, subcutaneously; TTP, time to progression; V, bortezomib; VD, bortezomib and dexamethasone; VGPR, very good partial response. Mateos M-V, et al. Blood. 216;128: Abstract 115.

5 % Surviving Without Progression Updated Efficacy Results of CASTOR Trial No. at risk Vd DVd 12-month PFS a 6% 22% HR:.33 (95% CI, ; P<.1) Median (range) follow-up: 13. (-21.3) months Hazard ratio (HR):.33; 67% reduction in the risk of progression or death with DVd vs Vd An additional 7% of patients receiving DVd achieved CR with longer follow up CI, confidence interval; HR, hazard ratio; ITT, intent to treat; ORR, overall response rate; PR, partial response; scr, stringent CR; Note: PFS: Intent-to-treat (ITT) population; ORR: response-evaluable population; a Kaplan-Meier estimate; b P<.1 for DVd versus Vd Mateos M-V, et al. Blood. 216;128: Abstract 115. Vd DVd Median: 7.1 months Months ORR, % CR 26% b ORR = 84% 7% 19% 35% 22% P<.1 CR 1% VGPR 62% b ORR = 63% 2% 8% 19% 34% DVd (n = 24) Vd (n = 234) VGPR 29% scr CR VGPR PR

6 PFS: Prior Lines of Treatment 1 prior line 2 to 3 prior lines 1 12-month PFS a 1 12-month PFS a % Surviving Without Progression % 25% Vd Median: 7.9 months DVd % Surviving Without Progression Median: 9.8 months 44% DVd 22% Median: 6.3 months a Kaplan-Meier estimate No. at risk Vd 113 DVd 122 HR:.22 (95% CI, ; P<.1) DVd is superior to Vd regardless of prior lines of therapy, with greatest benefit observed in 1 prior line Mateos M-V, et al. Blood. 216;128: Abstract Months HR:.51 (95% CI, ; P =.2) Months Vd 1

7 CASTOR PFS by Cytogenetic Risk a % Surviving Without Progression 1 No. at risk Vd std risk DVd std risk Vd high risk DVd high risk Months DVd standard risk DVd high risk Vd standard risk Vd high risk High Risk b DVd n = 44 Vd n = 51 Median PFS, months HR (95% CI).49 ( ) P value.167 n = 44 n = 47 ORR, % P value.39 Standard Risk DVd n = 123 Vd n = 135 Median PFS, months NR 7. HR (95% CI).29 (.2-.43) P value <.1 n = 118 n = 131 ORR, % P value.3 DVd improves outcomes regardless of cytogenetic risk NR, not reached a ITT/Biomarker risk evaluable analysis set b Central next-generation sequencing. High-risk patients had any of t(4;14), t(14;16), or del17p. Standard-risk patients had an absence of high-risk abnormalities Mateos M-V, et al. Blood. 216;128: Abstract 115.

8 Efficacy of Daratumumab, Lenalidomide, and Dexamethasone Versus Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma Patients with 1 to 3 Prior Lines of Therapy: Updated Analysis of POLLUX Abstract 1151 Usmani SZ, Dimopoulos M, Belch A, White D, Benboubker L, Cook G, Leiba M, Morton J, Ho PJ, Kim K, Takezako N, Khokhar NZ, Guckert M, Wu K, Qin X, Casneuf T, Chiu C Sasser AK, San-Miguel JF

$not refractory Creatinine clearance 3 ml/min Stratification factors No.$

9 POLLUX: Study Design Multicenter, randomized (1:1), open-label, active-controlled, phase III study DRd (n = 286) Key eligibility criteria RRMM 1 prior line of therapy Prior lenalidomide exposure, but not refractory Creatinine clearance 3 ml/min Stratification factors No. of prior lines of therapy ISS stage at study entry R A N D O M I Z E 1:1 Daratumumab 16 mg/kg IV Qw in Cycles 1 to 2, q2w in Cycles 3 to 6, then q4w until PD R 25 mg PO Days 1 to 21 of each cycle until PD d 4 mg PO 4 mg weekly until PD Rd (n = 283) R 25 mg PO Days 1 to 21 of each cycle until PD d 4 mg PO 4 mg weekly until PD Cycles: 28 days Primary endpoint PFS Secondary endpoints TTP OS ORR, VGPR, CR MRD Time to response Duration of response Statistical analyses Primary analysis: ~177 PFS events Prior lenalidomide FDA approved daratumumab in patients with 1 prior therapy based on POLLUX and CASTOR studies FDA, US Food and Drug Administration; PO, oral; PD, progressive disease; R, lenalidomide; Rd, lenalidomide/dexamethasone; TTP, time to progression Usmani SZ, et al. Blood. 216;128: Abstract 1151.

