Stull, Dawn Marie

BACKGROUND: PIs combined with an Rd backbone are the most commonly used triplet combination regimens in patients (pts) with RRMM in the US. The hallmark trials supporting the efficacy of these regimens were predominantly in pts without prior exposure to lenalidomide (R).1,2 Real-world analyses have shown that R-based regimens are increasingly used in the front-line setting.3-5 Thus, real-world treatment patterns in pts with prior R exposure and the real-world comparative effectiveness of PI-Rd triplets in this population with RRMM needs further elucidation. METHODS: A retrospective cohort of RRMM pts initiating IRd, KRd, or VRd in line of therapy (LOT) ≥2 were followed between 7/2007-9/2018 in Optum's deidentified national electronic health records database. RRMM pts were defined as those initiating LOT ≥2 between 1/2014 and 9/2018 and were categorized as having or not having prior exposure to R (R-exposed; no-prior-R) in any prior LOT. Index regimen was the first use of I-/K-/or V-Rd. LOTs were defined via an algorithm developed with MM specialists to proxy the definition of a LOT in RCTs & in accordance with NCCN MM Guidelines.6 Baseline data included: CRAB (hyperCalcemia, Renal insufficiency, Anemia, and Bone lesions); high risk cytogenetics (defined as del[17p], 1q21 gain, t[4;14], or t[14;16]); Charlson Comorbidity Index (CCI) score; and modified frailty score using age and CCI score. Median duration of therapy (DOT) and time-to-next-treatment (TTNT) (a proxy for PFS; defined as time from index regimen start to subsequent LOT or death) were estimated using Kaplan-Meier methods and compared using covariate-adjusted Cox proportional hazard models (FIGURE). Observations were censored at time of loss to follow-up (f/u)/end of study period (9/30/2018). RESULTS: Of 650 pts included, 397 were R-exposed (IRd, n=112; KRd, n=115; VRd, n=170); 253 had no-prior-R (IRd, n=29; KRd, n=62; VRd, n=162). R-exposed pts, overall, were treated in later LOTs (LOT2: 55% v 78%) and had a longer median time from diagnosis to index LOT (26.7 v 13.4 months) than no-prior-R pts; this differed between treatment cohorts (TABLE). In R-exposed pts, more pts with symptomatic relapse (≥1 CRAB symptom, 87%) or high-risk cytogenetics (30%) received KRd than IRd (75% & 23%) or VRd (74% & 16%) (TABLE). More pts treated with IRd were ≥75 years old: 42% (IRd) v 36% (VRd) / 21% (KRd). In R-exposed pts, 35.3% of those receiving VRd in LOT ≥2 had prior V-IMID-based and 53.5% had IMID-based therapy (ie, IMID with no PI nor monoclonal antibody) in LOT1; >98% of LOT1 IMID use was R, across groups. In R-exposed pts, 56.5% of those receiving KRd had prior V-IMID-based and 16.5% had IMID-based therapy in LOT1; in IRd pts in LOT ≥2, 29.5% and 43.8% had prior V-IMID-based and IMID-based therapy in LOT1. In unadjusted analysis, at a median f/u of 11, 11.9, and 14.8 months for I-, K-, and V-Rd, median TTNT for R-exposed pts: 12.3 months (IRd), 7.8 months (KRd), and 13.9 months (VRd) (P=0.50); HRs for TTNTLOT stratified: 0.84 (IRd v KRd), 0.96 (IRd v VRd), 1.15 (KRd v VRd), and median regimen DOTs: 8.4 months (IRd), 7.5 months (KRd), and 9.5 months (VRd) (P=0.75). In no-prior-R pts, HRs for TTNTLOT stratified were significant for IRd v KRd (HR=0.33) and KRd v VRd (HR=1.62) (P<0.01, both); IRd v VRd (HR=0.53; P=0.11). In adjusted analysis, there were no significant differences for R-exposed pts by PI-Rd regimens for TTNT (FIGURE), nor for regimen DOT. For no-prior-R pts, adjusted HR for TTNT was significant for I- v K-Rd (HR=0.36; P=0.03) and for regimen DOT was significant for I- v V-Rd (HR=0.34; P=0.03). CONCLUSIONS: In this real-world study, the majority of pts received a PI-Rd combination after prior VRd or Rd in front-line. After controlling for baseline characteristics, including prior PI-exposure, PI-Rd triplets were comparable in TTNT in R-exposed pts treated in LOTs ≥2. TTNT was significantly longer for I- v K-Rd in pts with no-prior-R, although this is limited by small sample size. Published studies indicate that individualized treatment recommendations may improve real-world outcomes, such as IRd v KRd in frail pts which was associated with significantly longer TTNT.6 Prior-R exposure, in our analysis, does not appear to influence the relative PI-triplet regimen effectiveness in LOTs ≥2. With increasing use of R in earlier LOTs, understanding real-world treatment patterns and subsequent PI-Rd effectiveness in consequent LOTs is key for optimizing RRMM pt management. Disclosures Cherepanov: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Romanus:Takeda: Current Employment. Raju:Xcenda: Current Employment, Other: Xcenda received research funding from Takeda. Blazer:Xcenda: Current Employment, Other: Xcenda received research funding from Takeda. Farrelly:Xcenda: Current Employment, Other: Xcenda received research funding from Takeda. Stull:Takeda: Current Employment. Ailawadhi:Phosplatin: Research Funding; Celgene: Honoraria; Amgen: Research Funding; Takeda: Honoraria; Janssen: Research Funding; Pharmacyclics: Research Funding; Cellectar: Research Funding; BMS: Research Funding; Medimmune: Research Funding.

