Predictors Of Treatment Outcome With The Combination Of Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone (CRd) In Newly Diagnosed Multiple Myeloma (NDMM)
Authors: Jasielec Jagoda , Dytfeld Dominik , Griffith Kent A. , McDonnell Kathryn , Lebovic Daniel , Kandarpa Malathi , Vesole David H. , Jagannath Sundar , Mietzel Melissa A. , Vij Ravi , Faham Malek , Lee Liana , van Beers Erik H. , van Vliet Martin H. , Levy Joan , Alonge Mattina , Rosebeck Shaun , Kaminski Mark S. , Jakubowiak Andrzej J. 
Published: October 2019

Abstract

Background
NDDM patients (pts) treated with CRd in a phase 1/2 trial (NCT01029054) demonstrated high rates of complete response (CR, 62%) and stringent complete response (sCR, 55%) that correlated with excellent estimated 2-year progression-free survival (PFS; 94%) and overall survival (OS; 98%) (Jakubowiak et al, Blood, 2012; Jakubowiak et al, J Clin Oncol, 2013 abstract 8543). However, the correlation between risk factors or response rates and long-term treatment outcomes could not be demonstrated at that time, owing to a limited number of events. In this post hoc, retrospective analysis, we present an evaluation of outcomes based on pretreatment characteristics (including cytogenetics and gene expression profiling [GEP]) and their relationship to response and minimal residual disease (MRD) status.

Methods
Pts received 28-day cycles of carfilzomib (CFZ) 20-36 mg/m2 intravenously (days [d]1, 2, 8, 9, 15, 16), lenalidomide (LEN) 25 mg orally (PO; d1-21), and dexamethasone 40/20 mg PO weekly (cycles 1-4/5-8). For cycles 8-24, CRd was given with a modified CFZ schedule (d1, 2, 15, 16), and single-agent LEN was administered after cycle 24. Pts had the option to receive stem cell transplantation after cycle 4. Response was assessed by IMWG criteria, with the addition of near CR. Cytogenetic high-risk disease was assessed by IMWG criteria. RNA isolated from purified plasma cells at pretreatment was available in a subset of pts. GEP was performed using gene expression microarrays (Affymetrix U133 Plus 2.0 GeneChips), and a 92-gene signature (SKY92) was evaluated; pts in the subset were categorized as either SKY92 standard or high risk. MRD analysis was performed using multiparameter flow cytometry (MPF).

Results
As of May 31, 2013, 53 pts had received a median of 24 CRd cycles (range 2-24); 24 pts continued LEN maintenance for a median of 12 months (range 3-15). Thirty-four pts (64%) achieved at least a CR, and 29 pts (55%) achieved a sCR. Cytogenetic data were available for all but 2 pts: 33% of pts had high-risk disease, of which 47% had del p53. After a median follow-up of 31 months (range, 16-43), the estimated 3-year PFS and OS rates for all pts were 79% and 96%, respectively. There was a trend toward lower estimated PFS rate in pts with high-risk cytogenetics vs pts with standard-risk cytogenetics (69% vs 88%, P=.081; 10 pts had disease progression). Estimated OS rate was also lower in pts with high- vs standard-risk cytogenetics (83% vs 100%); although the number of events assessed was very low (2 pts have died), the difference was determined to be statistically significant (P=.041). There was a trend in the high- vs standard-risk groups toward a lower CR rate (53% vs 71%, respectively) and sCR rate (41% vs 62%, respectively), although the differences did not reach statistical significance (P=.233 and P=.234, respectively, using Fisher's exact test). A subset of 15 pts were analyzed by GEP, including 6 of 10 pts with disease progression. Based on GEP, 4 of 15 pts (27%) had SKY92 high-risk disease. All 4 pts relapsed, of which 2 pts had high-risk cytogenetics. In comparison, 2 of 11 pts (18%) with SKY92 standard-risk disease relapsed, of which 2 pts had high-risk cytogenetics. Twenty-five pts with CR/sCR (including 7 pts [28%] with high-risk cytogenetics) were evaluated for MRD; 22 pts (84%) were MRD-negative. Pts who achieved sCR at any time during CRd treatment showed a trend toward longer estimated 3-year PFS and OS compared with those who did not achieve sCR (PFS, 87% vs 68%, respectively, log-rank P=.222; OS, 100% vs 91%, log-rank P=.107). Among pts with MRD-negative disease, estimated 3-year PFS was 84%; OS was 100%.

Conclusions
CRd treatment in pts with NDMM resulted in excellent estimated 3-year PFS and OS rates after a median follow-up of 31 months, which compare favorably with historical results for both standard- and high-risk pts. Pts with high-risk cytogenetics by IMWG criteria or with SKY92 high-risk disease demonstrated a trend toward inferior PFS and OS compared with pts with standard-risk cytogenetics or SKY92 standard-risk disease, indicating that CRd treatment may not completely overcome the effect of poor disease characteristics on survival outcomes. However, our results suggest that achievement of sCR and having MRD-negative disease may be associated with superior PFS and OS. Follow-up analyses of MRD using MPF and deep-sequencing in pts with sCR are ongoing; results will be reported at the meeting.

Disclosures:
Off Label Use: Carfilzomib is a selective proteasome inhibitor that is approved in the US for the treatment of relapsed and refractory multiple myeloma (≥2 prior therapies including an immunomodulatory agent and a proteasome inhibitor, having progressed ≤60 days of completion of the last treatment). Lenalidomide is an immunomodulatory agent approved in combination with dexamethasone for patients with relapsed multiple myeloma (≥1 prior therapy). McDonnell:University of Chicago Medicine (Myeloma Program Coordinator) : Employment. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jagannath:Millennium: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Merck: Honoraria; Ortho Biotech: Membership on an entity's Board of Directors or advisory committees; Imedex: Membership on an entity's Board of Directors or advisory committees; Medicom Worldwide: Membership on an entity's Board of Directors or advisory committees; OptumHealth Education: Membership on an entity's Board of Directors or advisory committees; PER Group: Membership on an entity's Board of Directors or advisory committees. Vij:Onyx: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Lilly: Honoraria; BMS: Honoraria; Millenium: Speakers Bureau. Faham:Sequenta, Inc,: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Lee:Sequenta, Inc,: Employment, Equity Ownership. van Beers:Skyline Diagnostics: Employment. van Vliet:Skyline Diagnostics: Employment. Jakubowiak:BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen-Silag: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding.