Multiple Myeloma: Is it now a curable disease? Pritesh Patel, MD

OVErview Disease overview How I approach initial treatment Treatment considerations at relapse

How many people are affected by myeloma? ≈96,000 MM patients Rare disease Second most common hematologic malignancy National Cancer Institute Survival Epidemiology and End Results Program SEER Cancer Statistics Review 1975-2012. Available at seer.cancer.gov accessed 4/30/16

How many people are affected by myeloma? ≈30,000 new diagnoses Increasing incidence National Cancer Institute Survival Epidemiology and End Results Program SEER Cancer Statistics Review 1975-2012. Available at seer.cancer.gov accessed 4/30/16

Impaired immune system Bone related signs and symptoms Myeloma cells Impaired immune system M Protein Grow in bone marrow Bone related signs and symptoms Anemia 10-35% Lytic Lesions 70% Bone Pain 50% High blood calcium 15-20% Kidney failure 25-30% Infection 15% Neuropathy 5%

Production and release of clonal immunoglobulin into blood and/or urine Destruction and invasion of bone marrow cavity Impaired immune function High blood calcium and bone complications

What is the “m Protein”? Protein normally made by plasma cells Heavy chain Protein normally made by plasma cells Single type produced by myeloma cells Can be measured at diagnosis in urine and blood Level can be tracked for disease response and relapse Light chain

The natural history of myeloma MGUS Smoldering Myeloma Early Myeloma Late Myeloma Plasma Cell Leukemia M-PROTEIN 100 Asymptomatic Symptomatic Active myeloma 2ND RELAPSE 50 1ST RELAPSE 20 1st line PLATEAU REMISSION TIME “Operational” cure

Questions at diagnosis Do I have SYMPTOMATIC myeloma? What is my prognosis/ stage etc? Am I eligible for stem cell transplant? What initial treatment?

bone marrow plasma cells >10% or biopsy proven plasmacytoma and one of the following Hypercalcemia: >11mg/dL or 1mg/dL higher than ULN Sixty percent or greater plasma cells in bone marrow R Renal impairment: >2mg/dL or clearance <40ml/min Li Light chain ration of >100 A Anemia: >2g/dL below LLN or < 10g/dL M MRI lesion >5mm B Bone lesions: >1 bone lesion on CT, PET or x ray, osteopenia

Baseline testing Complete blood count Complete chemistry B2 microglobulin and albumin Electrophoresis, immunofixation, free light chains Bone marrow aspirate and biopsy FISH testing Cytogenetics Skeletal survey Consideration of MRI and PET/CT

5 year survival National Cancer Institute Survival Epidemiology and End Results Program SEER Cancer Statistics Review 1975-2012. Available at seer.cancer.gov accessed 4/30/16

How is myeloma staged? STAGE I II III β2 microglobulin <3.5mg/dL Albumin >3.5g/dL AND Normal LDH AND standard risk karyotype β2 microglobulin >5.5mg/dL AND EIITHER high LDH OR high risk karyotype Neither stage I or II CRITERIA

Who can undergo stem cell transplant? Decision based largely on functional class and comorbid illness Can be performed safely in many patients in 70s Patient choice

The principle of autologous transplant Cell freezing and storage Stem cell re-infusion Blood counts decrease then and recover High dose melphalan Blood stem cell mobilization

Risks and benefits of transplant Prolonging remission “Cure” in some patients Risks Prolonged hospitalization Diarrhea and mucositis Infection

Initial treatment- transplant eligible Induction 3-6 cycles Auto Transplant Consolidation and maintenance

Initial treatment- transplant ineligible Induction Maintenance

Considerations in initial treatment 2 vs. 3 Drugs Kidney function Convenience and Cost

Commonly used medications Blood sugar Weight gain Sleep distubance Steroids e.g. dexamethasone Blood counts DVT risk Immunomodulatory drugs e.g. lenalidomide Peripheral neuropathy Proteasome inhibitors e.g. bortezomib

Principle of “maintenance” Initial therapy reduces disease Maintenance is a less intensive phase of therapy Maintain remission as long as possible without significant compromise of quality of life

IFM 2009 Phase III Randomized Trial Treatment: 8 cycles of lenalidomide, bortezomib, and dexamethasone (RVD) Maintenance lenalidomide for 1 year ASCT at relapse Conventional Arm Treatment: RVD x 3 cycles and ASCT Consolidation: 2 cycles of RVD Maintenance: Lenalidomide for 1 year ASCT arm N=700 Untreated Patients VS. Results (f/u 39 months) Complete remission 58% in ASCT arm vs. 46% in RVD arm 3-year PFS 61% in ASCT arm vs. 48% in RVD arm Median OS similar at 3 years (88%) Attal, et al. Blood. 2015; 126: abst 391.

Supportive care Anti-infection prophylaxis Anti-thrombotic prophylaxis e.g. acyclovir with bortezomib Anti-thrombotic prophylaxis Risk factors include medications and immobility Bone health Bisphosphonates and calcium

Considerations in Relapsed myeloma When to treat? Which treatment to use? Organ dysfunction Side effects Re-treatment

Newly Approved agents for relapsed disease New generation IMIDs Pomalidomide New generation proteasome inhibitors Carfilzomib Ixazomib Histone Deacetylase Inhibitors Panobinostat Monoclonal antibodies Daratumumab Elotuzumab

Summary Prolonged remissions are achievable in 2016 Goal to achieve deep response Maintained with less intense therapy Now a large number of options at relapse