Mezzi, Khalid

Abstract Frailty is most prevalent among elderly multiple myeloma (MM) patients, and frail patients have a higher risk of poor outcomes due to reduced performance status or comorbidities. This post hoc analysis assessed efficacy and safety of carfilzomib combinations in frail patients with relapsed and/or refractory MM from the phase 3 ASPIRE (carfilzomib [27 mg/m2]-lenalidomide-dexamethasone [KRd27] vs lenalidomide-dexamethasone [Rd]), ENDEAVOR (carfilzomib [56 mg/m2]-dexamethasone [Kd56] vs bortezomib-dexamethasone [Vd]), and ARROW (once-weekly carfilzomib [70 mg/m2]-dexamethasone [Kd70] vs carfilzomib [27 mg/m2]-dexamethasone [Kd27]) studies. A frailty algorithm incorporating age, Charlson comorbidity index, and performance status classified patients as fit, intermediate, or frail. Results are presented for frail patients (ASPIRE, n = 196; ENDEAVOR, n = 330; ARROW, n = 141). In ASPIRE, median progression-free survival (PFS) (hazard ratio; 95% confidence interval) was 24.1 (KRd27) vs 15.9 months (Rd) (0.78; 0.54-1.12); median overall survival (OS) was 36.4 vs 26.2 months (0.79; 0.57-1.08). In ENDEAVOR, median PFS was 18.7 (Kd56) vs 6.6 months (Vd) (0.50; 0.36-0.68); median OS was 33.6 vs 21.8 months (0.75; 0.56-1.00). In ARROW, median PFS was 10.3 (once-weekly Kd70) vs 6.6 months (twice-weekly Kd27) (0.76; 0.49-1.16). In all 3 studies, rates of grade ≥3 treatment-emergent adverse events were consistent with those observed in the primary studies. The ASPIRE, ENDEAVOR, and ARROW primary analyses demonstrated favorable benefit-risk profiles with carfilzomib-containing regimens compared with controls. Across clinically relevant subgroups, including those by frailty status, consistent efficacy and safety were observed with KRd27, Kd56, and weekly Kd70, and treatment with these regimens should not be restricted by frailty status.

e19505 Background: CFZ combined with dexamethasone is approved to treat pts with RRMM, with CFZ given once-weekly at 70 mg/m2 (Kd70 QW) or twice-weekly at 56 mg/m2 (Kd56 BIW). No randomized trials have directly compared Kd70 QW with Kd56 BIW. We performed a post hoc comparison between pts who received Kd56 BIW in the ENDEAVOR trial and pts who received Kd70 QW in the A.R.R.O.W. or CHAMPION-1 trials. Methods: Data were analyzed from 3 trials of CFZ in RRMM: A.R.R.O.W. (240 pts in Kd70 QW arm; 2–3 prior therapies and refractory to most recent therapy), CHAMPION-1 (104 pts received Kd70 QW; 1–3 prior therapies), and ENDEAVOR (464 pts in Kd56 BIW arm; 1–3 prior therapies). Pts who received Kd70 QW in A.R.R.O.W. and CHAMPION-1 were pooled and compared with pts who received Kd56 BIW in ENDEAVOR. As study populations slightly varied among the 3 trials, an analysis of safety and efficacy was performed in a subgroup of pts who received 2–3 prior therapy lines and were not refractory to bortezomib (BTZ). Also, we performed regression analyses (controlling for age, ISS stage, BTZ and lenalidomide refractory status, and number of prior regimens) among all pts in the trials who received Kd70 QW or Kd56 BIW. Results: Among BTZ non-refractory pts with 2–3 lines of prior therapy, median progression-free survival (PFS) was 12.1 months (95% CI 8.4–14.3) for Kd70 QW (n = 146) and 14.5 months (95% CI 10.2–NE) for Kd56 BIW (n = 217), and the overall response rate (ORR) was 69.9% (95% CI 61.7–77.2) for Kd70 QW and 72.4% (95% CI 65.9–78.2) for Kd56 BIW. The rate of grade ≥3 adverse events (Kd70 QW vs Kd56 BIW) was 67.6% and 85.3%; among adverse events of interest, the grade ≥3 rate was 1.4% and 5.1% for cardiac failure, 3.4% and 6.0% for renal failure, and 5.5% and 15.7% for hypertension. Kd70 QW represents a convenient and well-tolerated treatment modality for pts with RRMM. In a Cox proportional hazards model, the hazard ratio for PFS (Kd70 QW vs Kd56 BIW) was 0.91 (95% CI 0.69–1.19), and in a logistic regression model the odds ratio for ORR (Kd70 QW vs Kd56 BIW) was 1.12 (95% CI 0.74–1.69). Conclusions: This post hoc analysis suggests that once-weekly Kd70 has a comparable benefit-risk profile to twice-weekly Kd56. Clinical trial information: NCT02412878, NCT01677858, NCT01568866.

