2020 Spring Oncology Conference New Treatment Paradigms in Relapsed/Refractory : 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

AE = adverse event. 3 Multiple Myeloma

• B-cell–derived disorder ‒ Clonal proliferation of immunoglobulin (Ig)-secreting malignant plasma cells in bone marrow ‒ Secretion of M-protein into 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. 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. 4 Progress in Treating Multiple Myeloma

Preclinical and Clinical Studies Leading to FDA Approvals in MM

2006 2012,2012, 2015 2015 2015 2020 Improvement in OS From Median Thalidomide CarfilzomibCarfilzomib Panobinostat Isatuximab of 3 to 8 to 10 Years 1.0 1960-65 0.9 2005 2010 2015 2020 1965-70 1970-75 0.8 1975-80 0.7 1980-85 2003, 2005, 2008 2007 2013, 2015 2019 1985-90 Bortezomib (BTZ)(BTZ) Doxil + Pomalidomide Selinexor 0.6 1990-95 BTZ 1995-00 0.5 2015 2000-05 Ixazomib 2005-10 Ixazomib 0.4

2006, 2014 2015 2015 0.3 Lenalidomide Daratumumab Elotuzumab Proportion Surviving 0.2

0.1 Immunomodulatory agent Proteasome inhibitor XPO1 inhibitor 0.0 Monoclonal HDAC inhibitor 0 2 4 6 8 10 12 14 16 18 20

OS = overall survival; XPO1 = exportin 1. Follow-up From Diagnosis (years) Adapted with permission from Anderson KC. Clin Cancer Res. 2016;22:5419-5427. 5 Myeloma Can Be Treated, But Not Cured

Asymptomatic Symptomatic Relapsing Refractory Disease may respond or become refractory at any point

Active Relapse → myeloma

Relapse

Protein Level Level Protein MGUS or -

M indolent myeloma Remission 1st-line 2nd- or 3rd- 4th-line 4th-20th-line therapy line therapy therapy therapy ← 2-3 years ← 1-2 years ← 1-2 years ← 6 months-1 year → → → →

MGUS = of unknown significance. Adapted from: Durie BGM. www.myeloma.org/sites/default/files/images/publications/UnderstandingPDF/concisereview.pdf. Accessed Mar 23, 2020. 6 Response and Survival in RRMM

12 Response Duration With Subsequent 100 Survival Outcomes Lines of Treatment Median, Months 10 80 Events, n/N (range) OS 170/286 9 (7-11) 8 217/286 5 (4-6) 60 EFS

6 40

4 (%) Patients 20 2

0 0 First Second Third Fourth Fifth Sixth 0 12 24 36 48 60 Median Response (months) Duration Response Median Treatment Regimen Months

EFS = event-free survival. Kumar SK, et al. Leukemia. 2012;26:149-157; Kumar SK, et al. Mayo Clin Proc. 2004;79:867-874. 7 International Myeloma Working Group: Standard Response Criteria

Criteria Definition MRD-negative In patients who have achieved ≥CR, MRD negative in bone marrow by NGS plus disappearance of areas 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 , and <5% plasma cells in bone marrow aspirate VGPR Serum and urine M-protein detectable on immunofixation but not on electrophoresis, or ≥90% reduction in serum M-protein plus urine M-protein <100 mg/24 h

PR ≥50% reduction of serum M-protein plus ≥90% reduction in urine M-protein or to <200 mg/24 h

Minimal response ≥25% but ≤49% reduction in serum M-protein and reduction in 24 h urine M-protein of 50% to 89%

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. Kumar S, et al. Lancet Oncol. 2016;17:e328-e346. 8 Major Classes of Treatment Used in Multiple Myeloma

IMiDs PIs mAbs Others Agents in • Lenalidomide (R) • Bortezomib (V) • Daratumumab (D) • HDI: Panobinostat (F) class • Pomalidomide (P) • Carfilzomib (K) • Isatuximab • XPO1: Selinexor (abbreviation) • Thalidomide (T) • Ixazomib (N, I) • Elotuzumab (E)

Mechanism of • Antiangiogenic and • Promote apoptosis • Daratumumab • Panobinostat: 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 enhancement creation and • Elotuzumab: • Selinexor: Inhibits • NK cell function SLAMF7-mediated growth and promotes augmentation NK cell apoptosis by blocking enhancement actions of XPO1

HDI = histone deacetylase inhibitor; mAbs = monoclonal ; 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. 2011;364:1046-1060. 9 Current Treatment Paradigm for Active Myeloma

SCT Eligible Induction SCT/Consolidation Maintenance

Diagnosis Managing and Risk Relapse Stratification SCT Induction Followed by Ineligible Continuous Maintenance Therapy

Tumor Burden

SCT = stem-cell transplant. 10 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/m2: 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

