optimal treatment sequencing for patients with relapsed

Optimal treatment sequencing for patients with relapsed/refractory multiple myeloma

Ajai Chari, MD

Associate Professor of MedicineDirector of Clinical Research

Icahn of School Medicine at Mount Sinai

2

▶

Disclosures

Nature of Relevant Financial Relationship Commercial Interest

Grant or research support Amgen, Array Biopharma, Celgene, Millenium/Takeda, Novartis Pharmaceuticals,

Janssen, PharmacyclicsPaid consultant Amgen, Celgene, Millenium/Takeda, Novartis

Pharmaceuticals, Janssen, Karyopharm, Sanofi

3

Steroids ConventionalChemo

ImIDs ProteasomeInhibitors

HDAC inhibitors

Immunologic approaches

Prednisone Melphalan Thalidomide Bortezomib Panobinostat Daratumumab: anti CD38

Dexamethasone Cyclophosphamide Lenalidomide Carfilzomib(low/high dose)

Elotuzumab :anti CS1/SLAMF7

Doxil Pomalidomide Ixazomib

DCEP/D-PACE

METRO28

BCNU

Bendamustine

Innumerable Combinations and Sequences of Anti- Myeloma Agents

Overview

1. First Relapse 1. Lenalidomide Backbone Randomized Studies2. Bortezomib Backbone Randomized Studies 3. High risk disease

2. Second and Third Relapse3. Fourth Relapse and beyond4. Cardiovascular Risk in Multiple Myeloma

PATIENT DISEASE TREATMENT

• Age/Frailty

• Performance Status

• Lifestyle/Pt preferences

• Drug Metabolism

• Compliance/Adherence

• Caregiver support

• Renal Insufficiency

• Comorbidities

– Neuropathy

– Cardiac

– Diabetes

– Low blood counts

Burden • ISS/LDH

• Marrow burden

• Biochemical vs CRAB symptoms

• Rate of progression• Extramedullary

Biology - LDH elevation

- Molecular - Del[17p], t(4;14)

•

Access/Trial AvailabilityIf Previously Treated• Depth/duration

• Relapse > 60d vs progression

Toxicity • Myelosuppresion• Neuropathy• VTE• Secondary cancers

Administration Route

Single or Combination

Cost and Copays

Factors in Selecting MM Therapy

Single Agent and Doublet Efficacy are Modest

Trial Phase nIMiD

exposedPI

exposed ORRPFS

(months)OS

(months)

Thalidomide 2 169 0% 0% 30% 2y : 20% 2y : 48%BTZ vs DEX 3 669 49% 0% 38% 6.22 30

BTZ vs Vdoxil 3 646 41% 0% 43% 9.3 33LenDex MM009 3 177 41% 10% 61% 11.1 29.6LenDex MM010 3 349 30% 4.5% 60% 11.3 38CFZ (+dex 8) 2 266 100% 99% 23.7% 3.7 15.6 Pom D vs Dex 3 302 100% 95% 31% 4.2 13.1Dara 2 106 100% 100% 29.2% 3.7 17.5

Barlogie, B., (2001). Blood 98(2): 492-494.Richardson, P. (2005). NEJM 352(24): 2487-2498.Orlowski RZ, (2007) JCO: 25:3892-3901.Weber, D. (2007). NEJM 357: 2133-2142

Dimopoulos, M.(2007). NEJM 357: 2123-2132Siegel, D. S (2012). Blood 120: 2817-2825.San Miguel J, (2013). Lancet Oncol. 14:1055-1066Lonail (2016). Lancet. 387: 1551-1560

Randomized Studies in Early Relapse1–3 lines of Prior Therapy

• Cross trial comparisons should not be done as– Patient populations are different– Disease burden and high-risk genetics are different– Prior therapy exposures are different– As a result, outcomes of identical control arms vary

significantly between trials• Study design – duration of planned therapy – can

differ• Choice of PI- or IMiD-based partner depends on prior

treatment• Triplets consistently perform better than doublets

Measure of PFS/OS Across the Entirety of the Study Duration: Hazard Ratio

Use/Benefits

• Estimates the risk of progression and/or death in investigational arm vs control arm at any given point in a study1*

• HR is assumed to remain constant over time, so it can be used to encapsulate the overall benefit of one arm vs another across the study population and throughout the entire study period1

• Visualized as the difference between the two curves of a Kaplan-Meier survival plot2

Limitations

• Relative measure that is not immediately associated with a concrete value or unit of time1,3

Hypothetical Kaplan-Meier curve.*A log-rank test is conducted to determine statistical significance

between arms (represented by a P value).

1. Spruance SL et al. Antimicrob Agents Chemother. 2004;48:2787.2. Brody T. Biostatistics. In: Clinical Trials: Study Design, Endpoints and Biomarkers, Drug Safety, and FDA and ICH Guidelines. London:Academic Press; 2012:165.

3. Blagoev KB et al. Nat Rev Clin Oncol. 2012;9:178. 4. Bland JM, Altman DG. BMJ. 2004;328:1073.

1.00.90.80.70.60.50.40.30.20.10.0

Prob

abilit

y of

PFS

/OS

0 3 6 9 12 15 18 21 24 27 30 33 36Time, Months

Medianduration

Hazard ratio/relative risk reduction

measures the magnitude of the difference between

the two curves of a Kaplan-Meier plot2*

Time point analyses

Randomized Studies With Lenalidomide-Dex Control Arms: Patient Characteristics

Daratumumab Elotuzumab Carfilzomib Ixazomib

NDRd vs Rd

569ERd vs Rd

646KRd vs Rd

792IRd vs Rd

722Baseline characteristicsMedian age 65 65 64 66

ISS 3 20% 21% NR 12%

High-risk FISH 16% 30% 13% 19%

Median Lines 1 2 2 1

Refractory to PI 17% 22% 0% 2%

Refractory to IMiD 4% 10% 22% 23%

Refractory to last line 27% 35% NR 16%

Dimopoulos MA et al. N Engl J Med. 2016;375:1319; Dimopoulos MA et al. Br J Haematol. 2017;178:896; Stewart AK et al. N Engl J Med. 2015;372:142; Stewart AK et al. Blood. 2017;130: Abstract 743.; Dimopoulos M et al. J Hematol Oncol. 2018;11:49; Moreau P et al. N Engl J Med. 2016;374:1621.

In all studies, novel triplet given until progression except KRd where K givenD 1,2,8,19,15,16 for 12 cycles then D1,2,15,16 for 6 cycles then K d/c’d.

• All off-label contents are independent of the company’s view except for the scientific exchange.

