New Therapies for Relapsed Myeloma
Abramson Cancer Center Update in Hematologic Cancers
Dan Vogl, MD MSCE
Assistant Professor of Medicine Hematology/Oncology Division Abramson Cancer Center
January 22, 2016 Disclosures
Consulting: • Celgene Corporation • Onyx/Amgen • Millennium/Takeda Pharmaceuticals • Karyopharm Research support: • Millennium/Takeda Pharmaceuticals • Acetylon • GSK • Constellation • Calithera
Topics Proteasome Inhibitors • Carfilzomib • Ixazomib Histone Deacetylase Inhibitors • Panobinostat • Ricolinostat Monoclonal antibodies • Daratumumab • Isatuximab • Elotuzumab Other drugs • Ibrutinib, vemurafenib, filanesib, selinexor Proteasome Inhibitors carfilzomib, ixazomib Carfilzomib: ASPIRE Planned interim analysis of a randomized, open-label phase III trial
Pts with relapsed or KRd progressive MM, Carfilzomib Days 1, 2, 8, 9, 15, 16/cycles 1-12, Days 1, 2, 15, 16/cycles 13-18 1-3 prior treatments Lenalidomide Days 1-21 + with ≥ PR in Dexamethasone Days 1, 8, 15, 22 ≥ 1 prior regimen, 28-day cycle ECOG PS 0-2, and (n = 396) Until PD or CrCl ≥ 50 mL/min unacceptable (N = 792) toxicity Rd Lenalidomide Days 1-21 + Stratified by β2- microglobulin, prior Dexamethasone Days 1, 8, 15, 22 bortezomib, and prior 28-day cycle lenalidomide (n = 396)
Carfilzomib: 20 mg/m2 Days 1, 2 of cycle 1; 27 mg/m2 thereafter. Lenalidomide: 25 mg. Dexamethasone: 40 mg.
Stewart AK, et al. N Engl J Med. 2015;372:142-152. Carfilzomib: ASPIRE Better responses Toxicity • CR 32 vs 9% • More diarrhea, cough, fever, • ORR 87 vs 67% URI, hypokalemia, muscle Better PFS and (maybe) OS spasms, dyspnea, hypertension • No increase in heart failure or renal failure
Stewart AK, et al. N Engl J Med. 2015;372:142-152. Carfilzomib: ENDEAVOR
Study design: Randomized, open-label, multicenter phase III trial
Relapsed MM with 1-3 previous lines of therapy; prior Kd* V or K if response occurred (n = 464) Until PD or with no discontinuation due to unacceptable toxicity (N = 929) † toxicity Stratified by prior PI therapy, Vd prior lines of treatment, ISS (n = 465) stage, and route of V administration (IV vs SC)
*Carfilzomib: 20 mg/m2 IV on Days 1, 2 (cycle 1), then 56 mg/m2 on Days 1, 2, 8, 9, 15, 16 of a 28-day cycle; dexamethasone: 20 mg on Days 1, 2, 8, 9, 15, 16, 22, 23 of a 28-day cycle.
