Oncology Conference New Treatment Paradigms in Relapsed/Refractory - PowerPoint PPT Presentation

2020 Spring Oncology Conference

New Treatment Paradigms in Relapsed/Refractory Multiple Myeloma: Integrating Novel Agents Into Clinical Practice

Learning Objectives • Identify novel agents used in the treatment of relapsed/refractory (RR) multiple myeloma (MM) and guideline recommendations for their use • Apply established criteria to identify patients who have developed RRMM and individualize therapy based on relevant patient- and disease-related characteristics • Use current recommendations for monitoring and managing treatment-related AEs in patients with RRMM 3 AE = adverse event.

Multiple Myeloma • B-cell – derived plasma cell disorder ‒ Clonal proliferation of immunoglobulin (Ig)-secreting malignant plasma cells in bone marrow ‒ Secretion of M-protein into blood or urine • Abnormal Ig or Ig fragment; also called monoclonal protein, myeloma protein, or paraprotein ‒ Associated end-organ dysfunction • 32,270 new cases expected in the United States in 2020 • Median age at diagnosis is ~69 years, but 37% of patients are aged <65 years • Novel treatments have improved survival for newly diagnosed MM, but relapse is still expected ‒ 2-year survival rate (all patients): 87.1% in 2012, up from 69.9% in 2006 ‒ 5-year survival rate (all patients): 54% in 2009-2015, up from 27% in 1987-1989 • Important to use the best therapies in front-line treatment: treatment-free intervals are shorter with each subsequent line of therapy American Cancer Society. www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2020.html. Accessed Mar 23, 2020; Durie BGM. www.myeloma.org/sites/default/files/images/publications/UnderstandingPDF/concisereview.pdf. Accessed Mar 23, 2020; Fonseca R, et al. Leukemia. 2017;31:1915-1921; NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. 4 Accessed Mar 23, 2020; Palumbo A, Anderson K. N Engl J Med. 2011;364:1046-1060; Yong K, et al. Br J Haematol . 2016;175:252-254.

Progress in Treating Multiple Myeloma Preclinical and Clinical Studies Leading to FDA Approvals in MM Improvement in OS From Median 2006 2012, 2015 2015 2020 2012, 2015 of 3 to 8 to 10 Years Thalidomide Carfilzomib Panobinostat Isatuximab Carfilzomib 1.0 1960-65 0.9 1965-70 2005 2010 2015 2020 1970-75 0.8 1975-80 Proportion Surviving 1980-85 0.7 2007 2003, 2005, 2008 2013, 2015 2003, 2005, 2008 2019 1985-90 Doxil + Bortezomib (BTZ) Pomalidomide Bortezomib (BTZ ) Selinexor 0.6 1990-95 BTZ 1995-00 0.5 2015 2000-05 2015 Ixazomib 2005-10 Ixazomib 0.4 2006, 2014 2015 2015 0.3 Lenalidomide Daratumumab Elotuzumab 0.2 0.1 XPO1 inhibitor Immunomodulatory agent Proteasome inhibitor 0.0 0 2 4 6 8 10 12 14 16 18 20 Monoclonal antibody HDAC inhibitor Follow-up From Diagnosis (years) OS = overall survival; XPO1 = exportin 1. 5 Adapted with permission from Anderson KC. Clin Cancer Res . 2016;22:5419-5427 .

Myeloma Can Be Treated, But Not Cured Asymptomatic Symptomatic Relapsing Refractory Disease may respond or become refractory at any point Relapse M-Protein Level → Active myeloma Relapse MGUS or indolent myeloma Remission 4th-20th-line 1st-line 2nd- or 3rd- 4th-line therapy therapy line therapy therapy ← 2-3 years ← 1-2 years ← 1-2 years ← 6 months-1 year → → → → MGUS = monoclonal gammopathy of unknown significance. 6 Adapted from: Durie BGM. www.myeloma.org/sites/default/files/images/publications/UnderstandingPDF/concisereview.pdf. Accessed Mar 23, 2020.

Response and Survival in RRMM Median Response Duration (months) Response Duration With Subsequent Survival Outcomes 100 12 Lines of Treatment Median, Months 10 80 (range) Events, n/N Patients (%) 9 (7-11) 170/286 OS 8 5 (4-6) 217/286 EFS 60 6 40 4 20 2 0 0 0 12 24 36 48 60 First Second Third Fourth Fifth Sixth Months Treatment Regimen EFS = event-free survival. 7 Kumar SK, et al. Leukemia . 2012;26:149-157; Kumar SK, et al. Mayo Clin Proc . 2004;79:867-874.

International Myeloma Working Group: Standard Response Criteria Criteria Definition In patients who have achieved ≥CR, MRD negative in bone marrow by NGS plus disappearance of areas MRD-negative of disease previously seen on FPG-PET/CT Stringent CR CR and normal FLC ratio, absence of clonal cells in bone marrow biopsy by IHC CR Negative immunofixation on serum and urine, and disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow aspirate Serum and urine M-protein detectable on immunofixation but not on electrophoresis, or ≥90% reduction VGPR in serum M-protein plus urine M-protein <100 mg/24 h ≥50% reduction of serum M- protein plus ≥90% reduction in urine M -protein or to <200 mg/24 h PR ≥25% but ≤49% reduction in serum M-protein and reduction in 24 h urine M-protein of 50% to 89% Minimal response Stable disease No evidence of disease response or progression CR = complete response; FDG PET/CT = fluorodeoxyglucose positron emission tomography-computed tomography; FLC = free light chain; IHC = immunohistochemistry; MRD = minimal residual disease; NGS = next-generation sequencing; PR = partial response; VGPR = very good partial response. 8 Kumar S, et al. Lancet Oncol. 2016;17:e328-e346.

Major Classes of Treatment Used in Multiple Myeloma IMiDs PIs mAbs Others • • • • HDI: Panobinostat (F) Agents in Lenalidomide (R) Bortezomib (V) Daratumumab (D) • • • • XPO1: Selinexor class Pomalidomide (P) Carfilzomib (K) Isatuximab • • • (abbreviation) Thalidomide (T) Ixazomib (N, I) Elotuzumab (E) • • • • Panobinostat: Mechanism of Antiangiogenic and Promote apoptosis Daratumumab • action anti-inflammatory Inhibit osteoclast and Isatuximab: Damages DNA and properties formation CD38-mediated upregulates apoptosis- • • CD-4+/CD-8+ T-cell Increase osteoblast apoptosis promoting proteins • Selinexor : Inhibits enhancement creation and • Elotuzumab : • NK cell function growth and promotes SLAMF7-mediated augmentation apoptosis by blocking NK cell actions of XPO1 enhancement HDI = histone deacetylase inhibitor; mAbs = monoclonal antibodies; NK = natural killer; PI = protease inhibitor; SLAMF7 = signaling activation molecule F7. Bahlis NJ, et al. Blood. 2018;132:2546-2554; Cook G, et al. Crit Rev Oncol Hematol. 2018;121:74-89; Palumbo A, Anderson K. N Engl J Med. 9 2011;364:1046-1060.

Current Treatment Paradigm for Active Myeloma SCT Eligible Induction SCT/Consolidation Maintenance Managing Diagnosis and Risk Relapse Stratification Induction Followed by SCT Continuous Maintenance Therapy Ineligible Tumor Burden 10 SCT = stem-cell transplant.

Case Study 1: Jean, 68 Years Old History • Diagnosed with MM 4 years ago • Standard-risk cytogenetics: t(6;14) • Front-line treatment ‒ Bortezomib/lenalidomide/low-dose dexamethasone (VRd): achieved VGPR ‒ Successful ASCT with melphalan 200 mg/m 2 : achieved CR ‒ Lenalidomide 10 mg maintenance treatment Finding 4 Months Ago 2 Months Ago Serum M-protein 0.1 g/dL 0.2 g/dL Serum creatinine 0.7 mg/dL 1.2 mg/dL Hgb 12.5 g/dL 10.9 g/dL Bone lesions None None 11 ASCT = autologous stem-cell transplant; Hgb = hemoglobin.

Case Study (cont’d): Today’s Visit • 20 months after starting lenalidomide maintenance, Jean presents with pain in her ribs and back • Otherwise good health, but has residual PN from VRd; Jean says it is still slowly improving • Bone marrow biopsy: 14% bone marrow plasma cells, 50% increase over last biopsy • ECOG PS = 1 Finding 4 Months Ago 2 Months Ago Today Serum M-protein 0.1 g/dL 0.2 g/dL 0.9 g/dL Serum creatinine 0.7 mg/dL 1.2 mg/dL 2.0 mg/dL Hgb 12.5 g/dL 10.9 g/dL 9.5 g/dL Bone lesions None None Osteolytic lesions on X-ray 12 ECOG PS = Eastern Cooperative Oncology Group performance status; PN = peripheral neuropathy.

MM Cytogenetic Changes Over Time May Impact Prognosis • Myeloma evolves over time in response to treatment, epigenetics, and other factors • Presence of high-risk cytogenetics at diagnosis is associated with higher rates of clonal evolution • High-risk clones can develop de novo after successful front-line therapy and ASCT ‒ High-risk deletion 17p and gain 1q21 mutations • Development of high-risk mutations associated with poor prognosis • Acquired del17p associated with significantly shorter PFS and OS ‒ Lower-risk translocations; eg, t(11;14) or t(6;14) (rare) PFS = progression-free survival. Bianchi G, Ghobrial M. Curr Cancer Ther Rev. 2014;10:70-79; Lakshman A, et al. Blood Adv. 2019;3:1930-1938; Merz M, et al. Haematologica. 13 2017;102:1432-1438.