Randomized Studies With Lenalidomide-Dexamethasone Control Arms

Carfilzomib* Elotuzumab Daratumumab Ixazomib

NKRd vs Rd

792ERd vs Rd

646DRd vs Rd

569IRd vs Rd

722

Efficacy Tx Control Tx Control Tx Control Tx Control

Median follow up, mos 67 Min 48 mos 32.9 23

ORR 87.1% 66.7% 79% 66% 93% 76% 78.3% 71.5%

CR 32% 9.3% 5% 9% 55% 23% 12% 7%

Median PFS, mos 26 16.6 19 14.9 NR 17.5 21 14.7

PFS HR (95% CI) 0.69 (0.57–0.83) 0.71 (0.59–0.86) 0.44 (0.34–0.55) 0.74 (0.59–0.94)

Median OS, mos 48.3 40.4 48.3 39.6 NR NR NR NR

OS HR (95% CI) 0.79 (0.67–0.95) 0.78 (0.63–0.96) NR NR*PFS HR 0.58 @ 18 mos

Dimopoulos MA et al. N Engl J Med. 2016;375:1319; Dimopoulos MA et al. Br J Haematol. 2017;178:896; Stewart AK et al. N Engl J Med. 2015;372:142; Stewart AK et al. Blood. 2017;130: Abstract 743.; Dimopoulos M et al. J Hematol Oncol. 2018;11:49; Moreau P et al. N Engl J Med. 2016;374:1621.

PFS benefit can translate into OS benefit with adequate follow up (though drug access at relapse confounding issue).


Randomized Studies With Bortezomib-DexControl Arms: Patient Characteristics

Daratumumab Carfilzomib Panobinostat Elotuzumab Pomalidomide

NDVd vs Vd*

498Kd vs Vd

929FVd vs Vd

768EVd vs Vd†

152PVd vs Vd

559

Baseline Characteristics

Median age 64 65 63 65 67 68

ISS 3 20% NR 20% 18% 17% 18%

High-risk FISH 22% 22% NR NR 22% 18%

Median Lines 2 2 2 1 2

Refractory to PI 0% 0% 0% 0% 13%

Refractory to IMiD 33% 15% NR NR 71% 69%

Refractory to last line 32% NR 36% NR 70% 66%

Palumbo A et al. N Engl J Med. 2016;375:754; Spencer A et al. Haematologica. 2018; Sep 20 [epub ahead of print]; Dimopoulos MA et al. Lancet Oncol. 2016;17:27; San Miguel JF et al. Lancet Oncol. 2014;15:1195; Jakubowiak AJ et al. Blood. 2016;127:2833.; Richardson PG et al. J Clin Oncol. 2018;36: Abstract 8001.

*In all studies, VD in control arm given until PD except DVd vs VD where Vdcontinued only for eight 21 day cycles†Randomized phase 2


PFS benefit can translate into OS benefit with adequate follow up (though drug access at relapse confounding issue).

Randomized Studies With Bortezomib-Dexamethasone Control Arms

Pomalidomide Daratumumab* Carfilzomib Panobinostat Elotuzumab†

NPVd vs Vd

559DVd vs Vd

498Kd vs Vd

929FVd vs Vd

768EVd vs Vd

152

Efficacy Tx Control Tx Control Tx Control Tx Control Tx Control

Median follow up, mos 16 26.9 37.5 NR 15.9

ORR 82% 50% 85% 63% 76% 63% 55% 61% 66% 63%

CR 16% 4% 30% 10% 13% 6% 11% 6% 4% 3%

Median PFS, mos 11 7 16.7 7.1 18.7 9.4 12 8.08 9.7 6.9

PFS HR (95% CI) 0.61 (0.49–0.77) 0.32 (0.25–0.40) 0.53 (0.44–0.65) 0.63 (0.52–0.76) 0.72 (0.59–0.88)

Median OS, mos NR NR NR NR 47.6 40.0 40.3 35.8 NR NR

OS HR (95% CI) NR NR 0.79 (0.65–0.96) 0.94 (0.78–1.14) 0.61 (0.32–1.15)

Richardson PG et al. J Clin Oncol. 2018;36: Abstract 8001 Palumbo A et al. N Engl J Med. 2016;375:754; Spencer A et al. Haematologica. 2018; Sep 20 [epub ahead of print]; Dimopoulos MA et al. Lancet Oncol. 2016;17:27; San Miguel JF et al. Lancet Oncol. 2014;15:1195; Jakubowiak AJ et al. Blood. 2016;127:2833.;.


High Risk Disease

Lancman et al Clin Adv Heme & Onc. Oct 2017

Inferior survival based on currenthigh-risk molecular abnormalities

Worsened survival in high-risk patients receiving novel therapy

Improved survival in high-risk patients receiving novel therapy but still inferior to that of standard-risk

patients receiving novel therapy

High-risk status is overcome with novel therapy, and these

patients now have survivalequivalent to that of standard-

risk patients

Possible outcomes of a hypothetical Phase III study comparing a novel agent X to conventional therapy

Summary of High Risk Outcomes in Randomized Studies

Drug/StudyMolecular

Testing Methodology% Missing Molecular

DataPanobinostat Vd vs Vd (n=768) FISH (unspecified) 73.4%Carfilzomib Rd vs Rd (n=792) Centralized FISH (CD138-selected) 47.3%Daratumumab Rd vs Rd (n=569) Centralized NGS 45%Daratumumab Vd vs Vd(n=498) Centralized NGS 29%Ixazomib Rd vs Rd (n=722) Centralized FISH (CD138-selected) 24%Carfilzomib D vs Vd (n=929) Centralized FISH (unspecified) 6.4%

Elotuzumab Rd vs Rd (n=646) Centralized FISH (unspecified) 1.7%

Lancman G et al. Clin Adv Hematol Oncol. 2017;15:870.

• All novel agents improve PFS for high-risk patients, but still inferior to standard risk patients treated with novel therapies (ie high risk not overcome)

− Some data that PIs especially improve outcomes in t(4;14) • Future clinical trials should provide standard centralized risk assessments for all

patients and provide HRs for KM survival curves for high-risk vs standard-risk patients


Overview


2. Second and Third Relapse3. Fourth Relapse and beyond4. Cardiovascular Risk in Multiple Myeloma

Decreasing Response & Shorter Duration of Therapy With Each Subsequent Cycle of Therapy

Kumar et al. Unpublished data.Lohr JG et al. Cancer Cell. 2014;25;91.

70%

60%

50%

40%

30%

20%

10%

0%1 2 3 4 65

6

5

4

3

2

1

0

5.3

5.22.8

3.1

1.3

1.9

Ove

rall

(≥PR

) Res

pons

e R

ate

Regimen Number After TO

Duration of Therapy (M

onths)

58%

45%

30%

15%

0% 0%

Duration of therapy Response rate

PI + IMID + Dex (Triplet) Efficacy in Relapsed MM

Trial Phase nIMiD

ExposedIMiD

RefractoryPI

ExposedPI

Refractory ORRPFS

(mos)OS

(mos)

Bort Thal Dex 1–2 85 74% most 0% 0% 65% 6 22

Bort Len Dex 2 64 73% T6% L 3% 53% 8% 64% 9.5 30

Bort Pom Dex 1/21/2

2250

100%100%

100%100%

100%92%

NA17%

59%86%

NA13.7

NANR

Car-Len-Dex 2 52 73% 44% 80% 25% 77% 15.4 NA

Car-Pom-Dex 1/2 32 100% 100% 97% 94% 50% 7.2 20.6

Pineda-Roman M et al. Leukemia. 2008;22:1419; Richardson PG et al. Blood. 2014;123:1461; Richardson PG et al. Leukemia. 2017;31:2695; Paludo J et al. Blood. 2017;130:1198; Wang M et al. Blood. 2013;122:3122; Shah JJ et al. Blood. 2015;126:2284.

PI + IMID + Dex triplets result in superior efficacy relative to doublets.


Outcomes of Lenalidomide Refractory Patients in Randomized Studies With

Bortezomib-Dex Control Arms• Many recent phase 3 RRMM studies were len-based and excluded len-refractory patients• The increasing adoption of len maintenance highlights a need for large studies in len-

refractory RRMM

Lentzsch S et al. Presented at Japanese Society of Hematology 79th Annual Meeting; October 2017. Abstract OS3-12D-2; Moreau P et al. Leukemia. 2017;31:115; Dimopoulos MA et al. Lancet Oncol. 2016;17:27; Richardson PG et al. J Clin Oncol. 2018;36: Abstract 8001.

PFS of len refractory patients inferior to those of total study population.

Daratumumab* Carfilzomib Pomalidomide

N DVd vs Vd Kd vs Vd PVd vs Vd

N 251 247 464 465 281 278ORR 85% 63% 76% 63% 82% 50%Median PFS, months 16.7 7.1 18.7 9.4 11 7 PFS HR (95% CI) 0.32 (0.25–0.40) 0.53 (0.44–0.65) 0.61 (0.49–0.77)N = Len refractory 45 60 113 122 200 191ORR 81% 50%PFS 9.3 4.4 8.6 6.6 9.5 5.6PFS HR 0.36 (0.25–0.63) 0.80 (0.57–1.11) 0.65 (0.50–0.84)


Pomalidomide Approved for Lenalidomide-Resistant Myeloma

San Miguel Lancet 2013Dimpooulos Blood 2016Siegel ASCO 2018Mark ASH 2015Baz Blood 2016.

Larocca Blood 2013Chari ASH 2016Sivaraj Blood Can J 2018Shah Blood 2017

Chari Blood 2017Mikhael ASCO 2018Badros Blood 2017Mateos ASCO 2018 Dimopoulos EHA 2018

• Efficacy of pomalidomide improves as moves into earlier lines of therapy− Highlights need for randomized studies

Overview


2. Second and Third Relapse3. Fourth Relapse and beyond

1. VDCEP/VDTPACE2. Salvage stem cell transplant

4. Cardiovascular Risk in Multiple Myeloma

VDCEP/VDTPACE

• VDCEP = Velcade + Dex + Cytoxan + Etoposide + Platinum• VDTPACE = VDCEP + thalidomide + doxorubicin• N =141, median 4 lines of prior therapy, ORR 54.4%, median PFS 3.1 and OS 8.1 mos

• Use lower doses for cytopenic patients, concurrent XRT, poor KPS, renal insufficiency• Inpatient peripheral IV or port – latter mandatory with anthracycline• TLS prophylaxis and monitoring• GCSF support, gram negative antibiotic prophylaxis• Lab monitoring for transfusion support as clinically appropriate after 96 hours complete

- tiw to q week

Induction Consolidation

Laksman Am J Heme 2017• All off-label contents are independent of the company’s view except for the scientific exchange.

Salvage Stem Cell Transplant

Ref NDates of

SCT2

Lines of Prior

Therapy ORRPFS (mo)

OS (mo)

2 83 Before 2006 NR NR 15.6 34.84 106 1990–2002 NR 63% NR 378 81 1992–2009 1 97.4% 16.4 539 200 1992–2010 2 80.4% 15.2 42.3

10 83 1994–2011 NR NR 15.5 31.511 187 1995–2008 NR NR 11.2 3012 98 1994–2009 3 85% 10.3 3314 75 1995–2012 1 82% 10.1 22.715 111 2000–2013 NR 92% 18 48

Current study 74 1998–2016 4 68% 6.1 19.3

▶ 72% of thrombocytopenic (N=36) patients recovered to >75,000/μL

▶ 64% of neutropenic patients (N=14) recovered to ANC >1,500

▶ PFS after SCT1 correlates with PFS after SCT2– Consider addition of BCNU

to melphalan if first PFS short

Tremblay D et al. Bone Marrow Transplant. 2017;52:1468.

Overview


2. Second and Third Relapse3. Fourth Relapse and beyond

1. VDCEP/VDTPACE2. Salvage stem cell transplant

4. Cardiovascular Risk in Multiple Myeloma

Cardiovascular Risks in Multiple Myeloma

1. Factors that contribute to cardiac disease in patients with multiple myeloma• Patient factors• Disease factors• Treatment factors

2. Practical treatment recommendations for preventing and managing cardiac adverse events following carfilzomib treatment

Definitions: NCI-CTCAE v4.03: Hypertension, Dyspnea, and Heart Failure

National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), v4.03. June 14, 2010.

Adverse Event Grade 1 Grade 2 Grade 3 Grade 4 Grade 5

Hypertension Prehypertension Stage 1 hypertension; medical intervention indicated; recurrent or persistent (≥24 hrs); symptomatic

increase by >20 mm Hg (diastolic) or to >140/90 mm Hg if previously WNL;

one drug indicated

Stage 2 hypertension; medical intervention indicated; more than

one drug or more intensive therapy than previously used indicated

Life-threatening consequences (e.g. malignant hypertension, transient or

permanent neurologic deficit, hypertensive crisis); urgent

intervention indicated

Death

Dyspnea Shortness of breath with moderate exertion

Shortness of breath with minimal exertion; limiting instrumental ADL

Shortness of breath at rest; limiting self care ADL

Life-threatening consequences; urgent intervention indicated

Death

Heart Failure Asymptomatic with laboratory (e.g. BNP) or

cardiac imaging abnormalities

Symptoms with mild to moderate activity

or exertion

Severe with symptoms at rest or with minimal activity or exertion;

intervention indicated

Life-threatening consequences; urgent intervention indicated (e.g. continuous

IV therapy or mechanical hemodynamic support)

Death

ADL, activities of daily living; BNP, B-type natriuretic peptide; NCI, National Cancer Institute; WNL, within normal limits

▶ MM vs matched patients without MM: an observational, retrospective, cohort study▶ MM patients treated with > 3 drugs matched to non-MM patients by age, sex and distribution of index dates

CCI = Charlson comorbidity index; CHF = congestive heart failure; CKD ¼ chronic kidney disease; CV = cardiovascular; ID ¼ index date; MM = multiple myeloma; SD = standard deviation. Kistler KD, et al. Clin Lymphoma Myeloma. 2017;17:89-96.