ASCT = autologous stem-cell transplant; Hgb = hemoglobin. 11 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

ECOG PS = Eastern Cooperative Oncology Group performance status; PN = peripheral neuropathy. 12 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. 2017;102:1432-1438. 13 mSMART: Risk Classification of MM

Standard Risk High Risk** • All others, including: High-risk genetic • RISS stage 3 – Trisomies abnormalities by FISH or • High plasma-cell S phase equivalent – t(11:14)* • Gene expression profiling: • t(4:14) – t(6:14) High-risk signature • t(14:16) Jean now • Double-hit: any 2 high-risk Jean at diagnosis • t(14:20) genetic abnormalities • del(17p) • Triple-hit: ≥3 high-risk • p53 mutation genetic abnormalities • 1q gain

*t(11;14) may be associated with ; **Trisomies may ameliorate risk. FISH = fluorescent in situ hybridization; mSMART = Mayo Stratification of Myeloma and Risk-Adapted Therapy; RISS = Revised International Staging System. Mayo Clinic.static1.squarespace.com/static/5b44f08ac258b493a25098a3/t/5b802d8270a6adbc6a79a678/ 1535126914646/Risk+Strat+3.0rev_svr.pdf. Accessed Mar 23, 2020. 14 Relapse Patterns in Multiple Myeloma

Clinically symptomatic disease with increase Extramedullary disease in M-protein

Four patterns of relapse

Plasma cell leukemia Asymptomatic disease characterized by increase in M-protein

Alegre, et al. Haemotologica. 2002; 87:609-614. 15 Biochemical Relapse: IMWG Criteria

Biochemical relapse identified due to improved monitoring can catch progression before development of clinical symptoms • 25% increase from the lowest response value in ≥1of the following: ‒ Serum M-protein • Absolute increase ≥0.5 g/dL or • Increase ≥1 g/dL if the lowest M-protein level was ≥5 g/dL ‒ Urine M-protein: absolute increase ≥200 mg/24 hours ‒ For patients without measurable serum or urine M-protein levels • Difference between involved and uninvolved FLC levels: absolute increase >10 mg/dL • Absolute increase >10% in percentage of bone marrow plasma cells • Development of new lesions, increase in size of existing lesions,* or ≥50% increase in circulating plasma cells (minimum 200 cells/mcL) if only measure of disease

*50% increase from nadir in SPD of >1 lesion, or ≥50% increase in the longest diameter of a previous lesion >1 cm in the short axis. IMWG = International Myeloma Working Group; SPD = sum of the products of the maximal perpendicular diameters. Kumar S, et al. Lancet Oncol. 2016;17:e328-e346. 16 Clinical Relapse: IMWG Criteria

≥1 of the following: CRAB criteria: a mnemonic for myeloma-related organ dysfunction: • CRAB features C = calcium elevation: >11.5 mg/dL • Size* increase in existing (or development R = renal disease: serum Cr >2 mg/dL of new) soft tissue plasmacytomas or A = anemia: Hgb <10 g/dL or >2 g/dL bone lesions (not new osteoporotic fractures) below LLN • Hgb reduction ≥2 g/dL unrelated to MM B = bone lesions: ≥1 osteolytic lesion therapy or other conditions • Serum creatinine increase ≥2 mg/dL attributable to MM • Hyperviscosity related to serum paraprotein

*50% (and ≥1 cm) increase as measured serially by the SPD of the measurable lesion. Kumar S, et al. Lancet Oncol. 2016;17:e328-e346. 17 IMWG: High-Risk Disease Characteristics in Relapsed or Relapsed/Refractory Disease

• Adverse cytogenetic features • Complex karyotypes

• High β2 microglobulin (>5.5 mg/L) or low albumin (<3.5 mg/dL) • LDH above normal • Circulating plasma cells • Extramedullary disease • Short duration of response (DOR) to prior therapy or progression on current therapy • Aggressive clinical features: rapid symptom onset, extensive disease, CRAB features

LDH = lactate dehydrogenase. Dingli D, et al. Mayo Clin Proc. 2017;92:578-598; Laubach J, et al. Leukemia. 2016;30:1005-1017. 18 IMWG: Principles of Treating Progressive Disease

When to Treat • Clinical (symptomatic) relapse: CRAB criteria • Rapidly rising M-protein levels (eg, monoclonal peak doubling time ≤3 months) • Extramedullary disease • Early relapse, high-risk cytogenetics • Threatened organ function (ie, renal dysfunction)

Laubach L, et. al Leukemia. 2016;30:1005-1017. 19 Before Changing or Initiating Therapy

• Make sure the patient has actually progressed − Repeat myeloma lab tests − Don’t compare results from different labs • Characterize the relapse − Asymptomatic biochemical (indolent) vs symptomatic clinical − Slow vs rapid − Early vs late