Abstract Combination of carfilzomib with dexamethasone (Kd) is approved for use in relapsed and/or refractory multiple myeloma (RRMM), with carfilzomib administered twice weekly at 56 mg/m 2 (Kd56 BIW) or once weekly at 70 mg/m 2 (Kd70 QW). Post hoc cross‐trial comparisons were performed to compare efficacy and safety profiles of Kd70 QW vs Kd56 BIW dosing schedules using data from three trials of patients with RRMM: A.R.R.O.W., CHAMPION‐1, and ENDEAVOR. To select for comparable patient populations, side‐by‐side efficacy and safety comparisons were performed in subgroups of patients with 2‐3 prior lines of therapy who were not refractory to bortezomib. The overall response rate (ORR) was 69.9% (95% confidence interval [CI], 61.7‐77.2) for Kd70 QW and 72.4% (95% CI, 65.9‐78.2) for Kd56 BIW. Median progression‐free survival (PFS) was 12.1 months (95% CI, 8.4‐14.3) for Kd70 QW and 14.5 months (95% CI, 10.2—not evaluable) for Kd56 BIW. Frequency of grade ≥ 3 adverse events (AEs) was 67.6% for Kd70 QW and 85.3% for Kd56 BIW. Regression analyses (adjusting for prognostic factors) of all patients in the trials who received Kd70 QW vs Kd56 BIW estimated a PFS hazard ratio of 0.91 (95% CI, 0.69‐1.19; P = .47) and an ORR odds ratio of 1.12 (95% CI, 0.74‐1.69; P = .61). These results suggest that Kd70 QW has a comparable efficacy profile compared with Kd56 BIW and represents a convenient and well‐tolerated treatment for patients with RRMM.

Abstract Introduction: Renal impairment (RI) is a classic clinicopathological feature of MM, is associated with poor prognosis and shorter survival (Eleutherakis-Papaiakovou Leuk Lymphoma 2007), and can complicate drug dosing and limit treatment options. In clinical trials, the proteasome inhibitors K and V have demonstrated efficacy in RRMM pts with RI, with superior efficacy observed in K-treated pts (Dimopoulos Blood 2017). K and V have also been observed to improve renal function in RRMM pts (Dimopoulos Clin Lymphoma Myeloma 2009; Dimopoulos Blood Advances 2017). However, few studies have investigated the real-world effectiveness of K- and V-based regimens in renal rescue. This study aimed to describe and compare renal response rates in RRMM pts treated with K + dexamethasone (Kd) and V + dexamethasone (Vd) in oncology clinics. Methods: The Oncology Services Comprehensive Electronic Records (OSCER) database (Lau Clin Epidemiol 2011) contains electronic medical records (EMR) from community- and hospital-affiliated oncology clinics in the United States. MM pts aged ≥18 who entered an OSCER clinic Jan 2012‒Feb 2018; initiated Kd or Vd treatment as line 2 (2L), 3L, or 4L; and had baseline renal impairment (Modification of Diet in Renal Disease Study estimated glomerular filtration rate [eGFR] <50 mL/min from the most recent baseline serum creatinine measurement) were included. Index date was the date of Kd or Vd initiation. The baseline period was 60 d prior to index to 30 d post-index. Follow-up was 30 d after index date to 60 d after completion of the same line. Primary outcome was renal response during follow-up. Renal response was defined according to the International Myeloma Working Group criteria (Dimopoulos J Clin Oncol 2016): complete response (RCR; baseline eGFR <50 mL/min and best post-treatment eGFR ≥60 mL/min), partial response (baseline eGFR <15 mL/min and best post-treatment eGFR 30‒59 mL/min), minor response (baseline eGFR <15 mL/min and best post-treatment eGFR 15‒29 mL/min, or baseline eGFR 15‒29 mL/min and best post-treatment eGFR 30‒59 mL/min). Renal response rates in Kd- and Vd-treated pts were evaluated using the Kaplan-Meier method and log-rank test. Incidence rate ratios (IRR) and 95% confidence intervals (CIs) were calculated for renal overall response (ROR) and RCR using multivariate Cox proportional hazard models adjusted for baseline covariates (demographics, Eastern Cooperative Oncology Group Performance Status, International Staging System stage, baseline renal function, V use in 1L, time from MM diagnosis to line initiation, use of intravenous bisphosphonates, and baseline serum calcium, serum free light chain ratio, lactate dehydrogenase, and whole blood hemoglobin measurements). Missing baseline values were estimated by multiple imputations. Results: 543 Kd-treated and 1005 Vd-treated pts were included. Baseline characteristics were similar between cohorts, with no difference in baseline eGFR stages. More Kd pts were <65 yrs of age at MM diagnosis. Median time from diagnosis to line initiation was longer in Kd pts (Kd: 17.1 mos; Vd 16.1 mos). V-based regimens were the most common therapies in 1L. Median (interquartile range) treatment duration was 4.4 (2.3-8.3) mos for Kd and 4.3 (2.1-8.3) mos for Vd. Pts treated with Kd at 2L were more likely than those treated with Vd to achieve both ROR (51.4% [178/346] vs 39.6% [327/825]; log-rank test p<0.0001) and RCR (26.6% [92/346] vs 22.2% [183/825]; log-rank test p=0.0229). This pattern persisted when 3L and 4L pts were included, (ROR: 48.4% [263/543] vs 39.8% [400/1005]; log-rank p<0.0001; RCR: 26% [141/543] vs 22.1% [222/1005]; log-rank p=0.0084) (Figures 1A and 1B). Following adjustment for potential baseline confounders, 2L Kd pts were 45% more likely to achieve ROR (IRR, 95% CI: 1.45, 1.18‒1.78) and 68% more likely to achieve RCR (1.68, 1.24‒2.28) vs 2L Vd pts (Figure 2). Kd pts in 2‒4L were 36% more likely to achieve ROR (1.36, 1.15‒1.62) and 52% more likely to achieve RCR (1.52, 1.19‒1.94). Conclusions: Using one of the most complete oncology EMR databases available, we found that RRMM pts with baseline RI treated with Kd had higher rates of overall and complete renal response, and were more likely to have a renal response, compared with pts treated with Vd. A limitation of the study is that we could not account for all concomitant medications or comorbidities that affect renal function, as some may not be captured in OSCER. Disclosures Kumar: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fu:Amgen: Employment, Equity Ownership. Mezzi:Amgen: Employment, Equity Ownership. Braunlin:Amgen: Employment. Kim:Amgen: Employment, Equity Ownership. Iskander:Amgen: Employment, Equity Ownership. Niesvizky:Amgen Inc.: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Jagannath:Celgene: Consultancy; Novartis: Consultancy; Merck: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; Bristol-Myers Squibb: Consultancy. Boccia:Sandoz: Consultancy; Celgene: Speakers Bureau; Abbvie: Speakers Bureau; Genentech: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; BMS: Research Funding; Pfizer: Consultancy; AstraZeneca: Research Funding, Speakers Bureau. Raje:Celgene: Consultancy; Janssen: Consultancy; Merck: Consultancy; Takeda: Consultancy; AstraZeneca: Research Funding; Research to Practice: Honoraria; Medscape: Honoraria; BMS: Consultancy; Amgen Inc.: Consultancy.