Increased Risk of Cardiac Events in Patients with Previously Treated Multiple Myeloma

Patient CharacteristicsPatients With MM and Exposure

to≥ 3 Drugs* (n = 1723)Matched Comparator Cohort

(No MM; n = 8615) P ValueFollow-up duration (mo)

Median 9 19 < 0.001Range 0–60 0–66

CV comorbidities at baselineAny CV event 898 (52.1) 3021 (35.1) < 0.0001HTN/arterial events 663 (38.5) 2485 (28.8) < 0.0001Cardiac dysrhythmias 295 (17.1) 483 (5.6) < 0.0001Conduction disorders 37 (2.1) 66 (0.8) < 0.0001Cardiomyopathy 59 (3.4) 71 (0.8) < 0.0001CHF 155 (9.0) 174 (2.0) < 0.0001IHD 180 (10.4) 718 (8.3) 0.005Hypertension 627 (36.4) 2361 (27.4) < 0.0001Hyperlipidemia 302 (17.5) 1917 (22.3) < 0.0001Amyloidosis 34 (2.0) 2 (0.02) < 0.0001

Other comorbidities at baselineStem cell transplant 76 (4.4) 0 (0.0) < 0.0001CKD 293 (17.0) 161 (1.9) < 0.0001Diabetes 288 (16.7) 1171 (13.6) < 0.0001

CCIMean ± SD 4.2 ± 2.5 0.6 ± 1.2 < 0.0001Median 3 0Range 0–15 0–10

*Patients with MM had exposure to the following 3 drugs or drug classes taken on or before the disease ID: bortezomib, an immunomodulatory drug, and either an alkylating agent or anthracycline.

Incidence & Risk of Cardiac Events in Previously Treated MM Vs Matched Patients w/o MM :

An Observational, Retrospective, Cohort Study

▶ Adjusted Hazard Ratios (HRs) for Cardiac Events MM vs no MM: Factors Modifying the HR for MM by > 10%

28Kistler et al. Clin Lymphoma Myeloma. 2017 Feb;17(2):89-96

Multiple myeloma disease itself may be a pathogenic factor of heart failure

Myelomatousinfiltration of themyocardium and the pericardium2

3

Amyloiddeposition2

4

Restrictivecardiomyopathy

Hyperviscositysyndrome2

5

Restrictiveor dilated

cardiomyopathy

High-output failure(associated with

extensiveintramedullaryarteriovenous

fistulas)2

d

Potential Mechanisms of Heart Failure in Patients With Multiple Myeloma

1. Inanir S, et al. J Nucl Med. 1998;39:1-3; 2. Allegra A, et al. J Investig Med. 2010;58:859-874; 3. Multiple myeloma (1) MG stain.jpg. WikiMedia Commons website. https://commons.wikimedia.org/wiki/File:Multiple_myeloma_(1)_MG_stain.jpg. Accessed March 15, 2018; 4. Falk RH. Circulation. 2005;112;2047-2060; 5. George ED, et al. Am Fam Physician. 1999;59:1885-1892.

1

Potential Mechanisms of Hypertension in Patients With Multiple Myeloma

1. Sethi S, et al. Curr Opin Nephrol Hypertens. 2016;25:127-137; 2. Glavey SV, et al. Blood Rev. 2016;30:223-231; 3. Kapoulas S, et al. Nephrol Ther. 2015;11:135-143.

Precursor condition1,2

• Monoclonal gammopathy-associated renal lesionor

• Nephropathy secondary to monoclonal gammopathy of renal significance

Dysregulation of BP

Arterial hypertension

Hypertension in the patient with multiple myeloma may be linked to the gammopathy-related renal disease

Multiple myeloma3

• IgG-dependent mechanisms of renal diseaseand

• IgG-independent mechanisms of renal disease

Burden of Heart Failure in Patients With Multiple Myeloma

Hsu P, et al. Medicine. 2015;94:e2305.

Cau

ses

of E

arly

Dea

ths

(%)

Pneumonia Renal insufficiency

Heartfailure

Bleeding AMI Bacteremia Hepaticfailure

Suddendeath

UTIs Others

Contributing causeHeart failure as one significant condition that contributed to deathbut was not part of the underlying or immediate cause of death

Direct causeHeart failure as the final disease that directly led to the fatal outcome

451 consecutive patients newly-diagnosed with multiple myeloma (early mortality within 60 days after diagnosis was identified in 57 patients)

605040302010

0

Regardless of treatment, heart failure may be the second direct cause of death, and a major overall contributor to mortality in patients with multiple myeloma

Patient characteristicsMM patients

(n = 7895)Non-MM patients

(n = 23,685)Comorbidities at baseline, n (%)

Hypertension 3002 (38.0) 5750 (24.3)Renal failure 1698 (21.5) 696 (2.9)Hyperlipidemia 1399 (17.7) 3712 (15.7)Diabetes mellitus 1242 (15.7) 3007 (12.7)Ischemic heart disease 841 (10.7) 1777 (7.5)Cardiac dysrhythmias 563 (7.1) 1019 (4.3)Congestive heart failure 526 (6.7) 549 (2.3)Cardiomyopathy 168 (2.1) 176 (0.7)Amyloidosis 110 (1.4) 3 (0.01)Acute myocardial infarction 106 (1.3) 133 (0.6)Cerebrovascular diseasea 100 (1.3) 159 (0.7)Hypertension + renal failure 1034 (13.1) 494 (2.1)Hypertension + congestive heart failure 322 (4.1) 320 (1.4)Hypertension + renal failure + congestive heart failure 179 (2.3) 116 (0.5)

CCIMean ± SD 1.44 ± 1.93 0.41 ± 1.01Median (range) 1 (0–12) 0 (0–15)

▶ Retrospective cohort study▶ MM patients and non-MM patients matched for age, sex and distribution of index dates

aBased on inpatient claim only.Chari A, et al. BMC Cancer. 2016;16:912.

Increased Incidence and Risk of Hypertension in Patients with NDMM

▶ Risk of malignant HTN was significantly increased with the following comorbid conditions:– Cardiomyopathy, HR 2.79

(95% CI 1.20, 6.48)– Renal failure, HR 2.13

(95% CI 1.36, 3.34)– Diabetes mellitus, HR 1.59

(95% CI 1.05, 2.39)

CCI = Charlson comorbidity index; HR = hazard ratio; MM = multiple myeloma.Chari A, et al. BMC Cancer. 2016;16:912.