BACKGROUND: Proteasome inhibitors (PIs) combined with an Rd backbone constitute commonly used regimens in RRMM in the US. Lack of data from head-to-head clinical trials comparing the efficacy of these PI-Rd triplets and the extent to which efficacy translates to benefit in routine care highlight the need for real-world evidence. We conducted a comparative effectiveness analysis of time to next therapy (TTNT) of these PI-Rd triplet combinations in a real-world representative cohort of RRMM patients. METHODS: In this retrospective cohort study, RRMM patients who initiated an index regimen with IRd, KRd, or VRd in ≥2nd line of therapy (LOT 2+) were followed between 1/2014-9/2018 in Optum's deidentified national electronic health records database. This database captures information on all patients treated by >140,000 providers across 50 states in the US. It is representative of the US general population. Baseline data included: a modified frailty score utilizing age and Charlson Comorbidity Index1, ECOG performance status, CRAB symptoms, ISS stage, cytogenetic risk (high: del[17p], t[4;14], or t[14;16]), history of: cardiovascular disease, peripheral neuropathy, stem-cell transplant, and uncontrolled hypertension, prior PI and/or IMID exposure and refractory status, time from diagnosis to start of index LOT, time from start of frontline therapy to start of LOT 2, and treatment-free interval prior to index LOT. Duration of therapy (DOT) and TTNT were estimated using Kaplan-Meier methods and compared using stratified (by LOT) ± baseline-adjusted Cox proportional hazard models with a repeated measures analysis of pt-LOTs with robust sandwich estimators to account for inclusion of patients in multiple LOTs. The main analysis was repeated in subgroups a priori defined by frailty score, cytogenetic risk, prior PI and/or IMID exposure and LOT. Observations were censored at time of loss to follow up/end of study period (9/30/2018). RESULTS: Overall, 650 patients with 733 pt-LOTs (IRd, n=168; KRd, n=208; VRd, n=357) were included; 20% of the RRMM patients in this cohort were treated at academic centers. In the I-/K-/V-Rd groups, respectively, median age was 71/65/71 years and 42/22/38% patients were ≥75 years old; 39/55/46% and 28/14/29% patients had a modified frailty score of intermediate and frail, respectively; 71/88/80% had a symptomatic relapse with at least 1 CRAB symptom; 20/28/13% patients had high cytogenetic risk; 69/72/90% patients were treated in 2-3 LOT, and 63/70/32% patients had prior exposure to a PI+IMID (P<0.05 for all). The median follow-up was 14.4 months. Unadjusted median DOT of index LOT was 12.3/7.2/10.0 months, with a lower risk of discontinuation of the oral PI component for I in comparison to both K and V (HR[I vs K] of 0.66 and HR[I vs V] of 0.68) and R component in the IRd vs KRd and VRd groups (HR[I vs K] of 0.64 and HR[I vs V] of 0.75) (P<0.05 for all). Unadjusted median TTNT was 12.7/8.6/14.2 months for I-/K-/V-Rd in LOT ≥2; with HR for TTNT of 0.76 (IRd vs KRd; P<0.05); 1.01 (IRd vs VRd; P=0.96); 1.33 (KRd vs VRd; P<0.05). The adjusted HRs for TTNT I-/K-/V-Rd in LOT ≥2 were 0.82 (IRd vs KRd); 0.93 (IRd vs VRd); 1.13 (KRd vs VRd; P>0.05 for all), and were comparable between all 3 groups. A significant TTNT benefit for IRd vs KRd was observed among patients with high cytogenetic risk (HR: 0.47) and with intermediate frailtymodified score (HR: 0.60; P<0.05 for all). CONCLUSIONS: In this real-world representative RRMM cohort, in unadjusted analyses, the IRd group had a longer DOT of the PI and R components and a longer TTNT in comparison with KRd. After adjusting for baseline confounders to separate the treatment effect, the I/K/V-Rd triplet combinations were comparable in TTNT, but IRd was significantly better than KRd in patients with high-risk cytogenetics and with an intermediate frailty score. Residual confounding is always a potential limitation of any non-randomized study. Conversely, the results of randomized, clinical trials are limited in generalizability as 40-60% of patients are excluded due to inability to meet eligibility criteria. This is especially pertinent in an elderly RRMM population as demonstrated in the real-world effectiveness results in this study. Ref: 1. Palumbo, et al. Blood. 2015;125:2068-2074 Figure Disclosures Chari: Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Oncoceutics: Research Funding; Novartis Pharmaceuticals: Research Funding; GlaxoSmithKline: Research Funding; Array Biopharma: Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Romanus:Takeda: Employment. Raju:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Other: Xcenda received funding from Takeda to complete this analyses., Research Funding; Xcenda, LLC: Employment. Cain:Takeda: Employment. Blazer:Xcenda: Employment; Takeda: Other: Xcenda received funding from Takeda for completion of this analysis, Research Funding. Farrelly:Xcenda: Employment; Takeda: Other: Xcenda received funding from Takeda for completion of this analysis, Research Funding. Stull:Takeda: Employment. Ailawadhi:Pharmacyclics: Research Funding; Cellectar: Research Funding; Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding.