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.