Impact of Host and Disease Factors on Incidence and Risk of Hypertension in Treated NDMM

Predictor Level HR (95% CI) P ValuePatient cohort (reference: non-MM patients)

MM patients 1.30 (1.22, 1.37) < 0.0001

Age (reference: 18–54 years) 55–64 years 1.82 (1.69, 1.97) < 0.000165–74 years 2.55 (2.36, 2.76) < 0.000175+ years 2.88 (2.66, 3.11) < 0.0001

Comorbidities at baseline(yes vs no)

Ischemic heart disease

1.29 (1.20, 1.40) < 0.0001

Renal failure 1.43 (1.47,1.61) < 0.0001Diabetesmellitus

1.72 (1.59, 1.86) < 0.0001

Hyperlipidemia 1.16 (1.07, 1.26) < 0.0001CCI (reference: low [0]) Mild (1, 2) 1.1 (1.03, 1.20) < 0.01

Treatment-Related Factors: Examples of AntimyelomaTherapy and Cardiac AEs

1. Wang M, Cheng J. Oncology. 2013;27(Suppl 3):24–30; 2. Laubach J, et al. ASH. 2013 (abstract 3187); 3. Stewart, et al. N Engl J Med. 2015;372:142-52; 4. Dimopoulos MA, et al. Lancet Oncol. 2016;17:27-38; 5. Moreau, et al. N Engl J Med. 2016;374:1621-34; 6. POMALYST® [package insert]. Summit, NJ: Celgene Corporation; 2014; 7. REVLIMID® [package insert]; Summit, NJ: Celgene Corporation; 2015; 8. THALOMID ® [package insert]. Summit, NJ: CelgeneCorporation; 2015

*Preferred term; †represents multiple preferred termsAE, adverse event; BTZ, bortezomib; RRMM, relapsed and/or refractory MM; IMiD, immunomodulatory agent; NDMM, newly diagnosed MM; PLD, pegylated liposomal doxorubicin; POM, pomalidomide; LoDex, low-dose dexamethasone; IRd, ixazomib plus Rd; Rd, lenalidomide plus dexamethasone; PLD, pegylated liposomal doxorubicin; SAE, serious adverse event

Chemotherapy1

Proteasome Inhibitors

IMiDs

Systolic left ventricular dysfunction, heart failureAnthracyclines(e.g. doxorubicin, PLD)Alkylating agents (e.g. cyclophosphamide)

BortezomibGrade ≥3 heart failure*:• Ranged from <1.0% - 4.7% with BTZ-based regimens across NDMM & RRMM2

• Ranged from <1.0% - 3.9% with non-BTZ-based regimens across NDMM & RRMM2

Pomalidomide

Lenalidomide

POM + LoDex vs POM alone in RRMM6

• Cardiac failure congestive* SAE: 3% vs 0%• Atrial fibrillation* SAE: 3% vs 2%Rd vs placebo + dexamethasone in relapsed MM7

• Grade 3/4 cardiac failure congestive*: 1.4% vs 0.3%• Grade 3/4 atrial fibrillation*: 3.7% vs 1.1%

Systolic left ventricular dysfunction, heart failure, pericardial effusion, myopericarditis

ThalidomideThalidomide + dexamethasone vs placebo + dexamethasone in NDMM8

• Grade 3/4 atrial fibrillation: 5% vs 3%• Grade 3/4 myocardial ischemia: 3% vs 1%

Drug Class / Name Reported Cardiac AEs

Ixazomib Heart failure† (Grades 3/4):• TOURMALINE-MM1: 2.5% (IRd) vs 1.7% (Rd) in RRMM5

AE, adverse event; BSC, best supportive care; CV, cardiovascular; d, dexamethasone; K, carfilzomib; MDZ, midazolam; PK, pharmacokinetics; R, lenalidomide; RRMM, refractory or relapsed multiple myeloma; V, bortezomib. Chari A, et al. Blood Adv. 2018;2:1633-1644.

▶ Patient level data from 11 phase 1–3 carfilzomib studies (N = 2,044) evaluated for cardiovascular AE incidence

▶ Three phase 3 studies (ASPIRE, ENDEAVOR, and FOCUS) compared carfilzomib arms vs control arms to assess the benefit–risk profile in RRMM patients

‒ 1,012 patients in the carfilzomib arms

K dose escalation(PX-171-001)

Open-label single-arm pilot study(PX-171-003-A0/A1)

ASPIRE: KRd vs Rd(PX-171-009)

K twice-weekly dosing (PX-171-002)

K in V-naïve patients (PX-171-004)

ENDEAVOR: Kd vs Vd(2011-003)

KRd dose escalation(PX-171-006)

K in patients with renal impairment (PX-171-005)

FOCUS: K vs BSC(PX-171-011)

K effects on PK of MDZ(PX-171-008)

Expanded access to RRMM patients (2011-002)

Phase 1 Phase 2 Phase 3


Treatment-emergent cardiovascular AEs in carfilzomib treated patients across RRMM trials (N=2044)*

38

Any-grade AEsn (%)

Grade ≥3 Aesn (%)

SAEs, n (%)

Cardiac failure 137 (6.7) 90 (4.4) 79 (3.9)Cardiac failure congestive 51 (2.5) 36 (1.8) 34 (1.7)Cardiac failure 38 (1.9) 20 (1.0) 19 (0.9)Pulmonary edema 31 (1.5) 19 (0.9) 17 (0.8)Ejection fraction decreased 16 (0.8) 6 (0.3) 0Cardiac failure acute 7 (0.3) 5 (0.2) 4 (0.2)Acute pulmonary edema 6 (0.3) 6 (0.3) 5 (0.2)Right ventricular failure 3 (0.1) 3 (0.1) 2 (<0.1)Acute left ventricular failure 2 (<0.1) 1 (<0.1) 2 (<0.1)Cardiopulmonary failure 2 (<0.1) 1 (<0.1) 1 (<0.1)Hepatic congestion 2 (<0.1) 1 (<0.1) 0Cardiac failure chronic 1 (<0.1) 1 (<0.1) 0Cardiogenic shock 1 (<0.1) 1 (<0.1) 0Hepatojugular reflux 1 (<0.1) 0 0

Hypertension 378 (18.5) 120 (5.9) 13 (0.6)Dyspnea 653 (31.9) 92 (4.5) 48 (2.3)Ischemic heart disease 75 (3.7) 40 (2.0) 36 (1.8)

Pooled analysis is from the phase 1 trials (PX-171-001, PX-171-002, PX-171-006, PX-171-008), the phase 2 trials (PX-171-003-A0 and A1, PX-171-004, PX-171-005, and 2011-002), and phase 3 trials ASPIRE (PX-171-009), ENDEAVOR (2011-003), and FOCUS trial (PX-171-011).

Trea

tmen

t-em

erge

nt A

Es, %

20

15

10

5

0

6.7%

18.5%

Any-grade

4.4%5.9%

Cardiac failureHypertension

Grade ≥3

Cardiovascular AEs in carfilzomib treated patients across phase 1-3 trials

Chari A, et al. Blood Adv. 2018;2:1633-1644.