20 Selecting Treatment for RRMM: General Principles

• Duration of initial response informs the biology of RRMM • Regimen: triplet* (eg, KRd) is preferred over doublet ‒ Include ≥1 agent from a new or non-refractory class ‒ Previously used agents may be effective in different combinations • When selecting therapy and optimal doses, consider ‒ Disease risk, ECOG PS, age, comorbidities ‒ Bone marrow biopsy at each relapse to reassess risk ‒ Prior and residual toxicities • Treat to maximum response and maintain on ≥1 agent until progression or intolerability

*Two active classes plus dexamethasone. Laubach L, et al. Leukemia. 2016;30:1005-1017; NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 23, 2020; Sonneveld P, Broijl A. Haematologica. 2016;101:396-406. 21 Establish the Goals of Treatment for the Patient

Patient characteristics Prior therapy • Balance treatment efficacy with •Goals of treatment • Prior ASCT? impact on QoL •Age/frailty • Prior IMiDs? PIs? − May not need a regimen with a •Performance status • Depth/DOR high CR rate •Lifestyle/mobility • Time to progression? − Stable disease is an excellent •Comorbidities • Toxicities goal of therapy for many patients with RRMM Disease characteristics ‒ Little difference in clinical • Cytogenetics consequences between stable • CRAB present disease and CR • Extramedullary disease • Aggressive features • Short DOR

QoL = quality of life. 22 Recent FDA Approved Agents and Combinations

≥2 Prior Courses

≥1 or 1 to 3 Prior Courses Daratumumab + pomalidomide + dexamethasone ≥1: Carfilzomib monotherapy (PX-171–003; FOCUS) Isatuximab + pomalidomide + dexamethsone 1-3: Carfilzomib + lenalidomide + dexamethasone (ASPIRE) Elotuzumab + pomalidomide + 1-3: Carfilzomib, dexamethasone (ENDEAVOR) dexamethasone (ELOQUENT-3)

≥1: Daratumumab + either lenalidomide or bortezomib + dexamethasone Pomalidomide + dexamethasone (POLLUX & CASTOR) Panobinostat + bortezomib + ≥1: Ixazomib + lenalidomide + dexamethasone (TOURMALINE-MM1) dexamethasone (PANORAMA-1)

1-3: Elotuzumab + lenalidomide + dexamethasone (ELOQUENT- 2) ≥3 or ≥4 Prior Courses ≥3: Daratumumab monotherapy (SIRIUS)

≥4: Selinexor + dexamethasone (STORM)

Attal M, et al. Lancet. 2019;394:2096-2107; Chari A, et al. Blood. 2017;130:974-981; Chari A, et al. ASH 2018. Abstract 598; Dimopoulos MA, et al. Lancet Oncol. 2016;17:27-38; Dimopoulos MA, et al. N Engl J Med. 2016;375:1319-1331; Dimopoulos MA, et al. N Engl J Med 2018; 379:1811-1822; Hájek, et al. Leukemia. 2017;31:107-114; Lonial S, et al. Lancet. 2016;387:1551-1560; Lonial S, et al. N Engl J Med 2015; 373:621-631; Moreau P, et al. N Engl J Med. 2016; 374:1621-1634; Palumbo A, et al. N Engl J Med. 2016; 375:754-766; San-Miguel, et al. Lancet Haematol. 2016;3:e506-e515; Stewart K, et al. N Engl J Med. 2015; 372:142-152; Vij, et al. Br J Haematol. 2012;158:739–748. 23 Summary: mSMART Recommended Approaches After First Relapse

On Maintenance* Off Therapy/Unmaintained* Triplet Preferred: Add ≥1 New Agent, or Next Generation Agent Indolent Relapse From Same Class Fit Patients or Frail Patients Indolent Relapse Fit Patients or Frail Patients • KRd • IRd If lenalidomide maintenance: If lenalidomide maintenance: • DaraRd • EloRd • KPomD • DaraVd • PomD • DaraVd • Id + cyclophosphamide If bortezomib maintenance: If bortezomib maintenance: • DaraRd • IRd • DaraRd

*Consider salvage ASCT in eligible patients who have not had a previous ASCT. Consider second ASCT in eligible patients if response has been >18 months (unmaintained) or >36 months (maintained). DaraRd = daratumumab, lenalidomide, dexamethasone; DaraVd = daratumumab, bortezomib, dexamethasone; EloRd = elotuzumab, lenalidomide, dexamethasone; Id = isatuximab, dexamethasone; IRd = isatuximab, lenalidomide, dexamethasone; K/PomD = carfilzomib, pomalidomide, dexamethasone; PomD = pomalidomide, dexamethasone. Dingli D, et al. Mayo Clin Proc. 2018;92:578-598. 24 Ranking of Treatments Based on Meta-analysis Results