10 % Surviving Without Progression No. at risk Rd DRd Updated Efficacy Results of POLLUX Trial Months HR:.37 (95% CI,.28-.5; P<.1) month PFS a % 49% Median: not reached Median: 17.5 months 5 15 Rd 1 DRd Median (range) follow-up: 17.3 (-24.5) months Responses continue to deepen in the DRd group with longer follow-up ORR, % CR: 46% b ORR = 93% P<.1 VGPR: 78% b CR: 2% ORR = 76% DRd (n = 281) Rd (n = 276) VGPR: 45% scr CR VGPR PR Note: PFS = ITT population; ORR = response-evaluable population a Kaplan-Meier estimate; b P<.1 for DRd vs Rd Usmani SZ, et al. Blood. 216;128: Abstract 1151.

11 1 DRd Improved Outcomes Regardless of Prior Treatment With Lenalidomide Len Naive 18-month PFS a 1 Len Exposed 18-month PFS a 79% % Surviving Without Progression % 49% Rd Median: 17.1 months DRd % Surviving Without Progression % DRd Rd No. at risk Rd DRd a Kaplan-Meier estimate b Response-evaluable population c P<.1 for DRd vs Rd HR:.37 (95% CI, ; P<.1) Months Usmani SZ, et al. Blood. 216;128: Abstract No. at risk Rd DRd HR:.45 (95% CI,.2-.99; P =.42) Months

12 Refractory to Last Line of Therapy: 1 to 3 Prior Lines 1 18-month PFS a 1 9 ORR = 89% b P =.3 % Surviving Without Progression No. at risk HR:.45 (95% CI, ; P =.14) Median: 8.8 months Months 65% 37% DRd Rd ORR, % CR: 49% c 23 CR: 5 13% 26 9 VGPR: 74% c DRd (n = 73) ORR = 63% b 19 3 Rd (n = 67) VGPR: 33% scr CR VGPR PR Rd DRd a Kaplan-Meier estimate b Response-evaluable population c P<.1 for DRd vs Rd DRd treatment benefit observed in patients refractory to last line of therapy Usmani SZ, et al. Blood. 216;128: Abstract 1151.

13 Daratumumab in RRMM: MRD Negativity Daratumumab + Rd or Vd significantly improved MRD negativity rate vs Rd or Vd alone MRD Negative, % All patients POLLUX (N = 286) CASTOR (N = 251) Dara + Rd Rd P Value Dara + Vd Vd P Value <.1 <.1 < <.1 <.5 <.5 Patients with CR <.5 <.5 < < By cytogenetic risk High* Standard <.5 <.1 MRD-negative events accumulated rapidly and increased over time (within 3-18 months) <.5 <.5 *Includes patients with t(4;14), t(14;16), or del(17p) MRD, minimal residual disease Avet-Loiseau H, et al. Blood. 216;128: Abstract 246.

14 Clinical Efficacy of Daratumumab, Pomalidomide and Dexamethasone in Relapsed, Refractory Myeloma Patients: Utility of Retreatment With Daratumumab Among Refractory Patients Abstract 492 Nooka AK, Joseph N, Boise LH, Gleason C, Kaufman JL, Sagar Lonial

15 Daratumumab, Pomalidomide, and Dexamethasone (DARA-POM-D) We have evaluated our institutional experience of DARA in combination with POM and dexamethasone, and the utility of this combination among patients refractory to DARA and POM In this analysis, we have evaluated all patients that have received DARA-POM-D for relapsed or relapsed and refractory myeloma treated at Emory University from January 215 until July 216 Naïve to DARA and POM (cohort 1) N = 19 Refractory to DARA and/or POM (cohort 2) N = 22 Refractory to DARA and POM (cohort 3) N = 12 Responses were evaluated using the IMWG criteria IMWG, International Myeloma Working Group Nooka AK, et al. Blood. 215;126: Abstract 492.

