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

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• 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

Learning Objectives

AE = adverse event.

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• 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

Multiple Myeloma

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.

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Progress in Treating Multiple Myeloma

OS = overall survival; XPO1 = exportin 1. Adapted with permission from Anderson KC. Clin Cancer Res. 2016;22:5419-5427.

Improvement in OS From Median

• f 3 to 8 to 10 Years

Preclinical and Clinical Studies Leading to FDA Approvals in MM Proportion Surviving Follow-up From Diagnosis (years)

2005 2010 2015

2003, 2005, 2008 Bortezomib (BTZ) 2012, 2015 Carfilzomib

2015 Ixazomib

1960-65 1965-70 1970-75 1975-80 1980-85 1985-90 1990-95 1995-00 2000-05 2005-10 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 2020 0 2 4 6 8 10 12 14 16 18 20 2006 Thalidomide 2013, 2015 Pomalidomide 2006, 2014 Lenalidomide Immunomodulatory agent Proteasome inhibitor 2012, 2015 Carfilzomib

2015 Ixazomib 2003, 2005, 2008 Bortezomib (BTZ) 2007 Doxil + BTZ 2019 Selinexor XPO1 inhibitor 2015 Panobinostat HDAC inhibitor 2020 Isatuximab 2015 Elotuzumab 2015 Daratumumab Monoclonal antibody

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M-Protein Level →

Asymptomatic Symptomatic Relapsing Refractory

← 2-3 years → ← 1-2 years → ← 1-2 years → ← 6 months-1 year →

MGUS or indolent myeloma Active myeloma Remission Relapse 1st-line therapy 2nd- or 3rd- line therapy 4th-line therapy

Disease may respond or become refractory at any point

4th-20th-line therapy

Myeloma Can Be Treated, But Not Cured

MGUS = monoclonal gammopathy of unknown significance. Adapted from: Durie BGM. www.myeloma.org/sites/default/files/images/publications/UnderstandingPDF/concisereview.pdf. Accessed Mar 23, 2020.

Relapse

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Response Duration With Subsequent Lines of Treatment

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Response and Survival in RRMM

EFS = event-free survival. Kumar SK, et al. Leukemia. 2012;26:149-157; Kumar SK, et al. Mayo Clin Proc. 2004;79:867-874.

Patients (%)

12 24 36 48 60

Months

10 8 2 First Second Third Fourth Fifth Sixth

Treatment Regimen Median Response Duration (months)

4 OS EFS Events, n/N 170/286 217/286 Median, Months (range) 9 (7-11) 5 (4-6)

Survival Outcomes

100 80 60 40 20 6

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International Myeloma Working Group: Standard Response Criteria

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.

Criteria Definition

MRD-negative In patients who have achieved ≥CR, MRD negative in bone marrow by NGS plus disappearance of areas

• f 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 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

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Major Classes of Treatment Used in Multiple Myeloma

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. 2011;364:1046-1060.

IMiDs PIs mAbs Others

Agents in class (abbreviation)

• Lenalidomide (R)
• Pomalidomide (P)
• Thalidomide (T)
• Bortezomib (V)
• Carfilzomib (K)
• Ixazomib (N, I)
• Daratumumab (D)
• Isatuximab
• Elotuzumab (E)
• HDI: Panobinostat (F)
• XPO1: Selinexor

Mechanism of action

• Antiangiogenic and

anti-inflammatory properties

• CD-4+/CD-8+ T-cell

enhancement

• NK cell

augmentation

• Promote apoptosis
• Inhibit osteoclast

formation

• Increase osteoblast

creation and function

• Daratumumab

and Isatuximab: CD38-mediated apoptosis

• Elotuzumab:

SLAMF7-mediated NK cell enhancement

• Panobinostat:

Damages DNA and upregulates apoptosis- promoting proteins

• Selinexor: Inhibits

growth and promotes apoptosis by blocking actions of XPO1

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Current Treatment Paradigm for Active Myeloma

SCT = stem-cell transplant.

Tumor Burden Maintenance SCT Eligible SCT Ineligible

Diagnosis and Risk Stratification

Induction Followed by Continuous Maintenance Therapy

Managing Relapse

SCT/Consolidation Induction

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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

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

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

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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

ECOG PS = Eastern Cooperative Oncology Group performance status; PN = peripheral neuropathy.

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

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• 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)

MM Cytogenetic Changes Over Time May Impact Prognosis

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.

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Standard Risk High Risk**

• All others, including:

– Trisomies – t(11:14)* – t(6:14) High-risk genetic abnormalities by FISH or equivalent

• t(4:14)
• t(14:16)
• t(14:20)
• del(17p)
• p53 mutation
• 1q gain
• RISS stage 3
• High plasma-cell S phase
• Gene expression profiling:

High-risk signature

• Double-hit: any 2 high-risk

genetic abnormalities

• Triple-hit: ≥3 high-risk

genetic abnormalities

mSMART: Risk Classification of MM

*t(11;14) may be associated with plasma cell leukemia; **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.

Jean at diagnosis Jean now

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Relapse Patterns in Multiple Myeloma

Alegre, et al. Haemotologica. 2002; 87:609-614.

Clinically symptomatic disease with increase in M-protein Extramedullary disease Plasma cell leukemia Asymptomatic disease characterized by increase in M-protein Four patterns

• f relapse

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• 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

Biochemical Relapse: IMWG Criteria

*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.

Biochemical relapse identified due to improved monitoring can catch progression before development of clinical symptoms

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≥1 of the following:

• CRAB features
• Size* increase in existing (or development
• f new) soft tissue plasmacytomas or

bone lesions (not new osteoporotic fractures)

• Hgb reduction ≥2 g/dL unrelated to MM

therapy or other conditions

• Serum creatinine increase ≥2 mg/dL

attributable to MM

• Hyperviscosity related to serum paraprotein

Clinical Relapse: IMWG Criteria

*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.

CRAB criteria: a mnemonic for myeloma-related organ dysfunction: C = calcium elevation: >11.5 mg/dL R = renal disease: serum Cr >2 mg/dL A = anemia: Hgb <10 g/dL or >2 g/dL below LLN B = bone lesions: ≥1 osteolytic lesion

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• 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

IMWG: High-Risk Disease Characteristics in Relapsed or Relapsed/Refractory Disease

LDH = lactate dehydrogenase. Dingli D, et al. Mayo Clin Proc. 2017;92:578-598; Laubach J, et al. Leukemia. 2016;30:1005-1017.

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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)

IMWG: Principles of Treating Progressive Disease

Laubach L, et. al Leukemia. 2016;30:1005-1017.

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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

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• 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
• r intolerability

Selecting Treatment for RRMM: General Principles

*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.

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Establish the Goals of Treatment for the Patient

• Balance treatment efficacy with

impact on QoL − May not need a regimen with a high CR rate − Stable disease is an excellent goal of therapy for many patients with RRMM ‒ Little difference in clinical consequences between stable disease and CR

QoL = quality of life.

Disease characteristics

• Cytogenetics
• CRAB present
• Extramedullary disease
• Aggressive features
• Short DOR

Patient characteristics

• Goals of treatment
• Age/frailty
• Performance status
• Lifestyle/mobility
• Comorbidities

Prior therapy

• Prior ASCT?
• Prior IMiDs? PIs?
• Depth/DOR
• Time to progression?
• Toxicities

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≥1 or 1 to 3 Prior Courses

≥1: Carfilzomib monotherapy (PX-171–003; FOCUS) 1-3: Carfilzomib + lenalidomide + dexamethasone (ASPIRE) 1-3: Carfilzomib, dexamethasone (ENDEAVOR) ≥1: Daratumumab + either lenalidomide or bortezomib + dexamethasone (POLLUX & CASTOR) ≥1: Ixazomib + lenalidomide + dexamethasone (TOURMALINE-MM1) 1-3: Elotuzumab + lenalidomide + dexamethasone (ELOQUENT- 2)

Recent FDA Approved Agents and Combinations

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.

≥2 Prior Courses

Daratumumab + pomalidomide + dexamethasone Isatuximab + pomalidomide + dexamethsone Elotuzumab + pomalidomide + dexamethasone (ELOQUENT-3) Pomalidomide + dexamethasone Panobinostat + bortezomib + dexamethasone (PANORAMA-1)

≥3 or ≥4 Prior Courses

≥3: Daratumumab monotherapy (SIRIUS) ≥4: Selinexor + dexamethasone (STORM)

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Summary: mSMART Recommended Approaches After First Relapse

*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.

On Maintenance* Triplet Preferred: Add ≥1 New Agent, or Next Generation Agent From Same Class

Fit Patients Indolent Relapse

• r Frail Patients

If lenalidomide maintenance:

• KPomD
• DaraVd

If bortezomib maintenance:

• DaraRd

If lenalidomide maintenance:

• DaraVd
• Id + cyclophosphamide

If bortezomib maintenance:

• IRd
• DaraRd

Off Therapy/Unmaintained*

Fit Patients Indolent Relapse

• r Frail Patients
• KRd
• DaraRd
• IRd
• EloRd
• PomD

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Ranking of Treatments Based on Meta-analysis Results

Botta C, et al. Blood Adv. 2017;1:455-466.

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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

• f 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

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• 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

Relapsed vs Refractory Disease

Nooka AK, et al. Blood. 2015;125:3085-3099.

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Administration Considerations for PIs

*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 = complete blood count; 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.

Bortezomib (V) Carfilzomib (K) Ixazomib (N, I)

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

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Administration Considerations for mAbs

*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.

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

Route* IV IV AE prophylaxis Pre/post medication with corticosteroids, antipyretics, and antihistamines; oral steroid may not be needed after infusion if used in combinations that include dexamethasone ± Inhaled steroids for patients with COPD (Dara) 60 to 90 min before infusion, administer corticosteroids, H1 blocker, H2 blocker, acetaminophen Select AEs to assess Infusion reactions Interference with cross-matching, red blood cell antibody screening, and determination of CR Infection** Neutropenia, thrombocytopenia Infusion reactions Infection** Second primary malignancy Hepatotoxicity Interference with determination of CR Management considerations For infusion reaction risk, pre/post medicate as directed; interrupt infusion if reaction occurs 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)

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Administration Considerations for XPO1 Inhibitor

URI = upper respiratory infection. Xpovio [prescribing information]. Karyopharm Therapeutics; 2019.

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, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and URI Select AEs to assess Thrombocytopenia Neutropenia Considered highly emetogenic; GI adverse reactions, especially nausea Hyponatremia Infections Management considerations Monitor patients for cytopenia, neutropenia, hyponatremia, infections 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)

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• 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)

Cardiotoxicity With PIs: Is This a Class Effect?

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.

Bortezomib Carfilzomib Ixazomib

• MoA: Reversible PI inhibition

Analysis of 8 myeloma studies (N = 3954), Grade ≥3 with bortezomib:

• HF: 1.3% to 4.7%
• Arrhythmia: 0.6% to 4.1%
• Ischemic HD: 0.4% to 2.7%
• Cardiac death: 0 to 1.4%
• No significant differences between

bortezomib and placebo patients

• MoA: Irreversible PI inhibition

ENDEAVOR (phase 3, N = 929)

• Grade ≥3 hypertension
• 9% carfilzomib, 3% bortezomib
• Any grade hypertension
• 20.3% carfilzomib, 8.1% bortezomib
• MoA: Reversible PI inhibition

TOURMALINE Grade ≥3 CVAE:

• N = 361 IRd; 359 Rd patients
• Arrhythmia: 6%; 4%
• Thromboembolism: <3%; <4%
• HF: 3%; 2%
• MI: <1%; <2%

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Strategy Suggestions

Baseline CV risk assessment and

• ngoing

monitoring

• Assess risk, obtain ECG, and determine need for cardiology consultation
• Control hypertension
• 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

Assessing for Cardiotoxicity: Proactive Monitoring and Clinical Management of CV Events With Carfilzomib

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.

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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.

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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

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28-Day Cycle (4-Week Cycle)

Treatment Week 1 Week 2 Week 3 Week 4

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

Example of Calendar for All-Oral Regimen

Ninlaro [prescribing information]. Takeda; 2020; Pomalyst [prescribing information]. Celgene; 2019.