Botta C, et al. Blood Adv. 2017;1:455-466. 25 Case Study (cont’d)

• Jean was retreated with VRd and achieved a partial response at 6 months; she presents now with complaints of persistent fatigue, shortness of breath, swelling of ankles, and bone pain in lower legs • Updated cytogenetics: unchanged—still high-risk del(17p) • Current laboratory measurements

Finding At Diagnosis 6 Months Ago Today Serum M-protein 0.9 g/dL 0.6 g/dL 1.2 g/dL Serum creatinine 2.0 mg/dL 1.6 mg/dL 2.1 mg/dL Serum calcium — 10.2 mg/dL 11.6 mg/dL Hgb 11.0 g/dL 11.0 g/dL 10.2 g/dL Bone marrow — <10% plasma cells 16% plasma cells

26 Relapsed vs Refractory Disease

• Relapsed/refractory MM: progression on therapy after achieving at least minor response or progression within 60 days of most recent therapy • Primary refractory MM: progression on therapy without achieving at least minor response • Relapsed MM: meets IMWG criteria for progressive disease but does not fit definition of RR or primary refractory

Nooka AK, et al. Blood. 2015;125:3085-3099. 27 Administration Considerations for PIs

Bortezomib (V) Carfilzomib (K) Ixazomib (N, I) Route* SC** IV Oral Select AEs to assess PN Cardiac failure Thrombocytopenia Hypotension Renal insufficiency GI toxicity Cardiac toxicity Pulmonary toxicity, dyspnea Peripheral neuropathy Pulmonary toxicity Hypertension Rash GI toxicity Venous thrombosis Hepatotoxicity Thrombocytopenia Hemorrhage Neutropenia Thrombocytopenia Hepatic toxicity Rate of PN with PI + Rd Any grade: 35% Any grade: 11% Any grade: 28% Grade 3 or 4: 8% Grade ≥3: 2% Grade ≥3: 2% Management Monitor CBC; safe in renal failure, Monitor hydration, cardiopulmonary Reduce dose for hepatic/renal considerations herpes prophylaxis toxicities, herpes prophylaxis disease, herpes prophylaxis

*Recommended dose and schedules vary depending on regimen and patient factors. Check prescribing information; **An IV formulation is available but is not recommended for use. AE = adverse event; CBC = ; Rd = lenalidomide/low-dose dexamethasone. Kyprolis [prescribing information]. Amgen; 2019; NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 23, 2020; Ninlaro [prescribing information]. Takeda; 2020; Velcade [prescribing information]. Millennium Pharmaceuticals, Inc; 2019. 28 Administration Considerations for mAbs

Daratumumab (D, Dara) and Isatuximab (Isa) Elotuzumab (E, Elo) Route* IV IV

AE prophylaxis Pre/post medication with corticosteroids, antipyretics, and 60 to 90 min before infusion, administer antihistamines; oral steroid may not be needed after infusion corticosteroids, H1 blocker, H2 blocker, if used in combinations that include dexamethasone acetaminophen ± Inhaled steroids for patients with COPD (Dara) Select AEs to assess Infusion reactions Infusion reactions Interference with cross-matching, red blood cell antibody Infection** screening, and determination of CR Second primary malignancy Infection** Hepatotoxicity Neutropenia, thrombocytopenia Interference with determination of CR Management For infusion reaction risk, pre/post medicate as directed; interrupt infusion if reaction occurs considerations Monitor CBC periodically during treatment with Dara and Isa; monitor during neutropenia for infection; dose delay with Dara or Isa may be required to allow neutrophil recovery Monitor patients during treatment for second primary malignancies, per IMWG guidelines (lsa, Elo)

*Recommended dose and schedules vary depending on regimen and patient factors. Check prescribing information; **Patients should receive varicella zoster virus prophylaxis when receiving daratumumab or elotuzumab. Darzalex [prescribing information]. Janssen; 2019; Empliciti [prescribing information]. Bristol-Myers Squibb; 2019; Sarclisa [prescribing information]. Sanofi-aventis US; 2020. 29 Administration Considerations for XPO1 Inhibitor

Selinexor Route and dosage Oral, 80 mg days 1 and 3 of each week when combined with dexamethasone Frequent AEs (>20%) Thrombocytopenia, fatigue, nausea, anemia, decreased appetite/weight, diarrhea, vomiting, , neutropenia, leukopenia, constipation, dyspnea, and URI Select AEs to assess Thrombocytopenia Neutropenia Considered highly emetogenic; GI adverse reactions, especially nausea Hyponatremia Infections Management Monitor patients for cytopenia, neutropenia, hyponatremia, infections considerations Provide antiemetic prophylaxis May cause dizziness or confusion; optimize hydration, blood counts, and concomitant medications to minimize risk Dose reductions (if needed for hematologic/non-hematologic toxicity) • First: 100 mg once weekly • Second: 80 mg once weekly • Third: 60 mg once weekly (discontinue after third reduction)

URI = upper respiratory infection. Xpovio [prescribing information]. Karyopharm Therapeutics; 2019. 30 Cardiotoxicity With PIs: Is This a Class Effect?

