CHC 2019

T H E 9 T H A N N U A L

C A N A D I A N H E M A T O L O G Y C O N F E R E N C E - N A T I O N A L T O R O N T O , C A N A D A - S E P T E M B E R 2 0 T H - 2 1 S T , 2 0 1 9

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P L A S M A C E L L D Y S C R A S I A S

S E S S I O N S U M M A R Y

PLASMA CELL DYSCRASIASCHC 2019

• Use of Daratumumab

Now available and funded in most Canadian jurisdictions for relapse and is being investigated in front-line.

• Sequencing of active drugs (carfilzomib and pomalidomide)

• Continuous therapy

In patients who are both transplant eligible and transplant ineligible.

01 CHC 2019 REPORT: PLASMA CELL DYSCRASIAS

SECTION CHAIR: DR. PETER ANGLIN / PRESENTERS: DR. DONNA REECE & DR. SUZANNE TRUDEL

The following section features content on MM from CHC 2019, but updates in waldenstrom’s macroglobulinemia (WM) management (including Health Canada approvals) have prompted members of the CARE™ Hematology Faculty to create updated CARE™ WM Treatment Guidelines, which were published in the CARE™ Perspectives from ASCO/EHA 2019 Conference Report.

To view CARE™ Hematology Outputs including the updated CARE™ WM Guidance and the 2019 ASCO/EHA Conference Report, visit the Hematology page of the CARE™ website at: https://CAREeducation.ca/publications-media/?_sf_s=hematology

MYELOMA ISN’T THE ONLY PLASMA CELL DYSCRASIA THAT THE CARE™ FACULTY COVERS.

DR. PETER ANGLIN / STRONACH REGIONAL CANCER CENTRE

OPENING REMARKS SUMMARY

• The role of ASCT

• Bisphosphonate use

• Minimal residual disease (MRD)

Promising but not ready for routine use.

The treatment of plasma cell dyscrasias (PCDs) is dynamic, with significant improvements in survival and patient outcomes

over the last couple of decades. While CARE™ Faculty have covered advances across various PCDs, presentations at CHC 2019

focused on Multiple Myeloma (MM).

Evolving Multiple Myeloma themes prevalent in 2019 include:

G E T T H E F U L L C O N T E N T A T C A R E e d u c a t i o n . c aCLICK HERE to access the slides presented by Drs. Reece and Trudel at CHC 2019

02 CHC 2019 REPORT: PLASMA CELL DYSCRASIAS

1 Voorhees P, et al. American Society of Hematology (ASH) 2017, Abstract 1879; Voorhees P, et al. IIMW 2019: abstract OAB-087.2 Durie B, et al. Lancet. 2017;389:519-527.3 O’Donnell E, et al. Br J Haematol. 2018;182:222-230.

PRESENTED BY: DR. DONNA REECE / PRINCESS MARGARET CANCER CENTRE

FRONT-LINE MM IN 2019

In Canada, newly diagnosed patients with multiple myeloma are still classified as either transplant-eligible (TE) or ineligible (TI) based on age, comorbidities and frailty, as studies consistently show an improved PFS with ASCT in appropriate patients. For TE patients bortezomib-based triplet induction, ASCT and lenalidomide maintenance achieve a median PFS approaching 5 years, demonstrated in the results of phase 3 studies as well as real-world data from the Canadian national myeloma database.

Future directions for this setting:

• CyBorD followed by ASCT and Len-maintenance until progression yields results “competitive” with other modern regimens

• Tandem ASCT is still performed for high-risk patients

Definition of “high-risk” needs refinement (38-gene panel, immune parameters).

• Integration of immunotherapy will be a “game changer”

Canadian MCRN trial of adding isatuximab to CyBorD and Len maintenance to open next year.

GRIFFIN study results of dara-RVD presented at IMW (Figure 1).

Figure 1. GRIFFIN Trial Response Rates with DaraRVd vs RVd Followed by ASCT. 1

The introduction of newer agents such as carfilzomib or daratumumab as part of initial therapy has shown promising results for further improvements in these patients. For TI patients, until recently, the choice was either CyBorD or lenalidomide + dexamethasone in Canada. Now, RVd is available in most jurisdictions; the use of weekly bortezomib should allow this effective regimen to be administered with minimal toxicity in many elderly patients. For more frail patients without high-risk FISH cytogenetics, lenalidomide and dexamethasone may still be useful. Phase 3 studies integrating immunotherapy with daratumumab into first-line therapy with either VMP (Figure 2) or lenalidomide + dexamethasone (Figure 3) have demonstrated better outcomes and once available, will favorably impact the TI myeloma patient as well.

Response rates and depths were greater for D-RVd at all time points

Click here to see slide 14 of Front-line MM in 2019.

Figure 2. PFS Results of the ALCYONE Study (DaraVMP vs VMP). 2

Figure 3. PFS Results of the MAIA Study (DaraRd vs Rd). 3

Click here to see slide 17 of Front-line MM in 2019.

PRESENTED BY: DR. SUZANNE TRUDEL / PRINCESS MARGARET CANCER CENTRERELAPSED MYELOMA IN 2019

Over the last years, there has been great progress in the treatment of multiple myeloma with many new agents and combinations having been approved and being now routinely incorporated into treatment strategies. As a result, patients are experiencing benefits in terms of survival and better tolerance. However, the multitude of treatment options also presents a challenge to select the best options tailored to the specific patient situation.