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

Myelosuppression: Frequent With IMiDs and mAbs*

*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.

Criteria Lenalidomide

• Platelets <30K/mcL
• Recovery ≥30K/mcL
• Interrupt treatment;

follow CBC weekly

• Resume at next lower

dose**

• ANC <1K/mcL
• Recovery ≥1K/mcL
• Interrupt treatment;

follow CBC weekly

• Resume at 25 mg or

starting dose**

• Subsequent drops in

platelets or ANC

• Interrupt; with recovery

resume next lower dose

Criteria Pomalidomide

• Platelets <25K/mcL
• Recovery >50K/mcL
• Interrupt treatment;

follow CBC weekly

• Resume at 3 mg/day
• ANC <500/mcL or

febrile neutropenia

• Recovery ≥500/mcL
• Interrupt treatment;

follow CBC weekly

• Resume at 3 mg/day
• Subsequent drops in

platelets or ANC

• Interrupt; with recovery

resume at 1 mg less than previous dose

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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

Toxicity Management

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.

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Toxicity Management (cont’d)

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.

Side Effect Clinical Management

Thromboembolic events Risk factors:

• Older age
• History of thrombotic event
• Obese
• Immobilized
• CV/renal disease
• Diabetes
• Baseline risk assessment, including personal and family history
• For patients receiving IMiDs:

− Low risk (<2 risk factors): full-dose aspirin − High risk (≥2 risk factors) or IMiD combined with high-dose dexamethasone: LMWH or full-dose warfarin (target INR 2-3)

• Educate patients on preventive strategies and early detection
• Can consider DOACs, although not well studied in this population

Infusion reactions

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

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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
• n 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 disease

• Consider induction with carfilzomib/Rd
• 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

Treatment Considerations: Special Populations

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.

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• 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

Infection Prophylaxis

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.

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• 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

Supportive Care for Bone Disease

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

NCCN: All patients should receive bisphosphonates or denosumab

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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 dysfunction

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

Other Supportive Care Recommendations

NSAIDs = nonsteroidal anti-inflammatory drugs. NCCN Guidelines. Multiple myeloma. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020

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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.

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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

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Drug Description FDA Status Clinical Trials Results in RRMM

Selinexor Oral nuclear export protein XPO1 inhibitor Accelerated approval for RRMM after ≥4 prior lines

• f therapy (incl. 2 PIs, 2

IMiDs, and an anti-CD38 mAB) Phase 2B trial (STORM): selinexor 80 mg plus dex

• N = 123 patients refractory to ≥3 prior therapies
• ORR (≥PR) = 26% (including 2 stringent CR)
• AE: fatigue, nausea, grade 3-4 thrombocytopenia

Venetoclax for t(11,14) translocation BCL-2 inhibitor Approved in other cancers Phase 3 RCT (BELLINI): venetoclax + Vd vs Vd

• N = 291; ≤3 prior therapies
• 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 ≥2 prior lines of therapy, including lenalidomide and a PI Phase 3 RCT (ICARIA-MM): Isatuximab + PomD vs PomD

• N = 307; ≥2 prior therapies
• Improved PFS (primary end point): 11.5 months vs 6.5 months
• Other phase 3 RCT with Kd and VRd ongoing

Novel Approaches for RRMM

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.

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Drug Description FDA Status Current Research Results in RRMM

Belantamab mafodotin Immunoconjugate targeting BCMA Investigational, granted priority review Jan 2020 Phase 2 (DREAMM-2): dose-ranging (2.5 & 3.4 mg), single agent

• N = 196; RRMM after ≥3 prior therapies; triple refractory
• 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 vicleucel (ide-cel) BCMA CAR T cell Investigational, has breakthrough therapy designation Nov 2017 Phase 2 (KarMMa): dose-ranging study

• N = 128; RRMM after ≥3 prior therapies; 84% triple-refractory
• Overall RR (all patients) = 73.4% (31.3% CR); 81.5% at highest dose
• 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

On the Horizon: BCMA-Targeted Agents in RRMM

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.

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• 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

Relapsed/Refractory Multiple Myeloma: Summary

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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

2020 Spring Oncology Conference