†Bortezomib: 1.3 mg/m2 IV or SC on Days 1, 4, 8, 11 of a 21-day cycle; dexamethasone: 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12 of a 21-day cycle
Dimopoulos MA, et al. ASCO 2015. Abstract 8509. Carfilzomib: ENDEAVOR
Response better with carfilzomib • ORR 77% vs 63% (p<0.0001) • CR 13% vs 6% (p=0.001)
PFS better with carfilzomib • HR 0.53, p<0.0001 • In patients with prior bortezomib • In patients with no prior bortezomib
Toxicity: • More anemia, dyspnea, fever, cough, hypertension, muscle spasms, headache, • Similar thrombocytopenia, diarrhea, edema, fatigue, nausea • Less constipation, neuropathy, dizziness Carfilzomib: Weekly dosing CHAMPION-1 • Carfilzomib over 30 min 1, 8, 15 of 28, with dexamethasone 40 weekly • Phase 1: 45, 56, 70, 88 mg/m2 (n=27) • MTD 70 mg/m2 (n=104) • 1-3 prior lines, carfilzomib-naïve, 52% Bz-refractory, 19% dual refractory • ORR: 77% (63% Bz-refractory, 55% dual-refractory) • Toxicity: fatigue (11% gr3), hypertension (8% gr3), nausea, diarrhea
Berenson, ASH 2015, abstract 373. wCCyD • Newly diagnosed, transplant ineligible • Weekly dosing on days 1, 8, 15 of 28 – Cyclophosphamide 300 mg/m2 PO – Carfilzomib 70 mg/m2 – Dexamethasone 40 mg • ORR 80% • Toxicity: neutropenia (22% gr3/4), thrombocytopenia (7% gr3/4),
pulmonary edema (5%) Bringhen, ASH 2015, Abstract 1828.. Ixazomib: TOURMALINE-MM1
Oral boronate proteasome inhibitor Toxicity: thrombocytopenia, neuropathy, nausea, diarrhea, rash Single agent responses: ≥PR 27% Kumar SK, Blood 2014;124(7):1047-1055
Stratified by prior therapy (1 vs 2-3), ISS stage (I-II vs III), and prior PI exposure (yes vs no)
Ixazomib 4 mg PO D1,8,15 + R/R MM pts with Lenalidomide 25 mg* D1-21 + measurable disease; Dexamethasone 40 mg D1,8,15,22 28-day cycles 1-3 prior treatments; (n = 360) CrCl ≥ 30 mL/min; until PD or not refractory to PIs or Placebo D1,8,15 + unacceptable lenalidomide Lenalidomide 25 mg* D1-21 + toxicity (N = 722) Dexamethasone 40 mg D1,8,15,22 (n = 362) *10 mg for pts with CrCl ≤ 60 or ≤ 50 mL/min.
Moreau P, et al. ASH 2015. Abstract 727 Ixazomib: TOURMALINE-MM1
Responses: better with ixazomib (ORR 78 vs 72%, CR 12 vs 7%) PFS: better with ixazomib (HR 0.74, p=0.01)
Toxicity: More thrombocytopenia, diarrhea, nausea, vomiting, neuropathy, rash
Moreau P, et al. ASH 2015. Abstract 727 HDAC inhibitors panobinostat, ricolinostat Panobinostat: PANORAMA1
Study design: Randomized, placebo-controlled, multicenter phase III trial
Stratified by # of prior therapies and prior bortezomib
(n = 387) Panobinostat 20 mg days 1, 3, 5, 8, 10, 12 of 21 Bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11* Pts with measureable Dexamethasone 20 mg days 1, 2, 4, 5, 8, 9, 11, 12* R/R MM after 1-3 prior treatments, excluding primary refractory or 21 day cycles bortezomib-refractory (N = 792) (n = 381) Placebo days 1, 3, 5, 8, 10, 12 of 21 Bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11* Dexamethasone 20 mg days 1, 2, 4, 5, 8, 9, 11, 12*
*After cycle 8, bortezomib given on Days 1 and 8 of 21 and dexamethasone on days 1, 2, 8, and 9 of 21
San Miguel JF, et al. Lancet Oncol 2014;15(11)1195-1206. Panobinostat: PANORAMA1
Responses: CR 11% vs 6% ≥PR 61% vs 55% Progression-free survival: 12 vs 8 months (HR 0.63, p<0.0001) Overall survival: 34 vs 30 months (HR 0.97, p=0.26)
Toxicity: • Diarrhea: 68 vs 42% (gr 3/4 25 vs 7%) • Fatigue 57 vs 41% (gr 3/4 24 vs 12%) • Nausea 36 vs 21% • Edema 29 vs 19% • Fever 26 vs 15% • Gr 3/4 thrombocytopenia 68 vs 31% • Gr 3/4 neutropenia 35 vs 11%