Treatment-emergent CV AEs in the ASPIRE and ENDEAVOR phase 3 trials

ASPIRE ENDEAVORKRd Rd Kd Vd

N 392 389 463 456

Carfilzomib dose, mg/m2 20/27 20/56

Cardiac AEs, any-gradeCardiac failure 25 (6.4) 16 (4.1) 38 (8.2) 13 (2.9)

Hypertension 62 (15.8) 32 (8.2) 120 (25.9) 44 (9.6)

Dyspnea 89 (22.7) 70 (18.0) 143 (30.9) 78 (17.1)

Ischemic heart disease 23 (5.9) 18 (4.6) 13 (2.8) 9 (2.0)

Cardiac AEs, Grade ≥3Cardiac failure 15 (3.8) 7 (1.8) 22 (4.8) 8 (1.8)

Hypertension 22 (5.6) 8 (2.1) 44 (9.5) 12 (2.6)

Dyspnea 12 (3.1) 8 (2.1) 26 (5.6) 10 (2.2)

Ischemic heart disease 13 (3.3) 8 (2.1) 8 (1.7) 7 (1.5)

39

Note: • open label - neither patient nor research team is blinded• AEs coded by oncology team• twice weekly regimen increases AE capture (ascertainment bias)• longer duration of treatment increases AE capture (ideally should be

adjusted for exposure)


Phase 3 Studies: Exposure to Study Treatments

26.8(1.0–106.1)

39.9(1.0–108.1)

56.7(0.4–200.7)

85.0 (0.1–185.0)

72(1.0–93.1)

Mediation duration of treatment for the drug indicated in blue. Median PFS (months) for ASPIRE (KRd, 26.3; Rd, 17.6) and ENDEAVOR (Kd, 18.7; Vd, 9.4). *Values for average dose per administration are for the time period beyond cycle 1 in ENDEAVOR.d, dexamethasone; K, carfilzomib; PFS, progression-free survival; R, lenalidomide; V, bortezomib.Chari A, et al. Blood Adv. 2018;2:1633-1644.

Median Duration of Treatment, Weeks (range)

KRdcarfilzomib

(n = 392)

KRdlenalidomide

(n = 391)

Rdlenalidomide

(n = 392)

Kdcarfilzomib

(n = 463)

Vdbortezomib

(n = 456)

ASPI

RE

END

EAVO

R

Average Dose*Median (range)

26.8 mg/m2

(15.3–26.9)

25.0 mg(6.3–25.1)

25.0 mg(6.6–25.0)

55.9 mg/m2

(19.5–59.9)

1.2 mg/m2

(0.7–1.7)

Treatment exposure was longer in the carfilzomib arms than in the control arms

Treatment Reduction/Discontinuation and Deaths in ASPIRE and ENDEAVOR phase 3 trials


N 392 389 463 456

Carfilzomib dose, mg/m2 20/27 20/56

Treatment reduction due toCardiac failure 4 (1.0) 3 (0.8) 7 (1.5) 0

Hypertension 3 (0.8) 3 (0.8) 15 (3.2) 3 (0.7)

Dyspnea 5 (1.3) 1 (0.3) 13 (2.8) 5 (1.1)

Ischemic heart disease 1 (0.3) 2 (0.5) 3 (0.6) 0

Treatment d/c due toCardiac failure 2 (0.5) 3 (0.8) 13 (2.8) 4 (0.9)

Hypertension 1 (0.3) 1 (0.3) 2 (0.4) 0

Dyspnea 0 1 (0.3) 5 (1.1) 6 (1.3)

Ischemic Heart Disease 5 (1.3) 2 (0.5) 5 (1.1) 3 (0.7)

Deaths due toCardiac Failure 3 (0.8) 4 (1.0) 2 (0.4) 2 (0.4)

Hypertension 0 0 0 0

Dyspnea 0 0 0 0

Ischemic Heart Disease 3 (0.8) 2 (0.5) 0 3 (0.7)

41Chari A, et al. Blood Adv. 2018;2:1633-1644.

ENDEAVOR Cardiopulmonary Substudy: Change in LVEF From Baseline

Kd = carfilzomib and dexamethasone; Vd = bortezomib and dexamethasone; LVEF = left ventricular ejection fraction.

Results from the ENDEAVOR Cardiopulmonary Substudy


Change from baseline in LVEF for each visit was similar across groups through the study

Outcome of cardiac failure events in ASPIRE and ENDEAVOR


Patients with Cardiac failure, N 25 16 38 13Any grade, n (%)

Resolved 15 (60.0) 6 (37.5) 14 (36.8) 8 (61.5)Resolved with Sequelae 2 (8) 0 0 0

Not Resolved 10 (40) 10 (62.5) 23 (60.5) 5 (38.5)Deaths 3 (12.0) 4 (25.0) 2 (5.3) 2 (15.4)

43Chari A, et al. Blood Adv. 2018;2:1633-1644.

Are There Differences in Incidence of Cardiac Failure AEs* by Age Subgroups?

ASPIRE1 ENDEAVOR1

1. Data on file, Amgen; 2015; 2. Berenson, et al. Blood. 2016; pre-published at doi:10.1182/blood-2015-11-683854; 3. Ludwig et al. ESMO 2014 (Abstract LBA28). 4. Chari A, et al. Blood Adv. 2018;2:1633-1644.

*Grouped term (SMQN)

• Patient numbers in age subsets are too small for meaningful comparisons in the CHAMPION-1 (n=104)2 and FOCUS (n=157 in K arm) studies3

Age SubgroupsAll Grades Cardiac

Failuren/N (%)

KRd Rd

<65 years 7/207 (3.4) 6/184 (3.3)65-74 years 7/142 (4.9) 7/155 (4.5)≥75 years 11/43 (25.6) 3/50 (6)

Age SubgroupsAll Grades Cardiac

Failuren/N (%)

Kd Vd

<65 years 10/223 (4.5) 5/208 (2.4)65-74 years 12/163 (7.4) 5/183 (2.7)≥75 years 16/77 (20.8) 3/65 (4.6)

Grade ≥ 3 Cardiac Failure and Progression or Death*

Grade ≥ 3 Cardiac Failure and Mortality*

ASPIRE: Time to First Event of Cardiac Failure and Survival Analyses

*X-axis is months since first dose for grade ≥ 3 cardiac failure adverse events and months since randomization for PFS or OS. d, dexamethasone; K, carfilzomib; OS, overall survival; PFS, progression-free survival; R, lenalidomide. Chari A, et al. Blood Adv. 2018;2:1633-1644.