16 Best Responses With DARA-POM-D Regimen ORR scr CR VGPR PR MR/SD PD Cohort 1 (n = 19) (DARA and POM Naïve) Cohort 2 (n = 22) (DARA or POM Refractory) Cohort 3 (n = 12) (DARA and POM Refractory) 17 (89%) 9 (4.9%) 4 (33.3%) 7 (36.8%) 1 (5.3%) 3 (15.8%) 1 (4.5%) 1 (8.3%) 8 (42.1%) 8 (36.4%) 3 (25%) 1 (5.3%) 9 (4.9%) 6 (5%) 1 (5.3%) 4 (18.2%) 2 (16.7%) Median cycles 15 (1-23) 3 (1-8) 3 (1-8) MR, minor response Nooka A, et al. Blood. 216;128: Abstract 492.

$1/24 Prior lines of therapy - 12 Daratumumab refractory - yes Pomalidomide refractory - yes Nooka A, et al. Blood.$

17 DARA-POM-D in Relapsed MM Retrospective analysis Absence of paired samples or correlatives Limited number of patients 73 F diagnosed 1/24 Prior lines of therapy - 12 Daratumumab refractory - yes Pomalidomide refractory - yes Nooka A, et al. Blood. 216;128: Abstract 492.

18 A Phase I/II Trial of Ixazomib (Ix), Pomalidomide (POM), and Dexamethasone (DEX) in Relapsed/Refractory (R/R) Multiple Myeloma (MM) Patients: Responses in Double/Triple Refractory Myeloma and Poor Risk Cytogenetics Abstract 3316 Krishnan A, Kappor P, Palmer J, Tsai N-C, Kumar S, Lonial S, Htut M, Daranes C, Nathwani N, Rosenweig M, Sahebi F, Somlo G, Duarte L, Forman SJ, Sanchez JF, Berdeja JG

19 Ixazomib (Ix), Pomalidomide (POM), and Dexamethasone (DEX) in Patients With RRMM: Dose Level Ix POM DEX DL1 3 mg 4 mg 4 mg* DL2 4 mg 4 mg 4 mf* 66% MR 52% MR Krishnan A, et al. Blood. 216;128: Abstract Phase I: Standard Design Phase II: Gehan Two-Stage Design (promising ORR: 3%, power: 8%, alpha.5

20 A Multicenter, Open Label Phase I/II Study of Carfilzomib, Pomalidomide and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma (MM) Patients Abstract 1145 Bringhen S, Magarotto V, Liberati AM, Belotti A, Larocca A, Gilestro M, Bonello F, Gaidano G, Bertazzoni P, Stocchi R, Ribolla R, Di Sano C, Patriarca F, Passera R, De Paoli L, Oliva S, Cafro AM, Sonneveld P, Palumbo A, Boccadoro M

21 Carfilzomib, Pomalidomide, and Dexamethasone in Patients With RRMM wkpd Induction Cycles 1-8 Response Assessments wkpd Maintenance Until progression Cycle day Carfilzomib Dose (mg/m 2 ) CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 5 CYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCE Pomalidomide 4 mg orally Dexamethasone 2 mg orally Phase I/II Multicenter *All patients received 2 mg/m 2 carfilzomib on D1 of cycle 1; subsequent doses were escalated to the indicated levels Bringhen S, et al. Blood. 216;128: Abstract Carfilzomib Cohort * mg/m

22 Response Rate and Time to Response 9 8 CR/nCR > VGPR ORR CBR Median time to PR: 2.7 months % of Patients Overall CBR, clinical benefit rate; ncr, near complete response Bringhen S, et al. Blood. 216;128: Abstract PR VGPR CR/nCR Months

23 Selinexor and Low Dose Dexamethasone (Sd) in Patients with Lenalidomide, Pomalidomide, Bortezomib, Carfilzomib and Anti-CD38 Ab Refractory Multiple Myeloma (MM): STORM Study Abstract 491 Vogl DT, Dingli D, Cornell RF,Huff CA, Jagannath S, Bhutani D, Baz R, Nooka AK, Richter J, Cole CE, Vij R, Jakubowiak A, Abonour R, Schiller GJ, Parker TL, Costa LJ, Kaminetzky D, Hoffman J, Yee AJ, Chari A, Siegel DS, Fonseca R, VanWier S, Ahmann G, Lopez I, Kauffman M, Shacham S, Saint-Martin J-R, Picklesimer C, Friedlander S, Choe-Juliak C, Stewart AK

Selinexor Mechanism of Action Exportin 1 (XPO1) is the nuclear exporter for the majority of tumor suppressor proteins (TSPs), the glucocorticoid receptor (GR), and eif4e-bound oncoprotein mrnas

24 Selinexor Mechanism of Action Exportin 1 (XPO1) is the nuclear exporter for the majority of tumor suppressor proteins (TSPs), the glucocorticoid receptor (GR), and eif4e-bound oncoprotein mrnas Selinexor is a first-in-class XPO1 inhibitor that induces nuclear retention and activation of TSPs and the GR in the presence of steroids and suppresses oncoprotein expression In a first-in-human Phase I study, selinexor in combination with dexamethasone showed a 27% ORR in heavily pretreated MM patients Vogl DT, et al. Blood. 216;128: Abstract 491.

25 STORM Patient Characteristics STORM Patient Characteristics Quad Refractory Penta Refractory Patients enrolled as of November 1, Median age, years (range) 62 (41-78) 68 (34-78) Males : Females 24 (5%) : 24 (5%) 13 (42%) : 18 (58%) Median prior regimens (range) 7 (3-16) 7 (5-17) Median years from diagnosis (range) 4 years (1-16) 4 years (<1-35) Prior therapies Glucocorticoid Alkylating agents Stem cell transplant Anthracyclines 48 (1%) 47 (98%) 37 (77%) 2 (42%) 31 (1%) 3 (97%) 24 (77%) 12 (39%) Patients treated with 6 doses : 8 doses / cycle 4 (83%) : 8 (17%) 11 (35%) : 2 (65%) Vogl DT, et al. Blood. 216;128: Abstract 491.

$(13%) 27 (35%) 9 (12%) 16 (21%) Quad refractory Penta refractory 6 Doses / month 8 Doses / month 48 1 (21%) 14 (29%) 2 (4%) 8 (17%) 4 (8%) 21 (44%) 4 (8%) 9 (19%) 3 6 (2%) 12 (4%) 2 (7%) 4 (13%) 6$

26 Independent Review Committee (IRC) Assessed Efficacy Category N * (%) ORR, n CBR, n (%) VGPR, n (%) PR, n (%) MR, n (%) SD, n (%) PD, n (%) NE, n (%) Overall (21%) 26 (33%) 4 (5%) 12 (15%) 1 (13%) 27 (35%) 9 (12%) 16 (21%) Quad refractory Penta refractory 6 Doses / month 8 Doses / month 48 1 (21%) 14 (29%) 2 (4%) 8 (17%) 4 (8%) 21 (44%) 4 (8%) 9 (19%) 3 6 (2%) 12 (4%) 2 (7%) 4 (13%) 6 (2%) 6 (2%) 5 (17%) 7 (23%) 51 1 (2%) 15 (29%) 3 (6%) 7 (14%) 5 (1%) 21 (41%) 4 (8%) 11 (22%) 27 6 (22%) 11 (41%) 1 (4%) 5 (19%) 5 (19%) 6 (22%) 5 (19%) 5 (19%) *1 patient did not have measurable disease at baseline Vogl DT, et al. Blood. 216;128: Abstract 491.

27 OS and PFS Category All Patients (N = 78) MR (N = 26) Median OS 9.3 Months Not Reached Median PFS 2.3 Months 5.5 Months Vogl DT, et al. Blood. 216;128: Abstract 491.

