Multiple MyelomaUpdates from ASCO and EHA

Nina Shah, MDDepartment of Stem Cell Transplantation and

Cellular TherapyM.D. Anderson Cancer Center

Multiple Myeloma – what’s new?

• Clinical trials - newly diagnosed MM• Clinical trials - relapsed MM• Interesting phase I trials• Immunotherapy

Newly diagnosed MM (NDMM)

Induction

High dose chemotherapy + ASCT

Maintenance or consolidation + maintenance

Consolidation/maintenance

Relapse

Salvage

Induction therapy in NDMM (NCCN) Preferred Regimen (Category 1) Other Regimens (Category 2)

Transplant Eligible Bortezomib/dexBortezomib.cyclophosphamide/ dexBortexomib/ doxorubicin/dexBortezomib/lenalidomide/dexBortezomib/thalidomide/dexLenalidomide/dex

Carfilzomib/len/dexDexaLiposomal dox/ vinc/dexThal/dex

Not eligible for transplant

Bortezomib/dexLenalidomide/low-dose dexMelphalan/pred/bortezomibMelphalan/pred/lenalidomideMelphalan/pred/thalidomide

DexLiposomal doxMel/predThal/dexVincrestine. Docoxubicin/dex

Maintenance therapy BortezomibLenalidomideThalidomide

Bortez/dexBotrtez/ thalInterferonSteoidsThal/pred

NEWLY DIAGNOSED MYELOMA

Newly diagnosed MM• Zimmerman et al (ASCO abs #8510)• Phase II trial of Carfilzomib/lenalidomide/dex

(KRd) extended treatment• KRd x 4 transplant CLD x 4 modified KRd

until cycle 18 lenalidomide maintenance• Early outcomes: – 88% with MRD-negative disease after cycle 8– Median f/u of 9.7 months: 52/53 progression-free

“The results to date compare favorably to any prior treatment of NDMM”

Newly diagnosed MM- transplant?

• Gay et al, EHA abs #S101• Multicenter randomized phase 3 trial to compare ASCT

with conventional chemotherapy plus lenalidomide • LD x 4 then tandem ASCT with melphalan 200 OR CRD x 6• N=389• Median PFS was 42 months for MEL200-ASCT and 28

months for CRD (HR 0.67, 95% CI 0.48-0.93, P=0.014).• The 4-year OS was 87% for MEL200-ASCT and 71% for

CRD (HR 0.51, 95% CI 0.28-0.93, P=0.028)• Transplant toxicities were short-lived

Newly diagnosed MM • Orchard et al, EHA Abs #P338• Ranodmized phase 2 of of 90Y-labelled anti-

CD66 + melphalan 200 vs melphalan 200 alone• Targets BM plasma cells for higher radiation

delivery• Significant improvement in CR for patients in

Arm A compared to Arm B (50% vs 25%, odds ratio [85% 1-sided CI]: 0.277 [0.102, 0.753]).

Newly diagnosed MM• Straka et al, ASCO abs #8511• Results from two phase III studies of bortezomib (BTZ)

consolidation vs observation (OBS) post-transplant• N=371• Greater response of ≥ VGPR after BTZ consolidation

than OBS• PFS was significantly improved by ~6 months• No improvement in OS• Possible most benefit for– Pts in less than VGPR– High risk cytogenetics

Newly diagnosed MM • Holstein et al, ASCO abs #8523• Updated analysis of CALGB/ECOG/BMT CTN 100104:

Lenalidomide (Len) vs. placebo (PBO) for maintenance post-auto transplant

• TTP is 53 mos for Len and 27 mos for PBO (hazard ratio (HR):0.54 (p < 0.001)

• Median OS has not been reached for the Len arm and is 76 mos for PBO (HR: 0.60, p = 0.001)

• SPM is higher for Len compared with PBO (p = 0.005) • TTP and OS benefit with Len was observed regardless of• whether pts were in a complete response or not at

randomization and for thalidomide vs. Len induction

Newly diagnosed MM-transplant ineligible

• Facon et al, ASCO abs #8524, updated EHA S105• Update of FIRST trial• SCT-ineligible NDMM pts, n=1623• Randomized 1:1:1– Continuous Rd (28-day cycles)– Rd for 18 cycles (Rd18)– MPT for 12 cycles (42-day cycles)

Rd Rd18 MPT

OS (months) 68.9 56.7 48.9

PFS2 (months) 42.9 40.0 35

HR Rd vs MPT + .75 (95% CI, 0.62-0.90)

Newly diagnosed MM (NDMM)

