Advances in Treatment Paradigms for Multiple Myeloma Bao Dao, PharmD, MBA, BCPS, BCOP Hematology/Bone Marrow Transplant Clinical Pharmacist Assistant Clinical Professor University of California San Francisco Medical Center Disclosure Advisory committee member for Seattle Genetics Learning Objectives • Identify the mechanism of action of select new therapeutic agents for multiple myeloma • Summarize literature regarding the use of new agents for multiple myeloma • Explain expected outcomes to a given therapeutic modality in terms of response and toxicity • State the place in therapy of the new therapeutic agents for multiple myeloma Multiple Myeloma (MM) • MM is the second most common hematologic malignancy • Malignancy of monoclonal plasma cells • 26,850 new cases estimated in US in 2015 o 11,240 deaths • Mean age of affected individuals: 62 years old • MM remains an incurable malignancy o Goal of therapy remains disease control o Overall survival has increased 3 - 5 years to 5 - 7 years with novel agents NCCN. Multiple Myeloma. V.3.2016. Available at: www.nccn.org/professional/physician_gls/pdf/myeloma. Evolution of Myeloma Therapy Bortezomib Panobinostat Melphalan Lenalidomide Daratumumab 1950’s Ixazomib Corticosteroids 2015 2000’s Elotuzumab Thalidomide Carfilzomib Autologous Stem Cell Transplant Pomalidomide 1990’s 2010’s 2 4 Kyle RA, et al. Blood. 2008; 111(6):2962-72. Current Approach to Treatment Primary Therapy Yes ASCT Maintenance x 2-4 cycles Therapy Relapse/ Newly Transplant Refractory Diagnosed MM Candidate? Therapies Maintenance No Primary Therapy Therapy NCCN. Multiple Myeloma. V.3.2016. Available at: www.nccn.org/professional/physician_gls/pdf/myeloma. Outline Mechanism of Action FDA Approval Trial Dosing/Administration Toxicity/Monitoring Place in therapy Daratumumab • IgG human monoclonal antibody to CD38 • CD38 = transmembrane glycoprotein highly expressed on myeloma cells ◦ Low expression on other myeloid/lymphoid cells • Complement and antibody dependent cytotoxicity Lokhorst HM, et al. N Engl J Med. 2015; 373:1207-19. Daratumumab Trial Phase I Patients: >2 prior MM treatment Dose escalation (0.005 – 24 mg/kg) IV once weekly N = 32 Phase II DOSE EXPANSION Schedule A Schedule B Schedule C Schedule D Schedule E 8 mg/kg 8 mg/kg 8 mg/kg 16 mg/kg 16 mg/kg N = 16 N = 8 N = 6 N = 20 N =22 Lokhorst HM, et al. N Engl J Med. 2015; 373:1207-19. Daratumumab Trial Part 1: Dose-Escalation ◦ Safety: No maximum tolerated dose was found ◦ PK: 16 mg/kg was lowest tested dose consistent with target saturation Part 2: Dose-Expansion ◦ 71% had Grade 1-2 infusion-related reaction ◦ 1 patient had Grade 3 infusion-related reaction Lokhorst HM, et al. N Engl J Med. 2015; 373:1207-19. Daratumumab Trial 8 mg/kg 16 mg/kg Dose (N = 30) (N= 42) Population Heavily pre-treated MM patients ORR 3 (10%) 15 (36%) CR 0 2 (5%) PR 3 (10%) 11 (26%) M-protein reduction 4 (15%) 19 (46%) Duration of response 6.9 m Not reached PFS 2.4 m 5.6 m OS at 12 months 77% 77% Lokhorst HM, et al. N Engl J Med. 2015; 373:1207-19. Daratumumab ≥ 3 prior lines of therapy including a PI or IMiD or who are double-refractory to a PI Indication and IMiD Weeks 1-8: 16 mg/kg IV weekly Dosing Weeks 9-24: 16 mg/kg IV every 2 weeks Weeks 25+: 16 mg/kg IV every 4 weeks Vials: 100 mg/5mL