Managing Patients with Multiple Myeloma: What the Specialty Pharmacist Needs to Know

Disclaimer: The information within this CME/CE activity is for continuing education purposes only, and is not intended to substitute for the medical judgment of the healthcare provider. Recommendations for use of any particular therapeutic agents or methods are based upon the best available scientific evidence and clinical guidelines. Reference in this activity to any specific commercial products, process, service, manufacturer, or company does not constitute its endorsement or recommendation. Disclosures: I have disclaimers and have served in the following roles: Advisory board: -Millennium Pharmaceuticals Speaker s Bureau: -Millennium Pharmaceuticals -Celgene Pharmaceuticals -Onyxx Pharmaceuticals

Faculty Biography Adam Peele, PharmD, BCPS, BCOP Oncology Pharmacy Manager Clinical Hematology/Oncology Specialist Cone Health Adam graduated from the University of North Carolina at Chapel Hill with a bachelor s degree in history and received a doctorate of pharmacy degree from the Campbell University College of Pharmacy and Health Sciences. He completed both his post graduate year one pharmacy practice residency and his second year post graduate residency in hematology/oncology with the Cone Health System. He is a board certified pharmacotherapist and oncology pharmacist by the American College of Clinical Pharmacy. Adam s current role is as an oncology pharmacy manager and clinical hematology/oncology pharmacy specialist with Cone Health. 3

Objectives Describe complications of multiple myeloma and adverse events associated with current therapies Discuss the assessment of patient, disease, and treatment specific factors to identify patients at risk for adverse events or complications Identify supportive care strategies to prevent and treat adverse events Recognize communication and collaborative practice techniques to participate in team based supportive care for patients with multiple myeloma

History of Multiple Myeloma Blood 2008; 111; 2962-2972

Multiple Myeloma

US Multiple Myeloma Statistics Statistic N Newly diagnosed cases (2013) 22,350 Deaths 10,170 Prevalence (2010) 77,617 http://seer.cancer.gov/statfacts/html/mulmy.html

Myeloma Demographics http://seer.cancer.gov/statfacts/html/mulmy.html

Incidence Over Time in the US Myeloma All Cancers http://seer.cancer.gov/statfacts/html/mulmy.html

Risk Factors of Multiple Myeloma Increasing age Male sex African American race Family history Monoclonal gammopathy of undetermined significance Radiation therapy Chemical Exposure Viral

Myeloma Description Multiple myeloma is a B-cell malignancy derived from antibody-producing plasma cells in the bone marrow The proliferation of myeloma cells leads to excessive production of a monoclonal antibody (M-protein) Also leads to adverse events in other organ systems http://www.cancer.gov/cancertopics/pdq/treatment/myeloma/patient/page1

Common Symptoms of Myeloma System Symptoms Common cause(s) Blood Kidneys Fatigue Recurrent infections Nausea and vomiting Confusion Anemia, Treatment Uninvolved Ig Treatment Renal failure Hypercalcemia Renal failure Hypercalcemia Bone Pain Peripheral neuropathy Fractures Nerve compression Treatment

Recommended workup Normal SPEP Blood Specimen Chemistry Serum beta-2 microglobulin Albumin LDH Serum free light chains Serum immunoglobulins Myeloma SPEP NCCN Guidelines v 2.2014 Multiple myeloma

Recommended Workup Continued Urine Specimen Routine urinalysis Bone Marrow Specimen Bone marrow aspirate and/or biopsy 24 hour urine collection Cytogenetics -- Bone survey NCCN Guidelines v 2.2014 Multiple myeloma

Recommended Workup Continued Journal of Clinical Imaging Science 2013, 3:6

Various Stages of Myeloma Monoclonal gammopathy of undetermined significance Smoldering myeloma Symptomatic myeloma Serum monoclonal protein Clonal BM plasma cells < 3 g/dl 3 g/dl And/or Presence of serum and/or urinary monoclonal protein < 10% 10% 10% End-organ damage None None CRAB Mayo Clinic Proc. 2013; 88(4): 360-376

Crab Criteria Must be present for diagnosis of myeloma to be made C = calicum 11.5 mg/dl R = Renal insufficiency: serum creatinine > 2 mg/dl A = Anemia: Hgb < 10g/dL or 2 g/dl below normal B = Bone Lesions: lytic or osteopenic

Durie-Salmon Staging System for MM Stage Criteria Myeloma Cell Mass ( 10 12 cells/m 2 ) I All of the following: Hemoglobin >10 g/dl Serum calcium level <10.5 mg/dl (normal) Normal bone or solitary plasmacytoma on X ray Low M-component production rate: IgG <5 g/dl; IgA <3 g/dl Bence Jones protein <4 g/24 hr <0.6 (low) II Not fitting stage I or III 0.6 1.2 (intermediate) III One or more of the following: Hemoglobin <8.5 g/dl Serum calcium level >12 mg/dl Advanced lytic bone lesions on X ray High M-component production rate: IgG >7 g/dl; IgA >5 g/dl Bence Jones protein >12 g/24 hr >1.2 (high) Subclassification A B Criteria Normal renal function (serum creatinine level <2.0 mg/dl) Abnormal renal function (serum creatinine level 2.0 mg/dl) Cancer 1975;36:842.