• Patients with MM are at increased risk for CV complications due to disease factors and comorbidity • Cardiotoxicity increased with irreversible inhibition of ubiquitin-proteasome system ‒ Pre-existing uncontrolled hypertension or left ventricular hypertrophy increase risk for CVAE with carfilzomib • Note: PIs often are used in combination with other agents that also may affect CV function (eg, IMiDs) Bortezomib Carfilzomib Ixazomib • MoA: Reversible PI inhibition • MoA: Irreversible PI inhibition • MoA: Reversible PI inhibition Analysis of 8 myeloma studies (N = 3954), ENDEAVOR (phase 3, N = 929) TOURMALINE Grade ≥3 CVAE: Grade ≥3 with bortezomib: • Grade ≥3 hypertension • N = 361 IRd; 359 Rd patients • HF: 1.3% to 4.7% • 9% carfilzomib, 3% bortezomib • Arrhythmia: 6%; 4% • Arrhythmia: 0.6% to 4.1% • Any grade hypertension • Thromboembolism: <3%; <4% • Ischemic HD: 0.4% to 2.7% • 20.3% carfilzomib, 8.1% bortezomib • HF: 3%; 2% • Cardiac death: 0 to 1.4% • MI: <1%; <2% • No significant differences between bortezomib and placebo patients CV = cardiovascular; CVAE = cardiovascular adverse event (heart failure, hypertension, ischemia, arrhythmia); HD = heart disease; HF = heart failure; MI = myocardial infarction; MoA = mechanism of action; RCT = randomized controlled trial; RR = relative risk of CVAE for patients receiving carfilzomib compared with non–carfilzomib-receiving control patients. Bruno G, et al. Cancers (Basel). 2019;11:pii E622; Dimopoulos MA, et al. Lancet Oncol. 2016;17:27-38; Laubach JP, et al. Br J Haematol. 2017;178:547- 560; Li W, et al. JAMA Oncol. 2017;3:980-988; Moreau P, et al. N Engl J Med. 2016;374:1621-1634; Plummer C, et al. Blood Cancer J. 2019;9:26; Waxman AJ, et al. JAMA Oncol. 2018;4:e174519. 31 Assessing for Cardiotoxicity: Proactive Monitoring and Clinical Management of CV Events With Carfilzomib

Strategy Suggestions Baseline CV risk • Assess risk, obtain ECG, and determine need for cardiology consultation assessment and • Control hypertension ongoing monitoring • Review prior history of anthracyclines or other cardiotoxic agents • Consider reduced fluid volume in cycle 1 if high CV risk, and adjust in subsequent cycles Intervention • Withhold carfilzomib for grade 3/4 CVAE until resolved or improved to baseline • Consider restarting carfilzomib therapy at 1 dose level reduction based on a benefit-risk assessment after consulting a cardiologist • When resuming therapy, consider follow-up echocardiograms and/or biomarkers (eg, BNP or NT-proBNP) based on cardiologist recommendations Patient education • Encourage recognition and prompt reporting of symptoms of CV decompensation • Recommend routine BP monitoring, keeping a daily record

BNP = B-type natriuretic peptide; NT-proBNP = N-terminal pro hormone BNP. Jakubowiak AJ, et al. Hematology. 2017;22:585-591; Plummer C, et al. Blood Cancer J. 2019;9:26. 32 Factor Patient’s Treatment History and Comorbid Conditions Into Treatment Decisions

• Most patients are older and have preexisting comorbid conditions: up to 69% have preexisting CV disease • Consider response and toxicity with previous lines of therapy • Consider disease factors that increase risk of CV complications, including renal impairment and anemia • Factor possible CV and other toxicities with recommended treatments into treatment decisions

Plummer C, et al. Blood Cancer J. 2019;9:26. 33 Case Study (cont’d)

• Jean expresses a preference for oral treatment over repeated infusions ‒ You explain that ixazomib carries a small risk for grade 3 PN that carfilzomib does not have ‒ Jean still would prefer an all-oral regimen • She is prescribed ixazomib + PomD ‒ You recommend loperamide OTC to minimize diarrhea with treatment ‒ You and Jean create a dosing calendar to aid adherence with the dosing schedule of her different medications

34 Example of Calendar for All-Oral Regimen

28-Day Cycle (4-Week Cycle)