or 400 mg/20 mL Preparation First infusion mix in 1000 mL of NS Second infusion and beyond mix in 500 mL of NS Daralex® [package insert]. Horsham, PA: Janssen Biotech; 2015 Daratumumab Corticosteroid: Methylprednisolone 100 mg IV (60 mg after 2nd infusion) Pre-medications Antipyretic: Acetaminophen 650 mg – 1000 mg H1-blocker: Diphenhydramine 25-50 mg First Infusion: 50 mL/hr x 1 hr, increase by 50 mL/hr every hour (max = 200 mL/hr) -1000 mL volume Second infusion: 50 mL/hr x 1 hr increase by 50 mL/hr every hour (max = 200 mL/hr) Infusion rate -500 mL volume Subsequent infusion: 100 mL/hr x 1 hr increase by 50 mL/hr every hour (max = 200 mL/hr) -500 mL volume Serum protein electrophoresis (SPEP) Interactions Coombs test Daralex® [package insert]. Horsham, PA: Janssen Biotech; 2015 Toxicity/Monitoring Prevention of infusion-related reactions ◦ Post-infusion: PO steroids on 1st and 2nd day after infusion Herpes Reactivation ◦ Initiate antiviral prophylaxis 1 week prior to starting therapy and for 3 months after stopping Inference with Coombs test ◦ Can cause false positive indirect Coombs test as daratumumab binds to red blood cells Place in Therapy Guidelines Recommendations • Relapse/refractory MM (category 2A) National Comprehensive Cancer Network • Recommendations follow FDA labeling European Society of Medical Oncology • Not mentioned • 2nd or later relapse mSMART (Mayo Clinic) • After bortezomib, lenalidomide, pomalidomide • Save for later lines of relapse • Lenalidomide-resistant patients • More to come with combination therapy Moreau P, et al. Annals of Oncology. 2013; 24:133-7 NCCN. Multiple Myeloma. V.3.2016. Available at: www.nccn.org/professional/physician_gls/pdf/myeloma. Elotuzumab • Humanized IgG antibody against SLAMF7 o Highly expressed on myeloma and natural killer cells • Direct activation: Binding to SLAMF7 activates natural killer (NK) cells, not myeloma cells • Tagging for recognition: Elotuzumab bound to myeloma cells are tagged for antibody-dependent cellular cytotoxicity (ADCC) from NK- cells Collins SM, et al. Cancer Immunol Immunother 2013; 62:1841-9. Elotuzumab: Mechanism of Action Activation NK Cell NK Cell Myeloma Cell Tagging Myeloma Cell ELOQUENT-2 Trial Elotuzumab Arm (n = 321) - Elotuzumab 10 mg/kg: Cycle 1 and 2 = weekly then every other week Inclusion Criteria - Lenalidomide 25 mg PO daily on days 1-21 - Dexamethasone 40 mg weekly equivalent • Relapse/Refractory MM • 1-3 Previous therapies Control Arm (n = 325) - Lenalidomide 25 mg PO daily on days 1-21 - Dexamethasone 40 mg PO weekly Cycles repeated every 28 days Primary Outcomes Secondary Outcomes • Progression Free Survival • Overall Survival • Overall response rate • Toxicity Lonial, et al. N Engl J MEd. 2015; 373:621-31 ELOQUENT-2 Results Elotuzumab (N = 321) Control Arm (N = 325) 1-3 previous therapies with CrCl >30 mL/min Population 30% of patients had high risk cytogenetics ORR* 252 (79%) 213 (66%) CR 14 (4%) 24 (7%) Efficacy Minimal Response/Stable Disease 16% 27% 19.4 months 14.9 months PFS* Hazard ratio: 0.7 (95% CI 0.57-0.85; P<0.001) Neutropenia 34% 44% Lymphopenia 77% 49% Events Infection 81% 74% Adverse Infusion reaction 10% -- * = statistically significant Lonial, et al. N Engl J Med. 2015; 373:621-31 Elotuzumab 1-3 prior therapies