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CARE™ Localized Module: Multiple Myeloma (MM)
Opening Remark
Slide content is informed by presentations made at the 2019 CARE™ at ASH or CHC West events. With Thanks to CARE™ Faculty for providing slides.
Content
Background: MM• Important concepts in MM• Depth of response• Combination Strategies
Updates from ASH 2019• The GRIFFIN Study• Abstract 862• The CANDOR study • The BELLINI Study • The MCRN-001 Study• Abstract 3173• The ALCYONE Study• Abstract 1875
Important Concepts in MM
Depth of response MRD negativity is the most
predictive of outcome Remains an important surrogate in
the reporting of early data
PI-IMID combos are important but still not widely available in Canada
RVd – not funded, approved for TI patients KRd – funded, but must choose between KRd
or Dara-Rd Ixazomib-Rd – not funded or approved
Pom-Vd – not funded
Monoclonal antibodies are important
Best used earlierPair well with other drugs
Ongoing refinement Optimize the use of new potent drugs that
significantly prolong disease control but require continuous therapy
Depth of Response: Achieving a CR Does Not Eliminate All Myeloma Clones
• Even in a CR, patients still have residual clonal disease that will lead to relapse. • Combination therapies can achieve deeper CRs. Depth of response is important.
Newer, more sensitive techniques define MRD – these may move to the clinic in the future
Techniques currently available in the clinic can detect up to an sCR
Combination Strategies:Which are the backbone drugs ?
• Dexamethasone• Bortezomib (?)• Lenalidomide (?)• Pomalidomide (??)• Carfilzomib (??)• Daratumumab (??)• Ixazomib (???)
• Dexamethasone• Bortezomib (?)• Lenalidomide (?)• Pomalidomide (??)• Carfilzomib (??)• Daratumumab (??)• Ixazomib (???)
Combination Strategies: Literature Review and Network Meta-Analysis of Treatment Outcomes in R/R Myeloma
Chrissy et al; J Clin Onc 2017, 35, 1312-1319
Updates from ASH 2019
691 Depth of Response to Daratumumab (DARA), Lenalidomide, Bortezomib, and Dexamethasone (RVd) Improves over Time in Patients (pts) with Transplant-Eligible Newly
Diagnosed Multiple Myeloma (NDMM): Griffin Study Update
Background• PI-IMID based triplets are an accepted standard induction regimen for transplant eligible patients
– VTd in Europe– RVd in USA– Still stuck with CyBorD in Canada
• The impact of adding a Mab to SoC remains of great interest, since MAb have been game changers give both marked improvement in efficacy as well as tolerability– CASSIPOEA study: VTD vs Dara-VTd
• CR:– Dara-VTD = 39% - VTD = 26%
• MRD negative:– Dara-VTD = 64% - VTD = 44%
Peter Voorhees et al
Of the patients achieving CR, MRD negativity:• Induction
• D-RVd = 42%• RVd = 8%
• Consolidation• D-RVd = 59%• RVd = 24%
MRD negative CR rate:• Induction
• D-RVd = 8%• RVd = 1%
• Consolidation• D-RVd = 29%• RVd = 10%
“The study met its primary endpoint; D-RVd improved the sCR rate by the end of consolidation (42.4% vs 32.0%; odds ratio 1.57; 95% CI, 0.87-2.82; 2-sided P = 0.1359); at the pre-set 2-sided alpha of 0.2.”
Abstract 691 results
862 Weekly Carfilzomib, Lenalidomide, Dexamethasone and Daratumumab (wKRd-D) Combination Therapy Provides Unprecedented MRD Negativity Rates in Newly Diagnosed
Multiple Myeloma: A Clinical and Correlative Phase 2 StudyOla Landgren et al
Questions addressed by the results of ASH 2019 abstract 862:
• Can you increase the potency of the PI-IMID combo?– KRd
• Can you make it more convenient?– Weekly carfilzomib dosing
• Can you safely add a MAb?– Dara-wKRd
Key aspects of abstract 862 Study design and results:
• Median cycles delivered = 6
• MRD primary end-point:– 15/18 (83%) MRD negative
• No added major clinical toxicities with wKRd-D vs bKRd
• wKRd-D vs bKRd-D
• Substantial reduction of the number of infusions (total of 51 vs 27 infusions with bKRd-D vs wKRd-D, respectively)
LBA-6 Carfilzomib, Dexamethasone, and Daratumumab Versus Carfilzomib and Dexamethasone for the Treatment of Patients with Relapsed or Refractory
Multiple Myeloma (RRMM): Primary Analysis Results from the Randomized, Open-Label, Phase 3 Study Candor (NCT03158688)
Saad Z. Usmani et al
Background • Potent triplets are approved in RRMM
– Dara-Vd– Dara-Rd– KRd– IRd (not in Canada)
• What does one use after progression on Lenalidomide-containing regimen?
– Ex: Len-Dex frontline or Len-maintenance• Kd is most potent PI-based doublet (ENDEAVOR: Kd vs Vd)• Does anything come close to median PFS of ~40 months
with DRd as per POLLUX study?
Study Design • Kd vs Dara-Kd until progression
• Carfilzomib (20/56 mg/m2) IV days 1, 2, 8, 9, 15, and 16 of each 28-day cycle
• 40 mg dexamethasone oral or IV weekly (20 mg for pts >75 years)
• Daratumumab (8 mg/kg) as per standard dosing
For Dara-Kd vs Kd:• ORR:
• 84.3% vs 74.7% (P=0.0040)• CR or better:
• 28.5% vs 10.4%(P= ???)
• MRD-negative CR at 12 mo: • 12.5% vs 1.3% (P<0.0001)
Abstract LBA-6 results
142 T(11;14) and High BCL2 Expression Are Predictive Biomarkers of Response to Venetoclax in Combination with Bortezomib and Dexamethasone in Patients with
Relapsed/Refractory Multiple Myeloma: Biomarker Analyses from the Phase 3 Bellini Study
Simon Harrison et al
Mechanism of action of venetoclax.
Marina Konopleva et al. Cancer Discov 2016;6:1106-1117
©2016 by American Association for Cancer Research
Background
• t(11;14) MM is overrepresented by higher dependency on BCL-2 as an anti-apoptotic pathway
• Increased sensitivity to BCL-2 inhibition (venetoclax)
• Bortezomib further inhibits the “back up system” of MCL-1 providing biological rationale for combination therapy
• Venetoclax-Vd vs Plb-VD– Notable increase in outcomes (PFS, RR) in t(11;14)
and high BCL2 expression• Note:
- 54% of t(11;14) were High BCL2- 20% of High BCL2 pts were t(11;14)
• Basis for biomarker driven use of this combination in future studies
Kumar et al, EHA 2019
Abstract 142 Results
33%
12%
39%
• Early deaths from infection higher in non-t(11;14) and low BCL2 expressors MM
Abstract 142 PFS and OS in key biomarker subgroups, venetoclax versus placebo treated patients
731. Bortezomib-Based Induction, Augmented Conditioning with Busulfan and Melphalan + ASCT and Lenalidomide Maintenance for Newly Diagnosed Multiple Myeloma: Long-Term
Results of the National Canadian Mcrn-001 StudyD. E. Reece et al.
Background• Melphalan has been standard approach for TE MM patients • The MCRN Canadian National trial augmented the regimen to optimize the results:
– Bortezomib-based induction• Weekly CyBorD
– Augmented HD chemotherapy with busulfan + melphalan before ASCT • Busulfan 3.2 m/kg IV days -5 to -3 or days -6 to -4 and Melphalan 140 mg/m2 days -2
or -3– Lenalidomide maintenance post-ASCT
• Day 100, 10mg/d, escalated to 15mg/d if appropriate, continued until progression • 78 patients enrolled, 19% with HR FISH cytogenetics
• Median F/U = 55.7 months • CR = 56%• VGPR = 40%
• ≥VGPR = 96%• PR = 4%
• MRD negativity rates = 28% after induction, rising to 39% at day 100 and 41% at 12 months
• As of 05/31/2019, 24 pts progressed, 12 have died (8 from MM)
• Median PFS and OS not yet reached • Estimated 5-year PFS = 60%• Estimated 5-year OS = 82%
• No early ASCT deaths • SPMs were diagnosed in 21% of patients,
median 29 months post-ASCT (3 after Len discontinuation)
Abstract 731 Results
3173. Treatment of Myeloma Patients Progressing on Lenalidomide-Based Maintenance after ASCT Performed As Part of 1st, 2nd or 3rd Line Therapy: Real-World Results from the
National Myeloma Canada Research Network (MCRN) DatabaseD.E. Reece et al.