Week 1 Week 2 Week 3 Week 4

Treatment Day 1 Days 2-7 Day 8 Days 9-14 Day 15 Days 16-21 Day 22 Days 23-28

Ixazomib Yes ✓ No Yes ✓ No Yes ✓ No No No

Pomalidomide Yes ✓ Daily ✓ Yes ✓ Daily ✓ Yes ✓ Daily ✓ No No

Dexamethasone Yes ✓ No Yes ✓ No Yes ✓ No Yes ✓ No

Ninlaro [prescribing information]. Takeda; 2020; Pomalyst [prescribing information]. Celgene; 2019. 35 Myelosuppression: Frequent With IMiDs and mAbs*

• Expect cytopenia to occur and manage patient expectations • Increased risk of infection, poorer QoL, and treatment interruption • Use transfusions and growth factors as appropriate

Criteria Lenalidomide Criteria Pomalidomide • Platelets <30K/mcL • Interrupt treatment; • Platelets <25K/mcL • Interrupt treatment; • Recovery ≥30K/mcL follow CBC weekly • Recovery >50K/mcL follow CBC weekly • Resume at next lower • Resume at 3 mg/day dose** • ANC <500/mcL or • Interrupt treatment; • ANC <1K/mcL • Interrupt treatment; febrile neutropenia follow CBC weekly • Recovery ≥1K/mcL follow CBC weekly • Recovery ≥500/mcL • Resume at 3 mg/day • Resume at 25 mg or • Subsequent drops in • Interrupt; with recovery starting dose** platelets or ANC resume at 1 mg less than • Subsequent drops in • Interrupt; with recovery previous dose platelets or ANC resume next lower dose

*Dose modifications for myelosuppression are not indicated with mAbs; **Do not use dose <2.5 mg/day. Darzalex [prescribing information]. Janssen; 2019; Empliciti [prescribing information]. Bristol-Myers Squibb; 2019; Pomalyst [prescribing information]. Celgene; 2019; Revlimid [prescribing information]. Celgene; 2019. 36 Toxicity Management

Side Effect Clinical Management Cardiopulmonary • Assess risk at baseline • Provide patients/caregivers with contact info and guidelines for reportable signs/symptoms, along with prevention and treatment strategies Constipation • Hydration, diet, stool softeners/laxatives Diarrhea • Hydration, diet, antidiarrheal agents, dose modify if needed Fatigue • Counsel patients on exercise, sleep, stress reduction; assess and treat for depression, if indicated; review concurrent meds Rash • Treat symptoms with topical agents and antihistamines • Discontinue drug for rare severe drug reactions Peripheral neuropathy • Educate patients on early symptoms and reporting to medical staff • Modify bortezomib dose per prescribing information for peripheral neuropathy grade ≥2

Brigle K, et al. Clin J Oncol Nurs. 2017;21(5 Suppl):60-76; Catamero D, et al. Clin J Oncol Nurs. 2017;21(5 Suppl):7-18; Faiman B, et al. Clin J Oncol Nurs. 2017;21(5 Suppl):19-36; Kurtin SE, Bilotti E. J Adv Pract Oncol. 2013;4:307-321; Noonan K, et al. Clin J Oncol Nurs. 2017;21(5 Suppl):37-46; Velcade [prescribing information]. Millennium Pharmaceuticals; 2019. 37 Toxicity Management (cont’d)

Side Effect Clinical Management Thromboembolic events • Baseline risk assessment, including personal and family history Risk factors: • For patients receiving IMiDs: • Older age − Low risk (<2 risk factors): full-dose aspirin • History of thrombotic event − High risk (≥2 risk factors) or IMiD combined with high-dose dexamethasone: • Obese LMWH or full-dose warfarin (target INR 2-3) • Immobilized • Educate patients on preventive strategies and early detection • CV/renal disease • Can consider DOACs, although not well studied in this population • Diabetes

Infusion reactions • Premedicate according to prescribing information • Ensure a hypersensitivity reaction protocol is in place

DOAC = direct oral anticoagulants; INR = international normalized ratio; LMWH = low-molecular-weight heparin. Gleason C, et al. J Adv Pract Oncol. 2016;7(suppl 1):53-57; Kurtin SE, Bilotti E. J Adv Pract Oncol. 2013;4:307-321; NCCN Guidelines. Cancer-associated venous thromboembolic disease. www.nccn.org. Accessed Mar 24, 2020; NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020; Noonan K, et al. Clin J Oncol Nurs. 2017;21(5 Suppl):37-46. 38 Treatment Considerations: Special Populations