Indication Use in combo with lenalidomide/dex Cycle 1-2: Elotuzumab 10 mg/kg IV days 1, 8, 15, 22 Lenalidomide 25 mg PO daily days 1-21 Dexamethasone 28 mg PO 3-24 hours before elotuzumab + 8 mg IV 45-90 min prior to infusion Dosing Cycle 3 and beyond: Elotuzumab 10 mg/kg IV days 1 and 15 Lenalidomide 25 PO days 1-21 Dexamethasone 28 mg PO 3-24 hours before elotuzumab + 8 mg IV 45-90 min prior to infusion (days 1, 15) Dexamethasone 40 mg PO on days 8 ad 22 Vials: 300 mg and 400 mg Preparation Further dilute with 230 mL of NS or D5W Empliciti® [package insert]. Princeton, NJ: Bristol-Myer Squibb; 2015 Elotuzumab Corticosteroid: Dexamethasone 28 mg PO given 3-24 hours before elotuzumab + dexamethasone 8 mg 45-90 minutes prior to infusion Pre-medications Antipyretic: Acetaminophen 650 mg – 1000 mg H1-blocker: Diphenhydramine 25-50 mg H2-blocker: Ranitidine 50 mg IV or 150 mg PO First Infusion: 0.5 mL/min x 30 mins, then double rate every 30 mins as tolerated (max: 2 mL/min) Infusion rate Second infusion: 1 mL/min x 30 mins, then 2 mL/min as tolerated (max 2 mL/min) Subsequent infusion: Initiate at 2 mL/min and continue to completion Interactions Serum protein electrophoresis (SPEP) Empliciti® [package insert]. Princeton, NJ: Bristol-Myer Squibb; 2015 Toxicity/Monitoring Infusion reactions ◦ Rechallenge when symptoms resolve Infections ◦ Higher Zoster reactivation ◦ Anti-viral prophylaxis ◦ Monitor CBC Hepatotoxicity ◦ Monitor liver function tests periodically Elotuzumab: Place in Therapy Guidelines Recommendations • Relapsed/refractory MM (category 1) National Comprehensive Cancer Network • Recommendations follow FDA labeling European Society of Medical Oncology • Not mentioned • 1st relapse mSMART (Mayo Clinic) • Indolent relapse or frail patients • Good choice for front-line relapse therapy Moreau P, et al. Annals of Oncology. 2013; 24:133-7 NCCN. Multiple Myeloma. V.3.2016. Available at: www.nccn.org/professional/physician_gls/pdf/myeloma. Ixazomib • MM cells have high protein turnover and accumulation • Proteasomes = main pathway for degradation of intracellular protein • Clearance of misfolded and unfolded proteins • Reversible PI inhibitor • Cell-cycle arrest • Apoptosis • Disruption of microenvironment Ocio EM. et al. Leukemia. 2013; 1:1-18 TOURMALINE Ixazomib Arm (n = 360) - Ixazomib 4 mg PO on days 1, 8, 15 - Lenalidomide 25 mg PO daily on days 1-21 Inclusion Criteria - Dexamethasone 40 mg on days 1, 8, 15, 22 • Relapse/Refractory MM • 1-3 Previous therapies Control Arm (n = 362) - Placebo PO on days 1, 8, 15 - Lenalidomide 25 mg PO daily on days 1-21 - Dexamethasone 40 mg on days 1, 8, 15, 22 Cycles repeated every 28 days Primary Outcomes Secondary Outcomes • Progression Free Survival • Overall Survival • Toxicity Moreau P, et al. N Engl J Med. 2016; 374:1621-34 RESULTS: TOURMALINE Ixazomib (N = 360) Control Arm (N = 362) MM who received 1-3 previous therapies with CrCl >30 mL/min Population 20% of patients had high risk cytogenetics ORR* 282 (78%) 259 (72%) CR* 42 (12%) 24 (7%) VGPR 131 (36%) 117 (32%) PR 240 (67%) 235 (65%) 20.6 months 14.7 months PFS* Hazard ratio: 0.74 (95% CI 0.59-0.94; P=0.01) Median time to response 1.1 months 1.9 months Median treatment cycles 17 (1-34) 15 (1-34) * = statistically significant Moreau P, et al.