The Evolving State of Relapsed/Refractory Multiple Myeloma Treatment MMRF ONS 2016 Patient Case Introduction Page Bertolotti, RN, BSN, OCN Clinical Practice Nurse Samuel Oschin Comprehensive Cancer Institute Cedars-Sinai Medical Center Los Angeles, California This material serves as an educational resource only. 1 The Evolving State of Relapsed/Refractory Multiple Myeloma Treatment MMRF ONS 2016 Disclosure Page Bertolotti, RN, BSN, OCN, has disclosed the following relevant financial relationships: – Speakers’ Bureau: Celgene Corporation and Takeda Pharmaceuticals Case Study 53-year-old woman presents with fatigue and nausea in 2009. Elevated total protein detected on routine exam. History and Labs on Diagnostic Physical Presentation Evaluation • Past medical history: MVA in Total protein 12.0 (6.3–8.2) • Bone marrow biopsy: 1985; melanoma in 1995 to Calcium 9.3 (8.4–10.2) − 80% plasma cells, CD38 right shin Creatinine 1.3 (0.7–1.2) antigen expression on flow • Past surgical history: cytometry tonsillectomy in 1980 Hgb 11.6 (13–16) IgG 7,912 (700–1,600) • Family history: paternal • Skeletal survey: grandmother with breast cancer, died at age 90 − Multiple bone lesions • Social history: recent marriage (5 months), no children, never smoked, social drinker • Physical exam: mildly cushingoid, some nausea, still menstruating Staging: Durie-Salmon stage IIIA This material serves as an educational resource only. 2 The Evolving State of Relapsed/Refractory Multiple Myeloma Treatment MMRF ONS 2016 Treatment Options? Is she eligible for an autologous stem cell transplantation? Factors to consider • Age and comorbidity • Response to induction therapy • Risk stratification • Social support and insurance coverage • Lifestyle, goals, choices • Does the patient want a transplant or not? Treatment Plan Induction therapy: Bortezomib/dexamethasone Acyclovir prophylaxis Manage adverse events: peripheral neuropathy Bone health: bisphosphonate every month Response was dramatic; decrease in IgG from 7,912 to 1,863 after 3 cycles This material serves as an educational resource only. 3 The Evolving State of Relapsed/Refractory Multiple Myeloma Treatment MMRF ONS 2016 Consultation With Myeloma Specialist R Continue bz/dex for three more cycles to achieve e maximum benefit of treatment and best possible c remission o m Patient proceeded to ASCT, December 2009, and had a m small M spike of 0.1 g/dL (near CR) e n Maintenance therapy prescribed 6 months post- d transplant: len/dex (prophylaxis with baby aspirin and a acyclovir) t i o Response: April 2011 (16 months post-ASCT), near CR with negative SPEP and trace IgG kappa spike n Relapse Post-Transplantation and Maintenance Therapy Relapse 3 yrs post transplant • Elevated kappa light chain (KLC) 22 to 46 to 69 • Elevated M spike 0.1 to 0.2 g/dL This material serves as an educational resource only. 4 The Evolving State of Relapsed/Refractory Multiple Myeloma Treatment MMRF ONS 2016 Relapse: Factors to Consider • Retreatment with a prior therapy? • Second transplant? • Multidrug combination? Synergy? • New agents? • Clinical trial? Understanding the Next Generation of Novel Agents in Multiple Myeloma Amy Pierre, RN, MSN, ANP-BC Nurse Practitioner John Theurer Cancer Center Hackensack University Medical Center Hackensack, New Jersey This material serves as an educational resource only. 5 The Evolving State of Relapsed/Refractory Multiple Myeloma Treatment MMRF ONS 2016 Disclosure Amy Pierre, RN, MSN, APN-BC, has disclosed the following relevant financial relationships: – Speakers Bureau: Amgen/Onyx Objectives Define relapsed/refractory multiple myeloma Review the approved usage, mechanism of action, safety concerns, and toxicity profile of the next-generation proteasome inhibitors, immunomodulators, and HDAC inhibitors Understand the combination regimens commonly utilized in refractory/relapsed multiple myeloma Discuss a patient-centered management plan to minimize the impact of treatment-related side effects This material serves as an educational resource only. 6 The Evolving State of Relapsed/Refractory Multiple Myeloma Treatment MMRF ONS 2016 Definitions Relapsed Myeloma • Previously treated myeloma patients who, after a period of being off- therapy, require salvage therapy Refractory Myeloma • Disease that is nonresponsive while on therapy or progresses within 60 days of the last therapy Relapsed and Refractory Myeloma • Refractory disease in patients who have never achieved a minor response or better that then either becomes nonresponsive while on salvage therapy or progress within 60 days of last therapy Anderson KC et al. Leukemia. 2008;22:231. Disease Phases of Multiple Myeloma Figure 2, page 7 Kurtin SE. Relapsed or relapsed/refractory multiple myeloma. J Adv Pract Oncol. 