28 Selinexor in Combination With Bortezomib and Dexamethasone (SdB) Demonstrates Significant Activity in Patients With Refractory Multiple Myeloma (MM) Including Proteasome-Inhibitor Refractory Patients: Results of the Phase I Stomp Trial Abstract 977 Bahlis NJ, Kotb R, Sebag M, Sutherland HJ, LeBlanc R, White D, Venner CP, Kouroukis T, Bergstrom D, McCurdy A, Lalancette M, Bensinger W, Lentzsch S, Del Col A, Kauffman M, Shacham S, Jeha J, Picklesimer C, Saint-Martin J-R, Choe-Juliak C, Chen C

29 Selinexor and Backbone Treatments of Patients with MM: STOMP Study Design Primary Objective: Determine the MTD and recommended phase II dose (RP2D) Patient Populations: Arm SVd: Selinexor + bortezomib + dexamethasone Patients with MM relapsing after 1 prior therapy may include prior bortezomib, as long as not refractory to bortezomib in their most recent line of therapy Arm SPd: Selinexor + pomalidomide + dexamethasone (ASH Poster 333) Arm SLd: Selinexor + lenalidomide + dexamethasone Dosing Scheme SVd: A standard design will be used for dose escalations: Drug Selinexor, PO Selinexor Once Weekly (QW) Dose level 1: 8 mg Dose level 2: 1 mg Selinexor Twice Weekly (BIW) Dose level 1: 6 mg Dose level 2: 8 mg BIW Dose Escalation QW Bortezomib, SC 1.3 mg/m 2 QW/BIW 1.3 mg/m 2 QW Dexamethasone, PO 4 mg QW 2 mg BIW Expansion at RP2D ~2 patients to be enrolled Bahlis NJ, et al. Blood. 216;128: Abstract 977.

$Status: Ref Refractory Exp Exposed$

30 Change in M-Protein From Baseline Phase I The majority of patients had reductions in M-Protein from baseline 18 patients (82%) had M-protein reductions >5% 8 patients (36%) had M-protein reductions 9% Prior PI Status: Ref Refractory Exp Exposed Naï Naïve Bahlis NJ, et al. Blood. 216;128: Abstract 977.

31 Schedule and Dosing 28-day cycles CFZ CFZ CFZ CFZ SEL SEL SEL SEL SEL SEL dex dex dex dex dex dex dex dex Cycles 1 4 Cycles 5-8: dex reduced from initial 4 mg/wk to 2 mg/wk Cycles 9+ : CFZ administered on days 1, 2 and 15, 16 Bahlis NJ, et al. Blood. 216;128: Abstract 977.

32 9 8 All Patients After 1 Cycle Response Rates All Patients Best Response a,b n = 19 n = 19 MR PR VGPR 11 a,b a 1 patient not evaluable (DLT prior to response evaluation) b 1 patient not evaluable (had not completed 1 cycle) Bahlis NJ, et al. Blood. 216;128: Abstract 977.

33 Venetoclax Monotherapy for Relapsed/Refractory Multiple Myeloma: Safety and Efficacy Results From a Phase I Study Abstract 488 Kumar S, Vij R, Kaufman JL, Mikhael J, Facon T, Pegourie B, Benboubker L, Gasparetto C, Amiot M, Moreau P, Alzate S, Ross J, Dunbar M, Xu T, Agarwal S, Leverson J, Maciag P, Verdugo M, Touzeau C

34 Outcome, % Venetoclax Monotherapy for RRMM: ORR Overall Population (N = 66) Patients With t(11;14) (n = 3) Patients Without t(11;14) (n = 36) Patients With High BCL2/BCL2L 1 (n = 9) Patients With Low BCL2/BCL2L 1 (n = 15) ORR scr CR VGPR PR In subset analysis of patients with t(11;14), similar ORR seen across subgroups with MM refractory to various single agents or multiple agents Kumar S, et al. Blood. 216;128: Abstract 488.

35 Kumar S, et al. Blood. 216;128: Abstract 488. PCL Patient Treated With 199

36 Kumar S, et al. Blood. 216;128: Abstract 488. Longest Responder

37 Bz Combination Results

38 Pembrolizumab in Combination With Pomalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma (RRMM) Abstract 49 Badros AZ, Hyjek E, Ma N, Lesokhin AM, Rapoport AP, Kocoglu MH, Lederer E, Philip S, Lesho P, Johnson A, Dell C, Goloubeva O, Singh Z

39 PD-1 Targeting in MM Treatment Schema Cycles are repeated every 28 days After 24 months; responding patients continued on monthly pembrolizumab with pomalidomide/dexamethasone PD-1, programmed cell death ligand-1 Badros AZ, et al. Blood. 216;128: Abstract 49.