Difference in the cumulative incidence of progression or death was greater than that for grade ≥ 3 cardiac failure, suggesting a favorable benefit–risk profile

Rd: Progression or death 389 338 287 245 206 176 151 135 117 103 72 39 18 6 1 1KRd: Progression or death 392 360 332 304 279 259 222 201 179 158 112 55 24 4 1 0

Rd: Cardiac failure 389 362 308 269 214 184 159 134 117 98 72 42 19 6 1 1KRd: Cardiac failure 392 364 335 307 275 255 221 192 172 148 113 59 26 8 1 0

Number of Subjects at RiskRd: Mortality 389 373 356 337 313 298 281 264 237 217 144 86 39 11 3 1 0

KRd: Mortality 392 379 369 358 343 329 315 297 280 261 191 109 52 16 2 0 0Rd: Cardiac failure 389 362 308 369 214 184 159 134 117 98 72 42 19 6 1 1 0

KRd: Cardiac failure 392 364 335 307 275 255 221 192 172 148 113 59 26 8 1 0 0

Number of Subjects at Risk

1.00.90.80.70.60.50.40.30.20.1

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42Months Since First Dose or Randomization

Cum

ulat

ive

Inci

denc

e (1

–KM

)

0.25

0.02

0.040.18

1.00.90.80.70.60.50.40.30.20.1

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45Months Since First Dose or Randomization

Cum

ulat

ive

Inci

denc

e (1

–KM

)

Rd: Progression or deathKRd: Progression or deathRd: Cardiac failureKRd: Cardiac failure

0.52

0.02

0.04

0.35

Rd: MortalityKRd: MortalityRd: Cardiac failureKRd: Cardiac failure

45 48

ENDEAVOR: Time to First Event of Cardiac Failure and Survival Analyses

*X-axis is months since first dose for grade ≥ 3 cardiac failure adverse events and months since randomization for PFS or OS. d, dexamethasone; K, carfilzomib; OS, overall survival; PFS, progression-free survival; V, bortezomib. Chari A, et al. Blood Adv. 2018;2:1633-1644.

Vd: Progression or death 456 354 252 161 81 30 12 2 1 0Kd: Progression or death 463 398 331 248 144 77 41 14 4 0

Vd: Cardiac failure 456 389 249 146 64 23 9 2 1 0Kd: Cardiac failure 463 412 341 242 126 64 32 8 1 0

Number of Subjects at RiskVd: Mortality 456 431 390 317 191 110 53 15 3 0 0Kd: Mortality 463 448 409 356 209 125 63 26 7 1 0

Vd: Cardiac failure 456 389 249 146 64 23 9 2 1 0 0Kd: Cardiac failure 463 412 341 242 126 64 32 8 1 0 0

Number of Subjects at Risk

1.00.90.80.70.60.50.40.30.20.1

0 3 6 9 12 15 18 21 24 27 30Month Since First Dose or Randomization

Cum

ulat

ive

Inci

denc

e (1

–KM

)

0.29

0.050.110.20

1.00.90.80.70.60.50.40.30.20.1

0 3 6 9 12 15 18 21 24 27Month Since First Dose or Randomization

Cum

ulat

ive

Inci

denc

e (1

–KM

)

0.78

0.05

0.11

0.48

Grade ≥ 3 Cardiac Failure and Progression or Death*

Grade ≥ 3 Cardiac Failure andMortality*

Difference in the cumulative incidence of progression or death was greater than that for grade ≥ 3 cardiac failure, suggesting a favorable benefit–risk profile

Vd: Progression or deathKd: Progression or deathVd: Cardiac failureKd: Cardiac failure

Vd: MortalityKd: MortalityVd: Cardiac failureKd: Cardiac failure

ASPIRE ENDEAVOR

Favorable effect: NNT (subject years)

Progression-free survival 8.2 2.5

Unfavorable effects: NNH (subject years)

Grade ≥ 3 cardiac failure* 102.8 30.8

Grade ≥ 3 hypertension† 75.1 12.9

ASPIRE and ENDEAVOR: Number Needed to Treat (NNT) and Number Needed to Harm (NNH)

*Based on Standardized MedDRA Query, narrow scope. †Based on preferred term.d, dexamethasone; K, carfilzomib; MedDRA, Medical Dictionary for Regulatory Activities; R, lenalidomide.Chari A, et al. Blood Adv. 2018;2:1633-1644.

Number needed to treat is less than the number needed to harm Results indicate a favorable benefit–risk profile

• For ASPIRE, approximately 8 patients need to be treated over one year in order to prevent one additional disease progression, and approximately 103 patients would need to be treated over one year in order to cause one event of grade ≥ 3 cardiac failure

What to Consider Prior to Carfilzomib Treatment

▶ Identify and assess potential risk of cardiac AEs in patients at risk:1,2

– Increased age: ≥ 75 years of age may be at increased risk– Uncontrolled hypertension – Amyloid– Pre-existing cardiac failure (NYHA Class III and IV)– Coronary Artery Disease – angina, recent myocardial infarction (within prior 4 months2)– Conduction abnormalities/ arrhythmias uncontrolled by medications– Prior anthraycline use

▶ Risk mitigation measures:– Optimize management of hypertension and active cardiac failure and consider cardiologist consultation before

initiating Kyprolis treatment1-3

• evaluate for active ischemia – EKG, stress test• assess baseline EF/contractility and BNP• Optimize anti-hypertensive therapy

– Educate patient re signs and symptoms of heart failure– Pay attention to dosing of carfilzomib (20/36/56/70), schedule (qwk vs biw), and partner drugs (IMID,

mAb, cyclophosphamide) - do not escalate higher than 56 mg/m2 q week with IMiD

▶ Plan fluid management:– Establish baseline weight of patient4– Oral: 30 mL fluid per kg at least 48 hours before Cycle 1, Day 11,3

– IV: 250-500mL fluid prior to each dose in Cycle 11,3 – make sure template chemo orders reflect this– Consider reducing fluid volume in patients with increased cardiac risk1-3

1. KYPROLIS® [Prescribing Information]. Thousand Oaks, CA: Onyx Pharmaceuticals, Inc., an Amgen subsidiary. 2016; 2. Kyprolis Summary of Product Characteristics (SmPC). Amgen Europe B.V. NL-4817 ZK Breda, The Netherlands. 2015; 3. Mikhael, J. Clin Lymphoma Myeloma Leuk. 2016 Feb 4 [epub ahead of print]; 4. American Heart Association. Get With The Guidelines® - Heart Failure. June 2011.

NYHA, New York Heart Association.

Recommended monitoring and management of possible carfilzomib-associated cardiac and vascular-related events

50

aRecommended for patints who are at increased cardiac risk (e.g., anthracyline exposure, age >60 years, amyloid, coronary artery disease).BNP, brain natriuretic peptide.

Chari and Hajje BMC Cancer 2014, 14:915

▶ Cardiac adverse events can occur due to host, disease, and treatment factors ▶ MM patients are at a greater risk of CV disease due to factors inherent to their

demographics and effects of multiple myeloma itself▶ Ideally randomized double blinded phase 3 studies with adjustment for time on

therapy are required to elucidate treatment contribution to cardiac Aes▶ Carfilzomib has a favorable benefit-risk profile

– While low rates of cardiac AEs occur more frequently with carfilzomib than controls, events are generally manageable

• Manageability of hypertension and cardiac failure events as evident by low rates of treatment discontinuation due to cardiac AEs

• Management strategies may assist in the prevention and treatment of cardiac events– Number needed to treat is << Number needed to harm – ENDEAVOR and ASPIRE have shown an overall survival benefit with carfilzomib

▶ To reduce both the burden of potential cardiovascular complications and the number of patients disqualified from specific multiple myeloma treatment because of emergent cardiovascular disease: – Careful initial cardiovascular and renal evaluation before starting treatment that is associated

with cardiovascular adverse events2,3

– Aim for optimal control of preexisting cardiovascular risk factors2,3

– Institute ongoing cardiac safety monitoring for early signs of cardiovascular adverse events and timely implementation of preventive or therapeutic measures3

1. Chari A, et al. Blood Adv. 2018;2:1633-1644; 2. Kisler KD, et al. Clin Lymphoma Myeloma Leuk. 2017;2:89-96; 3. Mikhael J. Clin Lymphoma Myeloma Leuk. 2016;16:241-245

Conclusions: Cardiovascular Risk in Myeloma

52

Conclusions: Relapsed Multiple Myeloma

First Relapse: ▶ Response rate and PFS progressively diminish with each relapse▶ 3-drug therapy results in superior efficacy

– In older/frail patients, consider monoclonal antibody–based triplets

▶ Select evidence-based regimen based on refractoriness to backbone control arms (lenalidomide vs bortezomib vs in near future daratumumab!)