Background• Lenalidomide (len) administered as maintenance improves the PFS and OS after
ASCT performed in the 1L • Also efficacy when administered after salvage ASCT in relapsed patients, in patients
who have not progressed previously on len• For patients progressing on len, optimal management is unclear• Utilized the MCRN database to investigate which regimes were utilized after
progression on len-based therapy and report the outcomes observed in the real-world Canadian setting
• Median PFS for 327 px who received treatment for progression on len-based therapy = 11 months
• OS = 39 months from post-len Rx
• Longer benefit observed in pts treated with newer proteasome inhibitors or Dara-based regimens
• Real-world results approximate the outcomes reported in clinical trials in pts progressing on len-based regimens after 1-3 prior lines of therapy
Abstract 3173 results
859 Daratumumab Plus Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Patients with Transplant-Ineligible Newly Diagnosed Multiple
Myeloma: Overall Survival in ALCYONEM.V. Mateos et al.
Background• Standard of care for ASCT-ineligible with NDMM is combination therapy, including
VMP, VRd or Rd • Phase III ALCYONE study assessed the addition of Dara to VMP in TI NDMM
patients • Primary analysis: (16.5 month F/U) Dara + VMP led to 50% reduction in risk of
progression or death vs VMP • Extended F/U (27.8 months) found 57% reduction in risk of progression or death
with Dara + VMP vs VMP • Addition of Dara to VMP also nearly doubled the rate of CR and introduced a ≥3-
fold increase in MRD-negativity • Median F/U of this analysis = 40.1 months
• 706 patients randomized 1:1 to receive up to nine 6-week cycles of VMP with or without DARA
• Primary endpoint: median PFS was 36.4 months (DARA-VMP) vs 19.3 months (VMP)
• Median PFS2 (PFS on subsequent line of therapy) was not reached with DARA-VMP vs 42.3 months with VMP
• Estimated 36-month OS was 78% DARA-VMP vs 68% with VMP
• Median OS not reached in either group – ongoing F/U
• Addition of DARA to VMP prolongs OS in patients with TI NDMM, and demonstrates a significant PFS benefit which was maintained during subsequent lines of therapy
Abstract 859 results
1875. Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM)
Ineligible for Transplant: Updated Analysis of MaiaN. Bahlis et al.
Background • In the primary analysis (median F/U = 28 months), a significant PFS benefit and a >3-fold
increase in MRD-negativity rates were observed for D-Rd vs Rd in patients with TI NDMM
• This study provides an additional 9 months of F/U
• 737 patients were randomized 1:1 To receive RD with or without DARA, stratified according to ISS stage, region and age
• All patients received 28-day cycles of RD, whilst the D-Rd arm received DARA weekly for cycles 1-2, bi-weekly for cycles 3-6 and every four weeks thereafter
• Patients were treated until disease progression or unacceptable toxicity
• After a median F/U of 36.4 months, median PFS was not reached with D-Rd vs 33.8 months with Rd
• Estimated 36-month PFS rate was 68% (D-Rd) vs 46% (Rd)
• Adding Dara increased the depth of response with higher rates of ≥CR and ≥ VGPR
• Median duration of response was not reached (D-Rd) vs 40.7 months (Rd)
• Median PFS2 was not reached (D-Rd) vs 47.3 months (Rd) – ongoing F/U
• 39% (D-Rd) vs 64% (Rd) discontinued treatment, 9% vs 18%, respectively, due to TEAEs
• These findings, combined with ALCYONE, support the addition of DARA to 1L TE NDMM treatment regimens
Abstract 1875 results