International Staging System for Multiple Myeloma Stage Laboratory value(s) Stage I Serum β-2 microglobulin < 3.5 mg/dl Serum albumin 3.5 mg/dl Stage II Neither stage I or III values Stage III Serum β-2 microglobulin 5.5 mg/dl Journal of Clinical Oncology 2005;23:3412-3420

Risk stratification in multiple myeloma Risk group Factors Frequency Median Overall Survival High Deletion 17p t(14;16) t(14;20) 20% 3 y Intermediate t(4;14) Cytogenetic del 13 or Hypodiploidy Plasma cell labeling index 20% 4-5 y Standard Hyperdiploid t(11;14) t(6;14) 60% 8-10 y Mayo Clinic Proc. 2013; 88(4): 360-376

Response Criteria Response Category scr, stringent complete response Response Criteria Normal free light chain ratio and absence of clonal bone marrow by immunofluroesence CR, complete response Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and 5% plasma cells in the bone marrow VGPR, very good partial response Serum and urine M-protein detectable by immunofixation but not on electrophoresis PR, partial response 50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by 90% or to < 200 mg per 24 hour SD, stable disease Not meeting criteria for CR, VGPR, PR, or progressive disease Progressive disease Increase of 25% from baseline in various categories Clinical relapse Direct indicators of increasing disease and/or end organ dysfunction (CRAB criteria) NCCN Guidelines v 2.2014 Multiple myeloma

FDA Approved Agents Cyclophosphamid e & Melphalan Bortezomib Thalidomide Lenalidomide PLD Carfilzomib Pomalidomide Pre- 2003 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Examples of Myeloma Regimens Regimen BiRD CyBorD MPT RVD Rd VMP Medication Clarithromycin 500 mg bid starting day 2 of cycle 1 Lenalidomide 25 mg qd days 3-21 cycle 1 and days 1-21 subsequent cycles Dexamethasone 40 mg days 1,2,3,8,15, and 22 then weekly Every 4 weeks Cyclophosphamide 300 mg/m2 PO days 1,8,15,22 Bortezomib 1.3 mg/m2 IV once per day on days 1,4,8,11 Dexamethasone days 1-4, 9-12, 17-20 Every 28 days x 4-12 cycles Melphalan 0.25 mg/kg PO daily days 1-4 Prednisone 2mg/kg PO daily days 1-4 Thalidomide 100 mg PO daily on days 1-28 Every 42 days x 12 cycles Lenalidomide 25 mg daily days 1-14 Bortezomib 1.3 mg/m2 IV days 1,4,8,11 Dexamethasone 20 mg days 1-5,8-9, 11-12 Every 21 days x 4-8 cycles Lenalidomide 25 mg daily days 1-21 Dexamethasone 40 mg days 1,8,15,22 Every 4 weeks Bortezomib 1.3 mg/m2 every 3 weeks x 8 cycles then days 1, 8 every 3 weeks x 10 cycles Melphalan 9 mg/m2 days 1-4 Prednisone 60 mg/m2 days 1-4

Alkylating Agents http://www.cellbiol.net/layout/imagesbook/groot/23.01%20chemotherapy%20alkylation.jpg

Proteasome inhibition J Natl Cancer Institute 2011; 103: 1007-1017

Proteasome Inhibitor Adverse Effects Neutropenia Thrombocytopenia Cardiac toxicity (minimal) Hepatic toxicity Renal toxicity Peripheral neuropathy Zoster reactivation

Immunomodulatory agents http://openi.nlm.nih.gov/gridquery.php?simcollection=3187576

Venous Thromboembolism with IMiDs Enhance platelet aggregation Cytokine-mediated disruption Increase in tissue factor activity May cause protein C resistance New England Journal of Medicine 2003; 349: 109-111

Smoldering Myeloma No symptoms and no related organ or tissue involvement Indolent course Low amounts of M-protein without Significant anemia Hypercalcemia Bone disease

Lenalidomide plus Dexamethasone for High-Risk Smoldering Multiple Myeloma 125 patients, High-risk smoldering multiple myeloma R E C E I V E D Lenalidomide 25 mg daily x 21 days every 28 days Observation T I M E T O P R O G R E S S I O N New England Journal of Medicine 2013; 369: 438-447

Lenalidomide plus Dexamethasone for High-Risk Smoldering Multiple Myeloma New England Journal of Medicine 2013; 369: 438-447

Initial Therapy of Multiple Myeloma Remains a challenge Numerous options and combinations available Factors that may influence therapy Availability of agents Comfort of treating provider Consensus among experts Individual patient

Standard of care by setting Transplant eligible Induction ASCT +/- Maintenance Newly Diagnosed Myeloma Transplant ineligible Induction Maintenance NCCN Guidelines v 2.2014 Multiple myeloma

Transplant-Eligible Patients First step is to evaluate patient Mayo clinic consider patients with a physiologic age of 70 years old for ASCT Patients who undergo ASCT generally receive 4 cycles Intent of therapy is to have achieved at least a partial response prior high-dose therapy Combination induction regimens vary widely High-dose chemotherapy with autologous stem cell support Mayo Clinic Proc. 2013; 88(4): 360-376

Transplant-Eligible Patients Bortezomib/dexamethasone Bortezomib/cyclophosphamide/ dexamethasone Primary Therapy for Transplant Candidates Bortezomib/doxorubicin/ dexamethasone Bortezomib/lenalidomide/ dexamethasone Bortezomib/thalidomide/ dexamethasone Lenalidomide/dexamethasone NCCN Guidelines v 2.2014 Multiple myeloma

Transplant-Eligible Patients Mayo Clinic Proc. 2013; 88(4): 360-376

Bortezomib Induction and Maintenance Treatment in Patients with Newly Diagnosed Multiple Myeloma Journal of Clinical Oncology 2012; 30: 2946-2955

Bortezomib Induction and Maintenance Treatment in Patients with Newly Diagnosed Multiple Myeloma Peripheral neuropathy First year of treatment VAD = 18% PAD = 40% Newly developed grade 3-4 PNP Thalidomide = 8% Bortezomib = 5% Journal of Clinical Oncology 2012; 30: 2946-2955

614 patients, Lenalidomide Maintenance after Stem-Cell Transplantation for Multiple Myeloma Post-ASCT performed within 6 months Lenalidomide 25 mg daily on days 1-21 every 28 days x 2 cycles R A N D O M Z E D Lenalidomide 10 mg daily x 3 months then increased to 15 mg if tolerated Placebo P R O G R E S S I O N F R E E S U R V I V A L New England Journal of Medicine 2012; 366: 1782-1791

Lenalidomide Maintenance after Stem-Cell Transplantation for Multiple Myeloma HR = 0.50; P<0.001 New England Journal of Medicine 2012; 366: 1782-1791

Lenalidomide Maintenance after Stem-Cell Transplantation for Multiple Myeloma HR = 1.25; P= 0.29 New England Journal of Medicine 2012; 366: 1782-1791

Lenalidomide Maintenance after Stem-Cell Transplantation for Multiple Myeloma New England Journal of Medicine 2012; 366: 1782-1791

Transplant-Ineligible Patients Not able to withstand high dose regimens with ASCT Can be treated with similar regimens as transplant eligible patients Increasing agents and regimens becoming available in this setting

Transplant-Ineligible Patients Bortezomib/dexamethasone Primary Therapy for Non-Transplant Candidates Lenalidomide/low dose dexamethasone Bortezomib/melphalan/ prednisone Melphalan/lenalidomide/ Prednisone Melphalan/prednisone/thalidomide NCCN Guidelines v 2.2014 Multiple myeloma

VISTA Trial 682 patients, Newly diagnosed, untreated, symptomatic Not transplant eligible R A N D O M Z E D Bortezomib Melphalan Prednisone Melphalan Prednisone D I S E A S E P R O G R E S S I O N New England Journal of Medicine 2008; 359: 906-917

VISTA Trial New England Journal of Medicine 2008; 359: 906-917

Relapsed, Refractory Disease Retreat with primary regimen if > 6 months Can use numerous combination regimens Most newer FDA approved agents have stipulation that patients must have been treated with Bortezomib Immunomodulatory agent