– Consider hazard ratios for PFS improvement– Some studies with longer follow up leading to OS benefit

▶ At attainment of persistent deep response ? de-escalate to 2 or 1 drugs▶ High-risk disease remains unmet medical need with novel therapies only improving

outcomes but not overcoming high risk

Nth Relapse: as above but combination therapy even more important▶ If significant/fast progression, then consider 96-hr based chemo regimen▶ If cytopenic due to disease, consider 96-hr based chemo regimen vs salvage SCT▶ Novel agents: selinexor (single agent/combination studies) promising

Supplemental

Summary of High Risk outcomes


% missing molecular data

47.3%

6.4%

73.4%




24%

29%

45%


All novel therapies resulted in an improvement in PFS for high-risk patients, but none provided clear statistical evidence that they overcame high-risk status.


1.7%


XPO1 in MM and Selinexor

57

• XPO1 transports >200 protein cargos from the nucleus to the cytoplasm• XPO expression increased in MM vs normal PC/MGUS/SMM• correlates with shorter survival and increase in lytic bone disease

Tai et al Leukemia 2014 Schmidt et al Leukemia 2013

• Selinexor inhibits XPO1 through reversible covalent modification of a cargo binding pocket

• Selective cytotoxicity vs. MM cell lines but not bone marrow stromal cells

Selinexor Mechanisms of Action1: Nuclear Retention/Activation of Tumor Suppressor Proteins & glucocorticoid receptor2: Reduction of Oncoproteins Through Nuclear Retention of their mRNAs Control

KPT-330

p53

Selinexor: First in Class Oral XPO inhibitor

N=122*

Age, years median (range) 65 (40 – 86)

Time from Diagnosis, Years median (range) 6.6 (1.1 – 23.4)

High Risk : (del17p, t(4;14), t(14;16), 1q21) 65 (53%)

Median Prior Regimens (range) 7 (3 – 18)

Refractory to PI / IMiD / Dara/GC-Refractory to K/P/D -Stem Cell Transplant

- ≥2 Transplants-Intensive Combination Chemo

(e.g. DT-PACE)- CAR-T Cell Therapy

122 (100%)117 (96%)102 (84%)

29 (28%)32 (26%)

2 (2%)

Penta Exposed, triple class refractory Cr Cl > 20, ANC > 1000, plts > 75k(50k if marrow > 50% PC) {Selinexor 80 mg + Dex 20 mg} both po D1, 3 q week

ORR 26.2%, including 2 sCRs PRs in both CART patients CBR 39.3% DCR 79%

Median time to response 1 month Median PFS 3.7 months Median OS 8.0 months

superior to Flatiron nonselinexor cohort

Grade 3/4 All Grades

Nausea 10% 67%

Anorexia 2% 50%

Vomiting 3.3% 35%

Fatigue/Asthenia 21% 68%

Hyponatremia 16% 31%

Thrombocytopenia 53% 67

Neutropenia 18% 36%

Jagannath SOHO 2018, Chari ASH 2018

59

STOMP PATIENT CHARACTERISTICS

SVd SPd SRd SDd SKd

Lines of Therapy≥ 1

Not V refractory

≥ 2 including PI and IMID

≥ 1Not R25

refractory

≥ 3including PI and IMID

Patients Enrolled 42 34 19 21 21

Median Age, Years 64 61 68 68 64

Median Time Dx to Rx, Years 5 6 4 5 4.5

Median Prior Regimens 3 4 1 4 4

Overall Response Rate 84% 50%* NR 74% 63%

ORR in backbone refractory 43% 38% NR N/A 67%

Progression Free Survival 9.2 mos 10.3 mos NR NR 3.7 mos

PFS in backbone refractory 6.1 mos 4.8 mos NR N/A NR

* N= 30 evaluable

• The RP2D for SVd, SRd, & SDd have been determined:• SVd – 100 mg selinexor QW + 1.3 mg/m2 V QW + 40 mg dex QW (ie 40%/25% less V/D than VD biw)• SRd – 60 mg selinexor QW + 25 mg lenalidomide + 40 mg dex QW• SDd – 100 mg selinexor QW + 16 mg/kg daratumumab + 40 mg dex QW

• Determination of RP2D for SPd + SKd with QW selinexor ongoing• Most common AEs: anorexia, nausea, fatigue, mainly grades 1/2, and thrombocytopenia mainly grades 3/4

Lonial et al. NCCN 2018. Bahils et al 2018, Chen et al 2018, Gasparetto et al 2018, Jakubowiak et al ASH 2016.

Selinexor and backbone Treatments Of multiple Myeloma Patients (STOMP): Phase 1 Preliminary Results

Phase 3 Studies:Patient Baseline Characteristics (2/2)

Characteristic

ASPIRE ENDEAVOR

Carfilzomib (KRd)

Control (Rd)

Carfilzomib (Kd)

Control (Vd)

n 392 389 463 456Serum β2 microglobulin, mg/L, median (range)

3.5(1.3–13.0)

3.6(1.5–31.7)

3.6(1.4–24.2)

3.7 (1.2–31.6)

CrCl, n (%), mL/min< 30 0 1 (0.3) 28 (6.0) 28 (6.1)30 to < 50 24 (6.1) 30 (7.7) 57 (12.3) 69 (15.1)50 to < 80 170 (43.4) 150 (38.6) 186 (40.2) 174 (38.2)≥ 80 197 (50.3) 203 (52.2) 192 (41.5) 185 (40.6)

Medical history, n (%)Hypertension* 194 (49.5) 178 (45.8) 233 (50.3) 221 (48.5)Cardiac failure* 17 (4.3) 5 (1.3) 14 (3.0) 13 (2.9)Cardiac arrhythmias 44 (11.2) 38 (9.8) 27 (5.8) 33 (7.2)

*Standardized MedDRA Query, narrow scope. BSC, best supportive care; CrCl, creatinine clearance; d, dexamethasone; K, carfilzomib; MedDRA, Medical Dictionary for Regulatory Activities; R, lenalidomide; V, bortezomib.Chari A, et al. Blood Adv. 2018;2:1633-1644.

ASPIRE ENDEAVOR

optimal treatment sequencing for patients with relapsed

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