Grand rounds MM

Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content Second Opinion: New Agents and Emerging Trial Data in the Management of Multiple Myeloma Noopur Raje, MD Director, Center for Multiple Myeloma Massachusetts General Hospital Cancer Center Associate Professor of Medicine Harvard Medical School Boston, Massachusetts Disclosures Advisory Committee Consulting Agreements Contracted Research Amgen Inc, Bristol-Myers Squibb Company, Celgene Corporation, Novartis Pharmaceuticals Corporation, Roche Laboratories Inc, Takeda Oncology Amgen Inc, Bristol-Myers Squibb Company, Celgene Corporation, Novartis Pharmaceuticals Corporation, Takeda Oncology AstraZeneca Pharmaceuticals LP, Lilly Grand Rounds Program Steering Committee Morie A Gertz, MD, MACP Joseph Mikhael, MD, MEd Roland Seidler Jr Professor of the Art of Medicine Professor of Medicine Chair, Department of Medicine Mayo College of Medicine Mayo Distinguished Physician Mayo Clinic Rochester Associate Dean, Mayo School Rochester, Minnesota of Graduate Medical Education Deputy Director – Education Mayo Clinic Cancer Center Mayo Clinic in Arizona Phoenix, Arizona Jonathan L Kaufman, MD Nikhil C Munshi, MD Associate Professor of Professor of Medicine Hematology and Medical Oncology Harvard Medical School Winship Cancer Institute of Director of Basic and Correlative Science Emory University Associate Director, Jerome Lipper Multiple Myeloma Center Atlanta, Georgia Department of Medical Oncology Dana-Farber Cancer Institute Boston, Massachusetts Grand Rounds Program Steering Committee Noopur Raje, MD Jeffrey A Zonder, MD Director, Center for Multiple Myeloma, Massachusetts General Professor of Oncology Hospital Cancer Center Karmanos Cancer Institute Associate Professor of Medicine Harvard Medical School Wayne State University Boston, Massachusetts Detroit, Michigan Jeffrey L Wolf, MD Project Chair Professor of Medicine Neil Love, MD Director, Myeloma Program Research To Practice Division of Hematology/Oncology Miami, Florida Blood and Marrow Transplantation University of California, San Francisco San Francisco, California New Agents and Emerging Trial Data in the Management of Multiple Myeloma Module 1: Induction and Maintenance Therapy for Newly Diagnosed MM Module 2: Management of Relapsed/Refractory Disease Module 3: Integrating Newly Approved Agents into Clinical Practice • • • • Ixazomib (Tourmaline-MM1) Daratumumab (GEN501, Sirius) Elotuzumab (ELOQUENT-2) Panobinostat (PANORAMA1) Module 4: Investigational Immunotherapy Strategies An otherwise healthy 60-year-old patient presents with ISS Stage II multiple myeloma (MM) Cytogenetics and FISH reveal no high-risk features In general, which induction treatment would you most likely recommend? What are your thoughts about autologous stem cell transplant (ASCT)? INDUCTION ASCT RVd Recommend RVd Recommend RVd Recommend but willing to delay RVd Recommend RVd Recommend RVd Recommend RVd Recommend but willing to delay R = lenalidomide; V = bortezomib; d = dexamethasone Treatment Sequence in Myeloma Bortezomib Lenalidomide Thalidomide VD Now Rev/Dex CyBorD Nothing SCT Thalidomide? Bortezomib VTD Lenalidomide VRD Carfilzomib Pomalidomide Panobinostat Daratumumab Ixazomib Elotuzumab Front-line treatment Induction New Consolidation Maintenance Postconsolidation Relapsed disease Rescue Oprozomib Carfilzomib combos “More induction” Lenalidomide months ? Ixazomib Isatuximab Bendamustine PD/PD-L1 inhibition ++++++++ Autologous Transplantation for Multiple Myeloma in the Era of New Drugs: A Phase III Study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009 Trial) Attal M et al Proc ASH 2015;Abstract 391 IFM/DFCI 2009: A Phase III Study of RVD ± ASCT in Newly Diagnosed Multiple Myeloma (NDMM) RVD cycles 2, PBSC collection Eligibility (N = 700) • • • Cyclophosphamide + G-CSF 1:1 ≤65 years old Symptomatic NDMM Treated with cycle of RVD RVD cycles 4-8 maintenance R 10-15 mg/d RVD cycles 2,3 PBSC collection Cyclophosphamide + G-CSF ASCT with MEL200 RVD cycles 4, Primary endpoint: Progression-free survival Attal M et al Proc ASH 2015;Abstract 391 Lenalidomide x 12 mo POLLUX: A Phase III Study of Daratumumab, Lenalidomide and Dexamethasone versus RD in Relapsed/Refractory MM — Reduction in Risk of Disease Progression or Death DRd 100 Rd Percent of patients progression-free and alive 80 DRd: Estimated median (95% CI) PFS: NE (NE-NE) 60 40 Rd: Estimated median (95% CI) PFS: 18.4 months (13.9-NE) 20 N = 569 HR: 0.37, p < 0.0001 12 Months Dimopoulos MA et al Proc EHA 2016;Abstract LB2238 15 18 21 Comments on Daratumumab Infusion Reactions (IRs) “IRs are common, easily managed with dose holding, premedication, slow restart Very common for dose to take full day; subsequent doses in one-half day.” st – Jonathan L Kaufman “IRs occur in 60% of patients and delays infusion in most We plan for a 9-hour first infusion, which improves with subsequent infusions.” – Joseph Mikhael “More IRs than I expected, but manageable Infusion time longer, particularly initially.” – Jeffrey A Zonder FDA Approval of Elotuzumab November 30, 2015 Today the US Food and Drug Administration granted approval for elotuzumab in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies Dosage and Administration • • Premedicate with dexamethasone, diphenhydramine, ranitidine and acetaminophen 10 mg/kg IV every week for the first cycles and every weeks thereafter until PD or unacceptable toxicity Warnings and Precautions • • • • Infusion reactions Infections Second primary malignancies Hepatotoxicity http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm474684.htm Elotuzumab Mechanism of Action Dimopoulos MA et al Proc ASH 2015;Abstract 28 ELOQUENT-2: Progression-Free Survival Median PFS: 19.4 vs 14.9 mo ORR: 79% vs 66%, P < 0.001 Lonial S et al N Engl J Med 2015;373(7):621-31 Dimopoulos MA et al Proc ASH 2015;Abstract 28 ELO + len/dex Len/dex Outcome (n = 321) (n = 325) HR Median PFS 19.4 mo 14.9 mo 0.70 1-yr PFS 68% 57% — 2-yrs PFS 41% 27% — 3-yrs PFS 26% 18% — ELOQUENT-2: Elotuzumab-Associated Infusion Reactions • Infusion reactions, including pyrexia, chills and hypertension occurred in 10% of patients receiving elotuzumab • No patient had Grade 4-5 infusion reactions • 70% of infusion reactions occurred with the first dose • Infusion reactions resolved in 31/33 patients Lonial S et al N Engl J Med 2015;373(7):621-31 FDA Approval of Panobinostat February 23, 2015 The US Food and Drug Administration today approved panobinostat in combination with bortezomib and dexamethasone for patients with multiple myeloma who have received at least two prior standard therapies, including bortezomib, an immunomodulatory agent Dosage and Administration • 20 mg, taken orally once every other day for doses per week (d1, 3, 5, 8, 10 and 12) of weeks and of each 21-day cycle for cycles • Consider continuing for an additional cycles for patients with clinical benefit Warnings • • • • • Severe diarrhea Severe and fatal cardiac ischemic events, arrhythmias and ECG changes GI and pulmonary hemorrhage Embryo-fetal toxicity Hepatotoxicity http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm435296.htm In which scenario would you be likely to use panobinostat? Progression on lenalidomide maintenance after RVd induction and transplant Refractory MM progressing on proteasome inhibitor Rarely — late stage if bortezomib sensitive After disease progression on lenalidomide, bortezomib, pomalidomide, carfilzomib and daratumumab Progression on lenalidomide maintenance and another line of treatment th line with carfilzomib Heavily treated who can tolerate bortezomib or carfilzomib Lancet Oncol 2014;15(11):1195-206 PANORAMA1: Survival Analyses PFS BTZ/dex + panobinostat BTZ/dex + placebo (n = 387) (n = 381) 11.99 mo 8.08 mo HR = 0.63, p < 0.0001 OS 33.64 mo HR = 0.87, p = 0.26 San-Miguel JF et al Lancet Oncol 2014;15(11):1195-206 30.39 mo Select Adverse Events (Gr 3-4) Event PAN + BTZ/dex Placebo + BTZ/dex (n = 381) (n = 377) Serious AEs 60% 42% Thrombocytopenia 67% 31% Lymphopenia 53% 40% Diarrhea 26% 8% Nausea 5.5%