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MANAGEMENT CONSIDERATIONS FOR ONTARIO 2020

CARETM MULTIPLE MYELOMA (MM)

H E M AT O L O G Y

M A R C H 2 0 2 0

The management of MM is an evolving field in Canada, one impacted by data releases and updates from around the globe. Members of the CARE™ Faculty represent KOLs from across Canada that produce treatment guidance materials (and much more) - incorporating the most recent medical updates and KOL projections for the future, framed from a Canadian perspective.

The following CARE™ Treatment Guidance in MM is based on CARE™ Faculty discussions and updates from recent major events including CARE™ programming such as CARE™ at ASH 2019, the CARE™ WHU 2020, various CARE™ Hematology Working Groups and more.

Supporting study data and insights from CARE™ Faculty members that impacted the following MM guidance are available on the CARE™ website. Canadian Clinicians are encouraged to visit www.CAREeducation.ca and review recent MM outputs to augment these management considerations.

CARE™ MM Management Considerations for Ontario 2020 include:

Treatment Guidance and Supporting Studies

Front-line MM• Front-Line Therapy in Transplant Ineligible• Front-Line Therapy in Transplant Eligible

Relapsed/Refractory MM• Early Relapse (1-3 prior lines)• Novel Regimens on the Horizon

Additional Clinical Considerations

• Minimal Residual Disease (MRD)• Identifying Ultra High-Risk Disease• CAR T-cell Therapy for MM• Projections for the Future

MANAGEMENT CONSIDERATIONS FOR ONTARIO 2020 CARETM MULTIPLE MYELOMA (MM)

01 CARETM Multiple Myeloma (MM)

CARETM Response to COVID-19

Canada’s health-care system is hard at work fighting COVID-19, but the 1 million Canadians living with cancer face an extra challenge. Treatments and tests may be altered or delayed and this patient group may be more vulnerable to COVID-19.

The current pandemic is forcing clinicians to react rapidly and develop solutions to deliver healthcare. In an effort to help understand clinician’s approach and needs, CARE™ Hematology Faculty have developed a short questionnaire with a focus on both today and the near term, with a commitment to review insights and and provide guidance by June. (Tied into the annual CARE™ report on news and developments from ASCO and EHA).

Front-Line MM

Front-Line Therapy - Transplant Ineligible

• DRd has the potential to be used often in this setting once it is publicly funded (in Ontario).

• The significant improvement in PFS and toxicity make it an enticing option, especially in patients that are older or more frail. How frailty is defined is an area that is rapidly evolving because of novel agents and advances.

02

Recent MM updates and data releases have provided new insights on the management of MM in Ontario. CARE™ Faculty presentations and discussion have highlighted updates to the front-line (1L) and early relapsed settings which could impact practice. Additionally, the CARE™ Faculty have identified select novel regimens “on the horizon” which may affect relapsed/refractory (R/R) MM in the near future.

Table 1. Front-line treatments for the transplant ineligible.1,2,3,4

PM RVd versions:

1. Btz 1.3mg/m2 days 1,8,15 q28 days for 12 cycles, Len 15-25mg, Dex 20-40mg until

2. Btz 1.5mg/m2 days 1,8,15 q28 days for 8 cycles, Rd until PD

*PM = Princess Margaret

Front-line Therapy - Transplant Eligible

OOR CR PFS study alarm OS benefit

VMP vs MP (VISTA) 71% 30% 18 mos Yes

D-VMP vs VMP (ALCYONE) 91% 45% 36.4 mos (median follow-up 40 mos) Yes (3 yr 78%)

Rd-cont vs Rd18 and MPT (FIRST) 75% 15% 26 mos Yes (vs MPT)

Dara-Rd vs Rd (MAIA) 93% 48% Median not reached (median follow-up 36 mos)

Median not reached in both

RVd vs Rd (SWOG S0777) 82% 16% 43 mos YesRd

-bas

edV

MP

-bas

ed

Relapsed/Refractory MM

Early Relapse (1-3 prior lines)

Figure 1. MM treatment guidance for early relapse (1-3 prior lines) in Ontario.

Early Relapse (1-3 prior lines)

Salvage Transplant

Len-naive or exposed but not refractory

Len-refractory

• If > 2 yrs PFS from first ASCT

• DVd Kd• (PVd)• CyborD

Preferred• DRd• KRd, IRd

• DVd Kd• (PVd)• CyborD *PM = Princess Margaret

• 76% had prior lenalidomide (25% refractory), 65% had prior proteasome inhibitor therapy. Median PFS was 18.7 months for all. Median PFS was 9.6 months for the lenalidomide refractory.

Novel Regimens on the Horizon

KDd – carfilzomib, daratumumab, dex (CANDOR, KDd versus Kd in patients with 1-3 prior LOT)6

SPd – selinexor, pomalidomide, dex (STOMP, investigating SPd in patient with 2-8 prior LOT)7

Ven-Bd – venetoclax, bortezomib, dex (BELLINI, Ven-Bd versus placebo - Bd in patients with 1-3 LOT)8

• Additional Insights:

• Carfilzomib (KDd), selinexor (SPd), and venetoclax (Ven-Bd) combinations are active, but toxicities are a concern.• Venetoclax (Ven-Bd) looks particularly promising for patients with t(11;14) who do not always respond well to standard

myeloma therapies.

T R E A T M E N T G U I D A N C E A N D S U P P O R T I N G S T U D I E S

*

*

A D D I T I O N A L C L I N I C A L C O N S I D E R A T I O N S

Minimal Residual Disease (MRD)

03 CARETM Multiple Myeloma (MM)

• MRD is an important endpoint and should be a treatment goal. There are multiple aspects that factor into how MRD is/will be used in practice.