Induction

High dose chemotherapy + ASCT

Maintenance or consolidation + maintenance

Consolidation/maintenance

Relapse

Salvage

Car/len/dex

Car/len/dex

Y-anti CD66

Continuous Rd

Maint len

Bortez consol

RELAPSED/ REFRACTORY MYELOMA

Relapsed/refractory myeloma• Dimopoulos et al, ASCO abs #8509 (ENDEAVOR study)• Carfilzomib and dexamethasone (Kd) vs bortezomib and

dexamethasone (Vd)• Stratification by prior treatment, ISS stage, prior lines of tx,

route of tx• N= 929• Kd: improvement in median PFS vs Vd (18.7 months [mo] vs

9.4 mo; hazard ratio = 0.53; P< .0001)• ORRs were 76.9% and 62.6% (P< .0001)• OS data immature• Kd had a favorable benefit-risk profile with similar AEs and

less PN

Relapsed/refractory myeloma

• Dimopoulos et al, ASCO abs #8525• Update of ASPIRE trial• Carfilzomib, lenalidomide, and dexamethasone (KRd)

vs lenalidomide and dexamethasone (Rd) • Secondary analysis based on number of lines of

previous therapy• KRd after first relapse: – 1-year improvement in median PFS vs Rd – 9-month improvement in median PFS vs Rd in pts with ≥ 2

prior lines of therapy, This is a salvage regimen that can be used after several lines of therapy.

Relapsed/refractory myeloma

• Jakubowiak, ASCO abs #8573• Randomized phase II study of bortezomib

(Btz)/dexamethasone (dex) +/- elotuzumab (Elo) (antibody against CS1 or SLAMF7)

• Median PFS was 9.7 mo (EBd) vs 6.9 mo (Bd) (HR 0.71; 70% CI 0.58, 0.87; p = 0.08

• Early overall survival (OS): HR of 0.61 (70% CI 0.43, 0.85)

• Limited added toxicity of antibody therapy

Relapsed/refractory myeloma• Lonial et al, NEJM August 2015• ELOQUENT-2: A phase III, randomized study of

lenalidomide (Len)/dexamethasone (dex) with/without elotuzumab (Elo)

• PFS: ELd 19.4 (16.6, 22.2) months, Ld 14.9 (12.1, 17.2) months (HR [95% CI] 0.70 [0.57, 0.85]; p = 0.0004

• ORR (95% CI) was 79% (74, 83) ELd, 66% (60, 71) Ld (p = 0.0002)

Relapsed/refractory myeloma• San Miguel, ASCO abs #8526• PANORAMA-1: Panobinostat plus bortezomib and

dexamethasone (improvement in PFS by 4 mo vs PB/bortez/dex)

• Subanalysis of pts who received prior bortezomib and IMiDs

• PFS PAN arm was 10.6 mo (95% CI, 7.6-13.8) vs 5.8 mo for PBO arm

• ORR 58.5% vs 41% (P = .0179) • Similar safety profile

This regimen is likely useful after exposure to novel induction regimens

Relapsed/refractory myeloma- single arm studies

• CHAMPION-1, a phase I/II study of weekly carfilzomib/ dexamethasone (Berenson et al, ASCO abs #8527)– ORR 72%– Clinical benefit rate 80%– PFS 10.6 months

• Phase II study of panobinostat/lenalidomide/ weekly dexamethasone (Chari et al, ASCO abs #8528) – ORR of 45%, – CBR of 85 % – PFS of 7.5 mo

Relapsed/refractory myeloma- single arm studies

• A phase I/II trial of very low to low-dose continuous azacitidine +Len/dex– Twelve pts achieved > MR, 9 > PR (3 VGPR) ]– 30% clinical benefit response (CBR) and 22.5% response rates. – Responses lasted between 3 months and 2 years

• Phase II study of daratumumab (DARA) monotherapy (Lonial et al, ASCO abs #LBA8512)– ORR 29.2%, with 3 sCR, 10 VGPR, and 18 PR – 7.4 month median duration of response– Median TTP 3.7 months– Median OS has not been reached – Estimated 1-year OS rate is 65%.

Relapsed/refractory myeloma- single arm studies

• Berenson et al, ASCO abs #8591• Pomalidomide (POM), dexamethasone (DEX),

and pegylated liposomal doxorubicin (PLD) • N= 46• ORR 35%• clinical benefit rate 47%• PFS 5.23 mo• Main AE’s: cytopenias

Relapse options

• Carfilzomib and dexamethasone• Carfilzomib, lenalidomide, and

dexamethasone • Bortezomib/dexamethasone /elotuzumab • Lenalidomide /dexamethasone /elotuzumab • Panobinostat plus bortezomib • Pomalidomide/dex

NOVEL PHASE I STUDIES

Phase I studies• Venetoclax (ABT-199/GDC-0199) monotherapy

(Kumar et al, ASCO abs #8576)– small-molecule BCL-2 inhibitor– Realtively well-tolerated– Poss effect in 11:14 pts?

Phase I studies

• Evofosfamide (TH-302), (hypoxia-activated prodrug) + bortezomib and dexamethasone (Laubach et al, ASCO abs #8579)– N=9– No DLTs– 1 CR, 2 PR, 4 SD and 2 PD

Other agents on the horizon

• Anti CD38 antibody MOR202• Oprozomib- oral proteosome inhibitor (Vij et

al, EHA abs #P646 and Hari et al, EHA abs #653)

• Ricolinostat - HDAC6 inhibitor (Raje et al, EHA abs #P279)

• CD19-Chimeric antigen receptor cells (Garfall et al, ASCO abs #8517)

Immunotherapy

• CAR-T cells• NK cells• Allogeneic transplant• PD-1 inhibition• Antibodies– CD38– CS1 (SLAMF7)

Thank you !