General principals to consider when selecting treatment for R/R patients:

• In relapsed MM, there is no uniform standard treatment

• Consider patient related factors: performance status, age, and comorbidities when selecting therapy and optimal doses

• Take into account prior and residual toxicities

• Cytogenetics and duration of initial response defines biology

• The majority of patients will have received prior therapy with drug combinations

• Triplet (2 active classes + dexamethasone) preferred over doublet (see Table 2)

With ≥ 1 agent from a new or nonrefractory class.

• Treat to maximum response and maintain on ≥ 1 agent until progression or tolerability

The lenalidomide refractory population represents the majority of patients at first relapse. Consider the results of the following phase 3 Len-sparing trials in R/R MM (Bortezomib/PI backbone).

Table 1. Phase III Len-sparing trials in relapsed MM. 4, 5, 6

Although caution should be used in cross-trial comparison given differences in patient baseline characteristics between studies - it is hard to ignore the HR of 0.44 and PFS of 44.5 months achieved with the combination of DaraRd.

Further, lenalidomide is increasingly being used as part of front-line therapy in newly diagnosed multiple myeloma. This agent is typically administered until disease progression. It is currently unclear, how to best manage patients, who relapse while receiving lenalidomide as part of their frontline treatment. It is the physician’s task to choose the right moment for the start of therapy and decide with the patient which goals need to be achieved. The choice of regimen is usually based on prior response, drugs already received, adverse effects, comorbidities of the patient, drug availability and expected efficacy and tolerability. It becomes important to consider the therapeutic options for the whole duration of the disease and integrate a systematic approach for the patient.

Patients with high-risk disease continue to be a particularly challenging group to treat and distinguishing the preferred treatment options for this cohort of patients will improve outcomes. Preplanned subgroup analysis demonstrate improved PFS with the addition of an IMiD triplet either in combination with PI or anti-CD38. Consider the following PFS results from triplet regimens by FISH cytogenetic subtype.

03 CHC 2019 REPORT: PLASMA CELL DYSCRASIAS

4 Dimopolous MA, et al. Lanc Onc 2017; 18(10) 1327-37.5 Palumbo A, et al. N Eng J Med 2016; 375(8) 754-66.6 Richardson P, et al. Lancet Oncol 2019; S1470-2045(19)30152-4.7 Stewart AK, et al. N Engl J Med. 2015;372:142-1521. 8 Moreau P, et al. N Eng J Med 2016; 374(17) 1621-34.9 Lonial S, et al. N Engl J Med 2015; 373(7) 621-31.

Click here to see slide 11 of Relapsed Myeloma in 2019.

Table 2. Triplet regimens versus Len + Dex in R/RMM after 1–3 prior regimens. 7, 8, 9, 10

Consider the results from the following studies investigating triplet regimens (versus lenalidomide + dexamethasone) in R/R MM after 1-3 prior regimens.

Table 3. PFS of triplet regimens in R/R myeloma by FISH cytogenetic subtype. 11, 12, 13, 14, 15

Regimen

All-comers(Months

)

High Risk Experiment

al Arm(Months)

High RiskSOC

(Months)

High Risk after 1 prior

line of treatment (Months)

IRd1 20.6 21.4 9.7 NR

KRd3 26.3 23.1 13.9 24.1 vs 14.0

DRd4 44.5 26.8 8.8 29.6 vs 6.6

Kd5 18.7 8.8 6.0 11.1 vs 7.4

DVd6 16.7 13.4 7.2 20.1 vs 8.4

PVd2 11.2 8.44 5.32 NRIMiD triplet is preferred in combination with PI or Dara

Click here to see slide 12 of Relapsed Myeloma in 2019.

Trial Treatment

Number of previous

therapies, Median (Range)

% with prior IMiD

ORR (%) TTP or PFS*(months)

Hazard Ratio OS

ENDEAVOR1

n=929Kd (high-dose K)Vd 2 (1–2) 38

7763

(p < 0.0001)

18.79.4

(HR=0.53)

0.53 47.6 40.0 mo

(HR=0.79)

CASTOR2

n=498DVdVd 2 (1–10) 36

8363

(p < 0.0001)

16.77.16

(HR=0.32)

0.32

OPTIMISMM3

n=559PVDVd 2 (1-3) 100

82.250

(P<0.0001)

11.207.10

(HR 0.61)

0.61

Could be Bortezomib exposed but non-refractory

Click here to see slide 8 of Relapsed Myeloma in 2019.

10 Dimopolous MA, N Eng J Med 2016; 375(14) 1319-1331.11 Moreau P, et al. N Engl J Med 2016;374:1621.12 Richardson P, et al. Lancet Oncol 2019; S1470-2045(19)30152-4.13 Avet-Loiseau H, et al. Blood 2016;128:1174.14 Kaufman J, et al. Presented at ASCO 2019, oral presentation (Abstract 8006).15 Chng W-J, et al. Leukemia 2017;31:1368; Weisel et al presented at ASCO 2019.

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 Canada, AstraZeneca Canada, Celgene Canada, Hoffmann-La Roche Ltd., Janssen Inc., Kite Pharma, Merck Canada Inc., Novartis Pharmaceuticals Canada Inc., Sanofi Genzyme, Seattle Genetics Inc, and Teva Canada Ltd. Copyright © 2019 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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