2013;4(Suppl 1):5-14. This material serves as an educational resource only. 7 The Evolving State of Relapsed/Refractory Multiple Myeloma Treatment MMRF ONS 2016 Treatment Selection for Relapsed/Refractory Myeloma Disease Characteristics Patient Characteristics • How deep was the patient’s • What is the patient’s response to prior therapy? performance status? • How long was the duration of • Does the patient have pre- response to the previous existing toxicities from either therapy? myeloma or previous treatment • How aggressive is the disease? regimens? • Is the patient eligible for a • What are the patient’s clinical trial? comorbidities? • Is the patient transplant eligible? • Is the patient eligible for a clinical trial? Lonial S. Hematology Am Soc Hematol Educ Program. 2010;303. Newly Approved Agents for the Relapsed/Refractory Setting Proteasome Inhibitors Immunomodulator HDAC Inhibitor • Carfilzomib • Pomalidomide • Panobinostat •Ixazomib This material serves as an educational resource only. 8 The Evolving State of Relapsed/Refractory Multiple Myeloma Treatment MMRF ONS 2016 Carfilzomib Approval Date • 2012 Drug Class • Second-generation proteasome inhibitor (IV) • Irreversibly binds to the N-terminal threonine-containing active Mechanism sites of the 20S proteasome of Action • Has antiproliferative and pro-apoptotic activities in tumor cells • Delays tumor growth in myeloma • In combination with dexamethasone or with lenalidomide + dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines FDA-Approved of therapy Indication • As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy Carfilzomib [package insert]. Thousand Oaks, CA: Onyx Pharmaceuticals Inc; 2016. Carfilzomib: ASPIRE Trial • The international, randomized, phase 3 superiority trial evaluating carfilzomib with lenalidomide and low-dose dexamethasone (KRd) vs lenalidomide and low-dose dexamethasone (Rd) in patients with relapsed or refractory MM who had received one to three lines of therapy. • Primary end point: progression-free survival (PFS) PFS = 26.3 ORR = KRD (N=396) ≥CR = 32% months 87% PFS increased by 9 months with KRd; N=792 higher ORR, deeper response, and longer median duration of response with KRd PFS = 17.6 ORR = RD (N=396) ≥CR = 9% months 67% Stewart AK et al. N Engl J Med. 2015;372:142. This material serves as an educational resource only. 9 The Evolving State of Relapsed/Refractory Multiple Myeloma Treatment MMRF ONS 2016 Carfilzomib: ENDEAVOR Trial • The phase 3, randomized, multicenter, superiority study comparing carfilzomib and dexamethasone (Kd) to bortezomib and dexamethasone (Vd) in patients with relapsed or refractory MM • Primary end point: PFS PFS = 18.7 ORR = KD (N=464) ≥CR = 13% months 77% Doubled the PFS with Kd; Higher ORR, deeper response, and longer N=929 median duration of response with Kd; PFS benefit was extended whether prior treatment with a PI or not PFS = 9.4 ORR = VD (N=465) ≥CR = 6% months 63% Dimopoulos MA et al. Lancet Oncol. 2016;17:27. Carfilzomib/Lenalidomide/ Dexamethasone (KRd) KRd Cycles 1–12 Cycles 13–18 Cycles 19+ Carfilzomib 27 mg/m2 IV Carfilzomib 27 mg/m2 IV Carfilzomib discontinued Days 1, 2, 8, 9, 15, 16 Days 1, 2, 15, 16 after Cycle 18 (20 mg/m2 Days 1, 2, Cycle 1 only, to assess tolerability to carfilzomib) Lenalidomide 25 mg: Days 1 to 21 Dexamethasone 40 mg: Days 1, 8, 15, 22 Stewart AK et al. N Engl J Med. 2015;372:142. This material serves as an educational resource only. 10 The Evolving State of Relapsed/Refractory Multiple Myeloma Treatment MMRF ONS 2016 Carfilzomib Monotherapy (K) Carfilzomib/Dexamethasone (Kd) CYCLE 1 Carfilzomib Carfilzomib Carfilzomib 20 mg/m2 56 mg/m2 56 mg/m2 NO CARFILZOMIB DOSING 1 2 34567 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Week Week Week Week 1 2 3 4 Dexamethasone, Dexamethasone, Dexamethasone, Dexamethasone, 20 mg 20 mg 20 mg 20 mg CYCLES 2-on, until disease progression or unacceptable toxicity Carfilzomib Carfilzomib Carfilzomib 56 mg/m2 56 mg/m2 56 mg/m2 NO CARFILZOMIB DOSING 1 2 34567 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Week Week Week Week 1 2 3 4 Dexamethasone, Dexamethasone, Dexamethasone, Dexamethasone, 20 mg 20 mg 20 mg 20 mg Dimopoulos MA et al. Lancet Oncol. 2016;17:27. Carfilzomib: Administration Precautions • Hydration – Adequate hydration is required prior to all dosing in Cycle 1 – Monitor for fluid overload • Premedications – Premedicate with dexamethasone • Thromboprophylaxis • Infection prophylaxis – Antiviral • Maximum BSA Dosing of 2.2 m2 Carfilzomib [package insert]. Thousand Oaks, CA: Onyx Pharmaceuticals Inc; 2016. This material serves as an educational