Patient Population Considerations Frail, elderly patients • Standard 3-drug regimens; use dose reductions to improve tolerability • Alternate: doublet therapy with Rd or use melphalan/bortezomib/prednisone Renal dysfunction • Bortezomib + IMiD: no dose adjustment needed with pomalidomide; adjust lenalidomide based on CrCl • Other options: bortezomib/daratumumab with high-dose dexamethasone or melphalan/bortezomib/prednisone Cardiac dysfunction • Avoid carfilzomib with preexisting uncontrolled hypertension or advanced HF • Use thromboprophylaxis with IMiD-based therapy Aggressive, high-risk • Consider induction with carfilzomib/Rd disease • Consider VTD-PACE and ASCT for extramedullary disease or PCL Peripheral neuropathy • Administer bortezomib SC using weekly dosing • Treatment with carfilzomib or ixazomib plus Rd

CrCl = creatinine clearance; VTD-PACE = bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide; PCL = plasma cell leukemia. NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020; Richter J, et al. Hematol Oncol. 2017;35:246-251. 39 Infection Prophylaxis

• Keep current on appropriate vaccinations, including annual flu vaccine ̶ Inactivated vaccines are safe for use • Herpes prophylaxis when receiving PIs or mAbs: acyclovir, famciclovir, valacyclovir ‒ HSV: consider during active therapy, possibly longer ‒ Herpes zoster (VZV): at least 6 to 12 months after ASCT; safe to use inactivated vaccine (Shingrix) in patients with MM • PJP/herpes/antifungal prophylaxis if using high-dose dexamethasone • Pneumococcal vaccine: PCV13, then PPV23 1 year later • IVIG in setting of recurrent, life-threatening infections • Counsel patients to alert treating clinicians to potential infection symptoms, to reduce unnecessary antibiotics

HSV = herpes simplex virus; IVIG = intravenous immunoglobulin; PCV = pneumococcal conjugate vaccine; PJP = Pneumocystis jiroveci pneumonia; PPV = pneumococcal polysaccharide vaccine; VZV = varicella zoster virus. Delforge M, et al. Blood. 2017;129:2359-2367; NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020; NCCN Guidelines. Infection prevention. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020. 40 Supportive Care for Bone Disease

NCCN: All patients should receive bisphosphonates or denosumab

• Bisphosphonates: pamidronate and zoledronic acid ‒ Similar efficacy, greater ONJ risk with zoledronic acid ‒ Monitor for renal impairment on bisphosphonates • SC denosumab preferred when renal disease is present ‒ May be given monthly; efficacy similar to zoledronic acid • Other supportive care ‒ Baseline dental exam and ONJ monitoring for all patients using a bone-modifying therapy ‒ Orthopedic consult if long-bone fracture present or imminent; consider vertebroplasty or kyphoplasty for vertebral compression fracture

ONJ = osteonecrosis of the jaw. NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 23, 2020 41 Other Supportive Care Recommendations

Condition Adjunctive Treatment

Hypercalcemia • Hydration, bisphosphonates (zoledronic acid preferred), denosumab, steroids, and/or calcitonin Anemia • Perform type and screen before using daratumumab if transfusions indicated

Liver function • Monitor for hepatotoxicity with PIs, IMiDs, daratumumab

Renal • Monitor patients on carfilzomib for acute renal failure dysfunction • Monitor renal function in patients on bisphosphonates • Adequate hydration • Plasmapheresis (although not generally useful) • Avoid NSAIDs, intravenous contrast

NSAIDs = nonsteroidal anti-inflammatory drugs. NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020 42 Assess Toxicity Risk and Implement Management Strategies

• Evaluate patient for unresolved toxicities • Evaluate risk for new or progressive toxicities with continued treatment • Incorporate recommended prophylaxis – Low-dose aspirin for thromboprophylaxis with IMiDs – Herpes prophylaxis prior to PIs or mAbs • Manage and minimize the severity of toxicities as appropriate • Use supportive care for myeloma-related conditions • Educate patients and caregivers about how they can take an active role in managing potential toxicities

Kurtin SE, Bilotti E. J Adv Pract Oncol. 2013;4:307-321; NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020; Trudel S, et al. OncoTargets Ther. 2019;12:5813-5822. 43 At Each Step, Consider All Possible Treatment Strategies

• Repeat previously effective drugs in new combinations and/or consider totally new combinations • Triple regimens preferred; consider doublets for frail patients • Include next-generation agent from same class or ≥1 new class ‒ Progression on a combination does not necessarily mean the individual drugs will be ineffective in combination with other agents ‒ Treatments that are ineffective alone are often effective when combined • Use drugs to which the patient has not been exposed • Refer patients for clinical trials where appropriate