Panobinostat with carfilzomib/dexamethasone
Phase I trial • Panobinostat 15-20 mg TIW 3 of 4 weeks • Carfilzomib 20/27-20/45 on days 1, 2, 8, 9, 15, and 16 of 28 • Dexamethasone 4 mg prior to each carfilzomib dose during cycle 1 MTD: panobinostat 20 mg, carfilzomib 20/36 Efficacy: • All patients: ≥PR 46%, ≥ MR 58%, median PFS 11.4 months • Bortezomib-refractory: ≥ PR 44%, ≥ MR 50% Toxcity: • Anemia (38% gr 3/4), thrombocytopenia (38% gr 3/4), neutropenia (19% gr 3/4), diarrhea (50%, 8% gr 3/4), nausea (65%), anorexia (27%, 8% gr 3/4)
Kaufman JL, et al. ASH 2014. Abstract 32. bortezomib/dex with ricolinostat (ACY-1215)
Ricolinostat is a selective inhibitor of HDAC6 Phase 1b study: • Ricolinostat 40 mg qd – 160 mg bid on days 1-5 and 8-12 of 21 • Bortezomib 1.3 mg/m2 IV (cycle 1+) or SC (cycle 2+) on days 1, 4, 8, and 11 • Dexamethasone 20 mg PO or IV on days 1, 2, 4, 5, 8, 9, 11, and 12 Prior therapies: • Median 5 lines • 77% refractory to most recent therapy • 88% prior lenalidomide • 100% prior bortezomib, 63% bortezomib-refractory Efficacy: • All patients: ≥PR 30%, ≥MR 34% • Bortezomib-refractory: ≥PR 14%, ≥MR 21% Toxicity: • Diarrhea (20 gr 1-2, 3 gr 3) • Fatigue (13 gr 1-2, 3 gr 3) • Thrombocytopenia (13 gr 3-4) Vogl et al, ASH 2014, Abstract 759 Vogl et al, ASH 2015, Abstract 1827 Monoclonal antibodies daratumumab, isatuximab, elotuzumab Daratumumab Human monoclonal antibody targeting CD38 Phase 2 dose: 16 mg/kg qwk x2m, q2 wks x4m, then q4 wks
Single agent activity: phase 1/2 study in rel/refr myeloma • ORR 31%, VGPR 13%, 1 year PFS 46% Usmani et al, ASH 2015, Abstract 29
Combination with len/dex: phase I/II trial in rel/ref myeloma • Phase 2 dose with len 25 mg on days 1-21 of 28 and dex 40 mg/wk • median 2 prior lines, 3/45 patients len-refractory • ORR 81%, 34% CR, 25% sCR • Toxicity: Cytopenias (c/w lenalidomide), Infusion reactions (19/45) • Updated ASH 2015 with similar results Plesner et al. ASH 2014. Abstract 84 Plesner et al. ASH 2015. Abstract 507
Daratumumab Combination with pom/dex: phase I/II trial in rel/ref myeloma • >= 2 prior lines of therapy, including len and Bz • 98 patients, refractory to Bz (66%), Cz (30%), Len (89%), dual (67%) • Phase 2 dose with pom 4 mg on days 1-21 of 28 and dex 40 mg/wk • ORR 71% overall, 67% dual refractory • Infusion reactions, cytopenias (60% gr 3/4 neutropenia), fatigue Chari, et al. ASH 2015. Abstract 508
Daratumumab: Infusion reactions 38% (1st infusion: 36%, 2nd: 2%, 3rd+: 3%) Mostly grade 1-2 Infusion Grade 3: reaction bronchospasm, prophylaxis dyspnea, chills/CRS, hypertension MonteleukastINFUSION: 101 mg qhs, days2 -1, 0, +1, +2 (x3+ 4 weeks) Volume 1000 mL 500 mL 500 mL MethylprednisoloneStart 50 mL/h 100 mg IV50 mL/h 100 mL/h Acetaminophen• increase to 200 mL/h 975 at 50mg mL/h PO intervals Diphenhydramine• with reaction: pause, restart25 mg at IV50% of previous rate PRNPremedication: famotidine 20 mg IV, lorazepam 1 mg IV Methylprednisolone 100 mg (1st and 2nd) or 60 mg (3rd +) Acetaminophen 650-1000 mg DexamethasoneDiphenhydramine 25-50 4 mgmg PO, days +1, +2 Post-medication COPD/asthma:Methylprednisolone 20 inhaled mg on days corticosteroid 2 and 3 of each days infusion 0, +1
Zoster prophylaxis Voorhees, ASH 2015, Abstract 1829. Daratumumab: RBC transfusion
Binds CD38 on RBCs, agglutinates on indirect antibody testing (IAT) Delays identification of RBC units
