MMRF Patient Summit West Palm Beach, FL 2/11/2017 Management of Multiple Myeloma: The Changing Paradigm Promising Clinical Trials in Multiple Myeloma Ajay Nooka, MD Assistant Professor Department of Hematology and Medical Oncology Winship Cancer Institute of Emory University Atlanta, Georgia Impact of Clinical Trials in Myeloma: Dramatic Improvements in Survival in <10 Years Bortezomib Lenalidomide Thalidomide Pomalidomide Elotuzumab Daratumumab Melphalan Carfilzomib Panobinostat ASCT Ixazomib Corticosteroids 1958 1962 1983 1999 2002 2012 2013 2015 Median OS 72 mo 64 mo 29.9 mo <12 mo ? 1958 1971–1998 2001–2005 2006–2011 2015– Kumar SK et al. Leukemia. 2014;28:1122. Kumar SK et al. Blood. 2008;111:2516. 1 MMRF Patient Summit West Palm Beach, FL 2/11/2017 Targets in Myeloma Plasma Cell Ocio EM et al. Leukemia .2014;28:525. Goal of Clinical Trials: Making Progress Against Myeloma • Increase understanding of the disease – Improve the way we use currently available drugs – Identify new treatments • Develop new medications that improve, and potentially lengthen, the lives of patients with cancer • Reduce toxicities/side effects • No placebos! 2 MMRF Patient Summit West Palm Beach, FL 2/11/2017 Pertinent Research Questions • How can treatments be matched to patients’ subtypes/genomics (personalized medicine)? Venetoclax Monotherapy for Relapsed/ Refractory Multiple Myeloma: Safety and Efficacy Results From a Phase 1 Study Venetoclax Pro-apoptotic BCL-2 protein BCL-2 Apoptosis initiation Pro-apoptotic BIM protein BAX BAK Cancer Cell Cancer Cell Death BAX Survival Activation of caspases Cytochrome c BCL-2 overexpression allows cancer Venetoclax binds selectively to BCL-2, freeing cells to evade apoptosis by pro-apoptotic proteins that initiate programmed sequestering pro-apoptotic proteins.3-5 cell death (apoptosis).6-8 1. Touzeau C et al. Leukemia 2014;28:210. 5. Plati J et al. Integr Biol (Camb). 2011;3:279. 2. Punnoose E et al. Mol Cancer Ther 2016. 6. Certo M et al. Cancer Cell. 2006;9:351. 3. Leverson JD et al. Sci Transl Med 2015. 7. Souers AJ et al. Nat Med. 2013;19:202. 4. Czabotar PE et al. Nature Reviews. 2014;15:49. 8. Del Gaizo Moore V et al. J Clin Invest. 2007;117:112. 3 MMRF Patient Summit West Palm Beach, FL 2/11/2017 Objective Response Rates in All Patients and by t(11;14) Status 50 sCR CR VGPR PR ORR 40% 40 4% 10% 30 ORR 21% 20 3% 13% 4% Percentage of Percentage Patients 10 8% 13% ORR 6% 3% 6% 3% 0 All Patients t(11;14) non-t(11;14) N=66 n=30 n=36 Data cutoff of 19Aug2016 Kumar S et al. J Clin Oncol. 2016;34: Abstract 8032. Pertinent Research Questions • How can treatments be matched to patients’ subtypes/genomics (personalized medicine)? • What are the best drugs and drug combinations for multiple myeloma at all stages of disease? 4 MMRF Patient Summit West Palm Beach, FL 2/11/2017 Efficacy of Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma Based on Prior Lines of Therapy: Updated Analysis of CASTOR MV Mateos, J Estell, W Barreto, P Corradini, C-K Min, E Medvedova, M Qi, J Schecter, H Amin, X Qin, W Deraedt, T Casneuf, C Chiu, AK Sasser, and A Nooka Mateos MV et al. Blood. 2016;128: Abstract 1150. Updated Efficacy P<0.001 100 12-month PFSa ORR=84% 100 90 80 7% ≥CR 80 70 19% ORR=63% 60% 26% ≥CR 2% 60 10% 8% 60 DVd 50 ≥VGPR ≥VGPR 62%b 19% 29% ORR, % 40 35% 40 22% 30 Progression Median: 20 7.1 months 20 34% % Surviving Without Vd 10 22% HR: 0.33 (95% CI, 0.26–0.43; P<0.0001) 0 DVd (n=240) Vd (n=234) 03691215182124 Months No. at risk sCR CR VGPR PR Vd 247 182 129 73 23 9 0 0 0 DVd 251 215 198 160 91 33 5 1 0 • Median (range) follow up: 13.0 (0–21.3) months • An additional 7% of patients receiving DVd achieved ≥CR with longer follow up Responses continue to deepen in the DVd group with longer follow-up ITT, intent to treat. Note: PFS: ITT population; ORR: response-evaluable population. aKaplan-Meier estimate; bP<0.0001 for DVd vs Vd. Mateos MV et al. Blood. 2016;128: Abstract 1150. 5 MMRF Patient Summit West Palm Beach, FL 2/11/2017 PFS: Prior Lines of Treatment 1 prior line 2 to 3 prior lines 100 12-month PFSa 100 12-month PFSa 80 77% 80 DVd Median: 9.8 months 60 60 44% 40 40 DVd 25% 22% Vd 20 20 Median: 6.3 months Median: 7.9 months % Surviving WithoutProgression % Surviving WithoutProgression HR: 0.22 (95% CI, 0.14–0.34; P<0.0001) HR: 0.51 (95% CI, 0.36–0.73; P<0.0002) Vd 0 0 0 3 6 9 1215182124 0 3 6 9 12 15 18 21 Months No. at risk Months Vd 113 91 69 43 11 5 0 0 0 106 73 50 27 11 4 0 0 DVd 122 109 104 99 59 19 3 1 0 107 87 77 51 27 10 1 0 DVd is superior to Vd regardless of prior lines of therapy, with greatest benefit observed in 1 prior line aKaplan-Meier estimate Mateos MV et al. Blood. 2016;128: Abstract 1150. Question 1 Which of the following statements is not correct? A. Enrollment in clinical trials using investigational agents is voluntary. B. Once you sign the consent form, you are bound to continue the study even if you change your mind. C. The goal of clinical trials is to develop new therapeutic choices. 