44 Novel Approaches for RRMM

Drug Description FDA Status Clinical Trials Results in RRMM Selinexor Oral nuclear Accelerated approval for Phase 2B trial (STORM): selinexor 80 mg plus dex export protein RRMM after ≥4 prior lines • N = 123 patients refractory to ≥3 prior therapies XPO1 inhibitor of therapy (incl. 2 PIs, 2 • ORR (≥PR) = 26% (including 2 stringent CR) IMiDs, and an anti-CD38 mAB) • AE: fatigue, nausea, grade 3-4 thrombocytopenia Venetoclax for BCL-2 inhibitor Approved in other Phase 3 RCT (BELLINI): venetoclax + Vd vs Vd t(11,14) cancers • N = 291; ≤3 prior therapies translocation • All patients: 61% ≥VGPR (vs 40%), MRD– :13% vs 1% • t(11,14)+ patients: 75% ≥VGPR (vs 27%); MRD– : 25% vs 0 • Grade ≥3 AEs: thrombocytopenia, anemia Isatuximab Anti-CD38 mAb Approved for patients with Phase 3 RCT (ICARIA-MM): Isatuximab + PomD vs PomD ≥2 prior lines of therapy, • N = 307; ≥2 prior therapies including lenalidomide • Improved PFS (primary end point): 11.5 months vs 6.5 months and a PI • Other phase 3 RCT with Kd and VRd ongoing

ORR = overall response rate Attal M. et al. Lancet. 2019;394:2096-2107; Chari A, et al. N Engl J Med. 2019;381:727-738; Kumar S, et al. Blood. 2017;130:2401-2409; Mikhael J, et al. Blood. 2019;134:123-133; Moreau P, et al. ASH 2019: Abstract 653; Richardson PG, et al. Future Oncol. 2018;14:1035-1047; Sarclisa. [prescribing information]. Sanofi-aventis US; 2020; Xpovio [prescribing information]. Karyopharm Therapeutics; 2019. 45 On the Horizon: BCMA-Targeted Agents in RRMM

Drug Description FDA Status Current Research Results in RRMM Belantamab Immunoconjugate Investigational, Phase 2 (DREAMM-2): dose-ranging (2.5 & 3.4 mg), single agent mafodotin targeting BCMA granted priority review • N = 196; RRMM after ≥3 prior therapies; triple refractory Jan 2020 • Overall RR: 31% with 3.4 mg, 34% with 2.5 mg • Grade ≥3 AE: keratopathy, thrombocytopenia, anemia Phase 1 (DREAMM-1): ≥PR: 60%; median PFS = 12 mo Toxicities: Thrombocytopenia, corneal events: manage with supportive care Idecabtagene BCMA CAR T cell Investigational, Phase 2 (KarMMa): dose-ranging study vicleucel has breakthrough • N = 128; RRMM after ≥3 prior therapies; 84% triple-refractory (ide-cel) therapy designation • Overall RR (all patients) = 73.4% (31.3% CR); 81.5% at highest dose Nov 2017 • Grade ≥3 AEs: CRS (5.5%), neurotoxicity (3.1%) Phase 1: ORR = 85% (45% CR); median PFS = 11.8 mo Toxicities: • CRS: manage with antipyretics, hydration, tocilizumab +/- dex • ICANS: manage with seizure prophylaxis or treatment; monitor for severe symptom development

BCMA = B cell maturation antigen; CAR = chimeric antigen receptor; CRS = cytokine release syndrome; ICANS = immune-effector cell neurotoxicity syndrome. Bristol-Myers Squibb. news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-and-bluebird-bio-announce-positive-top-li. Accessed Mar 24, 2020; Lonial S, et al. Lancet Oncol. 2020;21:207-221; Mikhael J. Clin Lymphoma Myeloma Leuk. 2019;1:1-7; Raje N, et al. N Engl J Med. 2019;380:1726-1737; Trudel S, et al. Blood Cancer J. 2019;9:37; Wang BY, et al. ASH 2019: Abstract 579; Zhao WH, et al. J Hematol Oncol. 2018;11:141. 46 Relapsed/Refractory Multiple Myeloma: Summary

• Relapse is still inevitable in MM • Current treatment strategies prolong DOR/PFS at each step of care ‒ Triplet therapies: PI + IMiD + Dex; combinations with PomD and/or mAbs ‒ ASCT for eligible patients, front-line or delayed ‒ Maintenance therapy after consolidation with lenalidomide or bortezomib • Longer survival underscores need to proactively manage disease- and treatment- related toxicities • For patients using oral agents, institute strategies to maintain adherence with sometimes complicated dosing schedules

47 PCE Action Plan

✓ Confirm and characterize a relapse before changing or reinitiating therapy ✓ Choose a regimen based on patient goals as well as balancing efficacy and safety ✓ Consider previous history and be proactive in anticipating issues with subsequent lines of treatment ✓ Evaluate toxicity risk and implement clinical management strategies ✓ Consider all possible treatment strategies, using patient and disease factors to guide subsequent lines of treatment

PCE Promotes Practice Change

48 2020 Spring Oncology Conference