• Currently, it has the most utility in clinical trials. Some trials use MRD directed approaches (i.e. dose reductions, randomization, etc.).

• MRD negativity has been shown to be a surrogate for OS so can also be used to expedite drug approvals. Waiting 5-10 years for OS is no longer necessary.

• The biggest impact will be on potential cost savings if MRD negativity can be used to direct treatment discontinuations.

• Routine use in practice is aspirational but not yet ready for prime time due to lack of access to necessary testing.

• The introduction and access to mass spectrometry testing may revolutionize how we monitor and measure disease.

Identifying Ultra High-Risk Disease

• The timing of first relapse defines prognosis.

• Overlapping genetic abnormalities (including 1q gain) + ISS stage can fine-tune risk and better predict ultra-high risk, early relapsers.

• Next step: identifying optimal approaches for ultra-high risk patients.

Figure 2. PM protocol for (ultra) high-risk.

(Ultra) High Risk

Transplant #1

Transplant #2

Doublet maintenence

(IMiD + PI)

MR

D t

esti

ng

MR

D t

esti

ng

Ev

ery

6 m

onth

s

MR

D t

esti

ng

MRD- consecutively

X 2

MRD+

De-escalate to single agent

IMiD

Consider AlloBMT?

CAR T-cell Therapy for MM

• These therapies are typically easy to give but have a unique side effect profile that may be difficult to manage.

• There are no clinical trials in Canada so there is little experience.

• How these agents will impact is unknown and there is concern with access and economic/systemic sustainability.

Table 2. BCMA CAR T-cell therapies for MM.

Bb2121 (n=33) JNJ-4528 (n=29)

ReferenceRaje NEJM

2019;308:1726Madduri ASH 2019 #577

Prior therapy

Median 7 lines97% prior ASCT

100% len and bortez82% dara

Median 5 lines86% prior ASCT

100% prior len, bortex, dara

CRS 76% (6% ≥ grade 3) 86% (6% ≥ grade 3)

Neurotoxicity 42% (3% ≥ grade 3%) 10% (3% ≥ grade 3)

Responses 85% (CR 45%) 100% (CR 69%)

PFS/DOR Median PFS 11.8 mos Median DOR 16 mos

FDA breakthrough designation Nov 16, 2017 Dec 6, 2019

Projections for the Future

• Continuing to add daratumumab to standard of care regimens for incremental benefit. The question remains, how will earlier use alter sequencing?

• There are emerging new agents and combinations - these warrant caution.

• CAR T-cell therapy approval for MM coming soon. Anticipate challenges with patient selection and resource allocation.

04

1 Alcyone trial update – Mateos ASH 2019 Abstract 859.

2 MAIA trial update – Bahlis ASH 2019 Abstract 1875.

3 Durie B, et al. SWOG S0777 Lancet 2017;389:P519.

4 O’Donnell et al. RVD-lite Br J Haematol 2018;182:222.

5 K. Weisel et al. ENDEAVOR. Leukemia and Lymphoma. 2020. 61. 1, 37-46. 6 Usmani et al. ASH 2019 Late-breaking abstract.

7 Chen et al. ASH 2019 Abstract 141.

8 Harrison et al. ASH 2019 Abstract 0142.

R E F E R E N C E S

Available Now!

The CARE™ Global Interview Series Issues of the CARE™ Global Interview series, featuring hematology leaders from Italy, England and the USA are available now.

CARE™ WHU 2020 Meeting Slides Though nothing beats attending a CARE™ event, the complete presentations from WHU 2020, as delivered by members of the CARE™ Faculty, are available on the CARE™ website. CARE™ Guidance material is augmented by reviewing recent education content from the CARE™ Faculty - we encourage you to visit the CARE™ website for additional context and insights.

CARE™ Localized Modules The CARE™ Faculty has produced general (non-regional focused) medical education slide decks on hematological topics in 2020. The CARE™ Localized Slide Decks are available on request. Contact CARE™ through the website to request one or more Localized Modules.

C A R E ™ P R O G R A M S : A V A I L A B L E A N D U P C O M I N G

CARE™’s work extends beyond guidance. Years of CLL medical education material is available or coming soon to the CARE™ Website: www.CAREeducation.ca

Coming Soon!

CARE™ CLL Patient Case Review and Publication A CARE™ CLL Patient Case Review, informed by CARE™ Programming at WHU 2020 and led by Dr. Peter Anglin (Stronach Regional Cancer Centre, CARE™ Hematology Faculty Lead) will be available soon.

CARE™ Retrospective Reviews 2020 marks 15 years of CARE™! To capitalize on years of experience, and to use the past to help make projections for the future, CARE™ will be creating a series of retrospective reviews in various categories.

05 CARETM Multiple Myeloma (MM)

This CARETM PUBLICATION provides educational updates on current trends in medicine. Content reflects the opinions, output and analyses of experts, investigators, educators and clinicians (“CARETM Faculty”), whose activities, while independent, are commercially supported by the noted sponsor(s). Program content is developed independently of sponsor(s). This content is intended for educational value only; to make scientific information and opinions available to health professionals, to stimulate thought, and further investigation. Decisions regarding diagnosis and/or management of any individual patient or group of patients should be made on individual basis after having consulted appropriate sources. Opinions expressed herein reflect the opinions and analyses of the experts who have authored the material. Support for the distribution of this report was provided by AbbVie and Janssen. Copyright © 2020 by CARETM. All rights reserved. This publication or any portion thereof, in print, electronic copy or any other form, cannot be reproduced without the express written consent of CARETM. Any information, data, analysis, or results reproduced from another source remains the property of its authors. CARETM is a registered trademark, Canada (Registration No. TMA931,165). United States of America (Registration No. 5,024,819).

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