Patients can be transfused safely even with +IAT Chari et al. ASH 2015 Abstract 3571 Pre-treating RBCs with DTT eliminates problem DTT also denatures Kell antigens, so Kell- RBC units must be transfused Chapuy, et al. ASH 2015 Abstract #3567
DO: • Send baseline type and screen • Transfuse type-specific, least incompatible units OR • Use DTT and transfuse Kell- units based on antibody testing
DO NOT: • Let blood bank waste 10-15 hours identifying antibodies • Transfer patients to Penn for transfusion Isatuximab (SAR650984) Humanized IgG1 mAb to CD38 receptor
Single agent activity: • Optimized phase 2 dose: 20 mg/kg weekly x4, then q2 wks • ORR 20-29% (depending on dose cohort) Martin et al, ASH 2015, Abstract 509
Combination with len/dex: • 3-10 mg/kg on days 1+15 of 28, with len 25 mg on 1-21 and dex 40 qwk • Heavily refractory population: median 4 prior lines, 84% IMiD refractory • 58% ≥PR, PFS median 6.2 months • Toxicity: Cytopenias (c/w lenalidomide), Infusion reactions (15/31 pts) Martin TG, et al. ASH 2014. Abstract 83
. Elotuzumab: ELOQUENT-2
Humanized IgG1 mAb targeting SLAMF7/CS1 Single agent response rate 0%
ORR 84% with elo/len/dex in len-naïve patients (Richardson, Blood 2014;124:302)
Study design: Randomized, open-label, multicenter phase III trial Elotuzumab 10 mg/kg IV QW cycles 1, 2 then Q2W + Lenalidomide 25 mg PO D1-21 + Pts with R/R Dexamethasone 40 mg PO QW MM and 1-3 (n = 321) Until PD or prior unacceptable treatments toxicity (N = 646) Lenalidomide 25 mg PO D1-21 + Dexamethasone 40 mg PO QW (n = 325)
28-day cycles
Dimopoulos MA, et al. ASH 2015. Abstract 28. Elotuzumab: ELOQUENT-2 Efficacy: • Improved RR (79 vs 66%) • 1y PFS 68 vs 57% • consistent across subgroups
Toxicity: • more lymphopenia • no more neutropenia • increase in zoster but not other infections • Possible increase in low-grade GI effects (diarrhea, constipation)
Lonial, NEJM 2015;373:621-631 Elotuzumab: combination with Bz/dex
Randomized phase 2 trial • 150 patients not refractory to proteasome inhibition • Elotuzumab 10 mg/kg with bortezomib/dexamethasone vs Bz/dex • PFS better with elo (HR 0.76, p=0.12) • Toxicity – More infections – Infusion reactions (very few)
Palumbo, et al. ASH 2015, abstract 510. Other drugs Ibrutinib, vemurafenib, selinexor, filanesib ibrutinib
oral BTK inhibitor PR MR SD ≥ 4 cycles 50
Multi-dose phase 2 study 40 25%
Toxicity: 30 • Infrequent cytopenias
• Diarrhea (~55%) Pts(%) 20 • Fatigue (~40%) 22% 33% 20% 8% • Nausea (~25%) 10 • Dizziness (~30%) 8% 0 6% 5% • Muscle spasms (~20%) 420 mg/d 560 mg/d 840 mg/d 840 mg/d • Arthralgias (~15%) (n = 13) + dex (n = 18) + dex (n = 18) (n = 20)
Vij R, et al. ASH 2014. Abstract 31. Phase 1 with carfilzomib/dex Chari, ASH 2015, Abstract 377
BRAF inhibition Targetable BRAF mutations in 4-6% of myeloma
Case reports of responses to vemurafenib • 960 mg twice daily
Vemurafenib • myeloma cohort in phase 2 study • 960 mg twice daily • 8 patients: 5 refractory to Imid or proteasome inhibitor • 1 VGPR, 4 SD, 3 patients still on study Raje et al. ASH 2015, Abstract 4263
Dabrafenib +/- MEK inhibitor (trametinib, cobimetinib) selinexor
XPO1 inhibitor, Selective inhibitor of nuclear export (SINE),
Phase 1/2 study: • 28 pts with refractory MM (median prior regimens: 6) • selinexor at 30-60 mg/m2 twice weekly with or without dexamethasone • Toxicity: Grade 1/2 nausea (70-82%), fatigue (40-86%), anorexia (36- 71%), and vomiting (10-57%) • Response: – selinexor 45 mg/m2 + dex 20 mg biw (n=10): ORR 60% – selinexor 30 mg/m2 + dex <20 mg (n=7): ORR 14%, CBR of 86% – selinexor (30-60 mg/m2), no dex (n=12): ORR 0%, SD 50% Chen, ASH 2014, abstract 4773