40 Badros AZ, et al. Blood. 216;128: Abstract 49. Summary of Responses

41 Median: 17.4 months; 95% CI ( ) PFS P =.366 Badros AZ, et al. Blood. 216;128: Abstract 49.

42 Badros AZ, et al. Blood. 216;128: Abstract 49. Adverse Events

43 First in Human Study with GSK , an Antibody Drug Conjugated to Microtubule-Disrupting Agent Directed Against B-Cell Maturation Antigen (BCMA) in Patients with Relapsed/Refractory Multiple Myeloma (MM): Results from Study BMA Part 1 Dose Escalation Abstract 1148 Cohen AD, Popat R, Trudel S, Richardson PG, Libby EN, Lendvai N, Anderson LD, Sutherland HJ, DeWall S, Ellis CE, He Z, Mazumdar J, Wang C, Opalinska JB, Voorhees PM

Background BCMA expression is restricted to B cells at later stages of differentiation and is requisite for the survival of long lived plasma cells BCMA is broadly expressed

protease resistant maleimidocaproyl linker Preclinical studies demonstrate its selective and potent activity ADC, antibody-drug conjugate; ADCC, antibody-dependent

44 Background BCMA expression is restricted to B cells at later stages of differentiation and is requisite for the survival of long lived plasma cells BCMA is broadly expressed at variable levels on malignant plasma cells GSK is a humanized, afucosylated IgG1 anti-bcma antibody conjugated to a microtubule disrupting agent MMAF via a stable, protease resistant maleimidocaproyl linker Preclinical studies demonstrate its selective and potent activity ADC, antibody-drug conjugate; ADCC, antibody-dependent cell-mediated cytotoxicity; BCMA, B-cell maturation antigen; Fc, Fragment crystallizable; IgG, immunoglobulin G; MMAF, monomethyl auristatin-f Cohen AD, et al. Blood. 216;128: Abstract 1148.

45 Maximum % Change in M-Protein or Free Light Chain FLC, free light chain; M-protein, myeloma protein Cohen AD, et al. Blood. 216;128: Abstract 1148.

46 Part 1: Summary of Clinical Activity and Duration on Study Cohen AD, et al. Blood. 216;128: Abstract 1148.

47 Part 1: AEs Regardless of Relationship No DLTs Were Reported at Any Dose Level AE, adverse event; DLT, dose-limiting toxicities; IRR, infusion-related reactions Cohen AD, et al. Blood. 216;128: Abstract 1148.

48 Conclusions Combinations represent the next best step for inducing deep and durable response New targets are in development Identify how to best use BCL-2 based treatments in the optimal subsets Immune therapy is continuing to grow

49 Emory Approach to Early Relapse Slow indolent relapse Aggressive relapse + Len maintenance - Len maintenance + Len maintenance - Len maintenance Consider adding Ixazomib/Dex* Consider Dara/Len/Dex Consider Dara/Pom/Dex Consider Dara/Len/Dex Consider Adding Elo/Dex* Consider Elo/Len/Dex Consider Car/Pom/Dex Consider Dara/Vel/Dex * Increase len dose Consider Car/Len/Dex Consider Car/Pom/Dex Car/Pan as second salvage if IMiD used

Thanks to: Jonathan Kaufman Ajay Nooka Charise Gleason Danni

Heffner Donald Harvey Colleen Lewis Amelia Langston Claire Torre Y.

Boise Cathy Sharp Hayley von Hollen And the Clinical Research Team

50 Thanks to: Jonathan Kaufman Ajay Nooka Charise Gleason Danni Cassabourne Melanie Watson L.T. Heffner Donald Harvey Colleen Lewis Amelia Langston Claire Torre Y. Gu S-Y Sun Jing Chen Fadlo Khuri Anand Jillella Leon Bernal Larry Boise Cathy Sharp Hayley von Hollen And the Clinical Research Team Patients and Families Golfers Against Cancer T.J. Martell Foundation And Many Others who are part of the B-cell Team IMS

Antibodies are a standard part of first relapse management in multiple myeloma (MM): Yes

Antibodies are a standard part of first relapse management in multiple myeloma (MM): Yes Ajay Nooka, MD MPH FACP Assistant Professor, Division of Bone Marrow Transplant Winship Cancer Institute, Emory