6 MMRF Patient Summit West Palm Beach, FL 2/11/2017 Misconceptions About Cancer Clinical Trials Misconceptions Facts I may get a sugar pill (placebo) instead of No placebos are given—every real therapy. patient receives treatment. I’ll be treated like a guinea Most patients receive care pig. that exceeds expectations. Clinical studies are Many involve an for people with no adjustment to a standard other options. of care that may improve outcome or quality of life. The greater the number of people who participate, the faster drug development can proceed. The Cleveland Clinic. 10 Biggest Cancer Clinical Trial Myths Busted. Available at http://health.clevelandclinic.org/2014/04/10-biggest-cancer-clinical-trial-myths-busted/. New Drug Development Identify a Confirm the Clinical trials target for anti-cancer (human therapy in the activity in studies) laboratory laboratory and to determine animal studies safety, dosing, and effectiveness 7 MMRF Patient Summit West Palm Beach, FL 2/11/2017 Clinical Trial Types Phase 1 Phase 2* Phase 3† Objectives • Optimal dose • Preliminary • Definitive efficacy • Side effects efficacy and safety • Metabolism • Additional safety Treatment • Single arm (all • Single arm • Two arms: patients receive • Two arms of patients experimental different randomly therapy) treatments or assigned to doses: patients receive randomly experimental assigned to an therapy or arm standard therapy Study Small (<50) Varies >200 Size *When no standard treatment is available, FDA may approve drugs based on trial results †Conducted to receive FDA approval of new drugs, in most cases Other Types of Clinical Trials Longitudinal Registry Expanded Access Studies Studies Programs • Long-term studies • Patients are treated • Allow early access with a large number using available to experimental of patients therapies therapies when no alternatives are • The MMRF • Efficacy and safety available CoMMpassSM Study are analyzed following treatment • Typically involve a large number of patients 8 MMRF Patient Summit West Palm Beach, FL 2/11/2017 Question 2 Which of the following statements is true? Please select the best answer from the following statements. A. All adverse events are closely monitored in a clinical trial. B. The efficacy of the investigational agents is closely monitored and confirmed in a clinical trial. C. Both A and B are true. D. Both A and B are false. Commonly Asked Questions • How does the study work? How often will I need to see my doctor or visit the cancer center? • Will I need to undergo additional tests? • What is currently known about the new drug or combination? • What benefits can I expect? • What side effects should I expect? Who should I notify if I have side effects? • Can I take my vitamins or other medications? • Can I get the treatment with my local doctor? • Will my insurance pay for my participation in the clinical trial? 9 MMRF Patient Summit West Palm Beach, FL 2/11/2017 Participating in the Study • Tell study personnel about what medications, vitamins, or dietary supplements you are taking, including the dose • Keep a diary of any side effects you experience • Take study medications as directed; keep days and times the same • Keep your appointments • Ask questions Drugs in Development: Phase 3 Trials Drug Administration Type Trials Side Effects Newly diagnosed MM • Myelosuppression • Revlimid + dex ± • Pneumonia Monoclonal pembrolizumab • Infection Pembrolizumab IV antibody RR MM • Pomalyst + dex ± pembrolizumab RR MM • Fatigue Monoclonal Nivolumab IV • Nivolumab, Empliciti, •Skinrash antibody Pomalyst, and dex • Muscle pain Newly diagnosed MM • Myelosuppression Monoclonal Daratumumab IV • VTD vs VTD+dara • IRRs antibody • Infection Newly diagnosed MM • Hypocalcemia Xgeva* Bone- • Xgeva vs Zometa (denosumab, IV targeted • Nausea, anemia, AMG 162) antibody dyspnea, fatigue, constipation RRMM, relapsed/refractory multiple myeloma; IRR, infusion-related reaction *FDA-approved for non-MM indication 10 MMRF Patient Summit West Palm Beach, FL 2/11/2017 Drugs in Development: Phase 2 Trials Small Molecule Monoclonal Inhibitors Antibodies • Ibrutinib • Tabalumab • Palbociclib • Dinaciclib • Erismodegib • Filanesib • Selumetinib • Tivantinib • Nelfinavir • Selinexor Bold = treatments studied in MMRC trials Selinexor and Low Dose Dexamethasone (Sd) in Patients with Lenalidomide, Pomalidomide, Bortezomib, Carfilzomib & anti-CD38 mAb Refractory MM: STORM Study DT Vogl, D Dingli, RF Cornell, CA Huff, S Jagannath, D Bhutani, R Baz, A Nooka, J Richter, C Cole, R Vij, A Jakubowiak, R Abonour, G Schiller, TL Parker, LJ Costa, D Kaminetzky, J Hoffman, AJ Yee, A Chari, D Siegel, R Fonseca, S VanWier, G Ahmann, I Lopez, M Kauffman, S Shacham, JR Saint-Martin, C Picklesimer, C Choe-Juliak, and A.