Combination studies with carfilzomib and bortezomib Jakubowiak, ASH 2015, Abstract 4223 Sullivan, ASH 2015, Abstract 3048 Filanesib (ARRY-520)
kinesin spindle protein (KSP) inhibitor targeting a microtubule motor protein critical to the function of proliferating cells Single agent response rate 16%
Phase 1/2 trial with carfilzomib • Up to 1.5 mg/m2 on days 1, 2, 15, 16 • carfilzomib up to 56 mg/m2 • G-CSF support weeks 1 and 3
• Phase 2 expansion – carfilzomib naïve patients – + carfilzomib 27 mg/m2 + dex 4 – ORR 44%
• Toxicity: cytopenias (18% gr 4 neutropenia), fatigue, diarrhea SUMMARY (1): Combinations for early relapse
3 new combination therapies with Rd • Elo-Rd, possible survival advantage • KRd, possible survival advantage • IRd
Other combinations for early relapse • VRd • Doublets (Vd, Rd, Kd, PomDex) • Cyclophosphamide combinations (CyBorD, CyCarDex) • Pomalidomide combinations (VelPomDex, CarPomDex)
SUMMARY (2): HDAC inhibition
Theoretic justification • Combined targeting of protein degradation pathways Biologic efficacy • Improved response rate and PFS from panobinostat with Vel/dex • Improved response rate and PFS from vorinostat with Vel/dex • Responses in bortezomib-refractory patients from ricolinostat with Vel/dex Approved combination: panobinostat with IV bortezomib/dex • Limited utility due to toxicity
Possible paths forward: • Panobinostat with subcutaneous (+/- weekly) bortezomib • Panobinostat with carfilzomib • Ricolinostat with bortezomib/dexamethasone • HDACi with lenalidomide or pomalidomide
SUMMARY (3): Daratumumab
Single agent efficacy
Early evidence for combinations with lenalidomide and pomalidomide
Minimal toxicity • Infusion reactions • Interference with IAT for RBC transfusions SUMMARY (4): Other agents
New targets • Ibrutinib • Vemurafenib (for patients with BRAF mutations) • Selinexor • Filanesib
Immunotherapy • Pembrolizumab with lenalidomide or pomalidomide • Antibody-drug conjugates • CAR T cells
Trials at Penn
Myeloma, relapsed/refractory • Randomized phase 2 study of carfilzomib 27 vs 56 mg/m2 • Phase 1/2 study of lenalidomide in patients with renal insufficiency
• Phase 2 study of daratumumab with backbone regimens • Phase 2 study of subcutaneous daratumumab (coming soon) • Phase 1/2 study of elotuzomab with anti-Kir or anti-CD137
• Phase 1 study of CPI-0610 (BET inhibitor) • Phase 1/2 study GSK2857916 (anti-BCMA immunoconjugate) • Phase 2 study of selinexor (SINE / XPO1 inhibitor)
• Phase 1 study of BCMA-directed CAR T cells
Penn’s Myeloma Program
Physician Investigators Nurse Practitioners Research Staff Edward Stadtmauer Patricia Mangan Diane Frazee Dan Vogl Brenda Shelly Rita Bhagat Brendan Weiss Colleen Erb Darneesha Smith Adam Cohen Mary Sanchez Jessica Savage Maria Raguza-Lopez Alfred Garfall Collaborating Researchers Rebecca Cimildoro Yulia Nefedova Gayle Mallon Hematologic Malignancies Yair Argon Dan Vernau David Porter Ravi Amaravadi Gabrielle Gosciniak Jakub Svoboda Nicole Aqui Manasi Vinod Noelle Frey Michael Milone Selina Luger Carl June Cellular Therapy Staff Stephen Schuster Bruce Levine Karen Dengel Sunita Nasta Naseem Kerr Alison Loren Regina Ferthio Donald Tsai Tenesia Carey Alexander Perl Rebecca Hirsh Laurel Caffee James Mangan Lee Dengel Anthony Mato Elizabeth Hexner Daniel Landsberg