Proteasome inhibition J Natl Cancer Institute 2011; 103: 1007-1017

Carfilzomib (Kyprolis) Cycle 1 20 mg/m2 Week 1 Week 2 Week 3 Week 4 Day 1 Day 2 Day 3-7 Day 8 Day 9 Day 10-14 Day 15 Day 16 Day 17-21 Day 22-28 20 20 No 20 20 No 20 20 No No Cycle 2 and Beyond 27 mg/m2 Week 1 Week 2 Week 3 Week 4 Day 1 Day 2 Day 3-7 Day 8 Day 9 Day 10-14 Day 15 Day 16 Day 17-21 Day 22-28 27 27 No 27 27 No 27 27 No No * Available as 60 mg single use vial

Carfilzomib (Kyprolis ) Dose Modifications Grade 3 or 4 neutropenia Grade 4 thrombocytopenia Cardiac toxicity Hepatic toxicity Renal toxicity Peripheral neuropathy

Phase 2 Study of single agent carfilzomib in patients with relapsed and refractory multiple myeloma Prepublished Online Blood-2012-05-425934

Pomalidomide (Pomalyst ) Dose 4 mg once daily x 21 days every 28 days Dexamethasone 40 mg day(s) 1, 8, 15, 22 every 28 days ( 75 years old) 20 mg day(s) 1, 8, 15, 22 every 28 days (> 75 years old) Dose Modifications Neutropenia Thrombocytopenia Availability Capsules 1 mg 2 mg 3 mg 4 mg

Pomalidomide (Pomalyst ) http://www.clinicaloptions.com/oncology/conference%20coverage/clin%20onc%20june%202012/myeloma/capsules/8016.aspx

Pomalidomide (Pomalyst ) Responsive Outcome Pomalidomide (n = 108) Pomalidomide + LD Dex (n = 113) ORR (CR + PR), % 9 30 CR 0 1 PR 9 29 MR 16 15 SD 46 35 PD 16 6 Median Duration of Response, months Median Time to ORR, months NR 7.4 2 1.9 http://www.clinicaloptions.com/oncology/conference%20coverage/clin%20onc%20june%202012/myeloma/capsules/8016.aspx

Proportion of Patients Pomalidomide (Pomalyst ) 1.0 0.8 0.6 0.4 0.2 Median PFS, Mos POM + LoDEX (n = 113) 3.8 POM (n = 108) 2.5 HR: 0.73 P =.037 0 0 2 4 6 8 10 12 14 16 PFS (Mos) Neutropenia (47%), thrombocytopenia (22%), anemia (22%), leukopenia (6%) were most common hematologic AEs in POM-alone arm Pneumonia (14%), fatigue (10%), back pain (12%), dyspnea (7%) were most common nonhematologic AEs in POM-alone arm http://www.clinicaloptions.com/oncology/conference%20coverage/clin%20onc%20june%202012/myeloma/capsules/8016.aspx

Bone Destruction in Myeloma Increased osteoclastic activation Myeloma cells interaction with bone marrow stromal cells Up-regulation of RANKL Osteoprotegrin down regulated Annals of Oncology 2005; 16: 1223-1231

Bone Destruction Treatment Bisphosphonates are standard of care Zoledronic acid Pamidronate RANK Ligand inhibitors contraindicated Denosumab

Peripheral Neuropathy IV formulation of bortezomib Subcutaneous formulation has shown decreased incidence Carfilzomib has less rates than bortezomib Less observed with newer IMiDs

Subcutaneous versus intravenous administration of bortezomib in relapsed multiple myeloma Lancet Oncology 20011; 12: 431-440

Where We are Headed in Myeloma Optimizing lengths of therapy with agents Using agents approved for relapsed/refractory disease earlier in treatment Newer, novel agents

American Society of Hematology Abstracts 2013 Regimen Line of therapy Data to Support Carfilzomib/lenalidomide/ dexamethasone lenalidomide (CRD-R) Newly diagnosed ASH 2013 Carfilzomib/ cyclophosphamide/ dexamethasone (CCd) Newly diagnosed ASH 2013 Carfilzomib/pomalidomide/dex amethasone Refractory ASH 2013 Ixazomib/lenalidomide/ dexamethasone Newly diagnosed ASH 2013 SAR650984 Refractory ASH 2013 Afuresetrib Refactory ASH 2013 Proc ASH 2013: Abstract 538; Proc ASH 2013: Abstract 685; Proc ASH 2013: Abstract 690; Proc ASH 2013: Abstract 535; Proc ASH 2013; Abstract 284; Proc ASH 2013: Abstract 283

Team-Based Collaborative Approach Assist providers in dose modifications rather than discontinuing medications Evaluate patients for toxicities Maximize effective supportive care measures to ensure compliance and efficacy Recommend supportive care medications for patients

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