Abstract Introduction: Multiple myeloma (MM) is a hematologic cancer that mostly affects elderly patients who are at increased risk for development of cardiac-related comorbidities due to age-, disease-, and treatment-related factors. In real world data, approximately 25-30% of MM patients are hospitalized for a cardiac event after MM diagnosis (Kistler et al. American Society Hematology 2012 Annual Meeting, poster 2916). The proteasome inhibitor, carfilzomib, is approved for treatment of patients with relapsed or refractory MM. In carfilzomib clinical trials, grade 3 or higher cardiac failure was reported for ~4% of patients (Stewart et al. NEJM 2015;372:142-52, Dimopoulos et al. Lancet Oncol 2016;17:27-38). In this retrospective analysis, we sought to evaluate the incidence rate (IR) of cardiac events in MM patients treated with carfilzomib in a real-world setting in the US and to describe differences in baseline characteristics between carfilzomib-treated MM patients who do and do not have cardiac events. Methods: Newly-diagnosed MM patients with symptomatic disease were identified in the Truven MarketScan claims database from 1/1/05 to 6/30/15 using an algorithm validated for ascertainment of MM patients in claims data (Princic et al. Blood 2015;126:4521). All carfilzomib-treated patients were included in the analysis. The first dose of carfilzomib was the index date. The baseline period was 12 months prior to the MM diagnosis date to the index date. Cardiac events (hypertension, heart failure, ischemic heart disease, arrhythmias and conduction disorders, and cardiomyopathy) were identified during baseline by inpatient (IP) or outpatient (OP) claims and after index date by primary diagnosis on IP claims (hospitalized events). Logistic regression was used to estimate baseline covariates associated with any cardiac event. Due to sample size constraints, multivariate regression was not performed. The incidence rate (IR) per 1000 patient-years (PYRs) and associated 95% confidence interval (CI) of hospitalized cardiac events during carfilzomib treatment which included 30 days after the last carfilzomib dose were calculated among patients without a history of the corresponding hospitalized event during the baseline period. Results: The cohort included 498 MM patients treated with carfilzomib; 108 (22%) patients had ≥1 cardiac event identified by both IP and OP claims and 24 (5%) had ≥1 hospitalized cardiac event. Of the 24 hospitalized patients, 14 were hospitalized during carfilzomib treatment (median days to onset = 104) and 8 were hospitalized after carfilzomib treatment (>30 days post dosing; median days to onset = 284). The median age (range) of the 24 patients with hospitalized cardiac events and those with no hospitalized cardiac claims (n=474) was 62 (37, 79) and 61 (36, 96) years, respectively (Table). Baseline medical history of any cardiac event was evident for 92% of hospitalized patients and 84% of non-hospitalized patients. Among hospitalized patients, 25% were over 75 years as compared with 13% of non-hospitalized patients. In univariate analysis, patients with baseline amyloidosis, hypertensive chronic kidney disease, and chronic kidney disease had higher odds of having a hospitalized cardiac event. No significant differences were seen in the proportion of patients with or without a hospitalized cardiac event when evaluated by line of therapy or by carfilzomib treatment regimen (monotherapy or combination). Among patients aged 75+ years, 8.7% were hospitalized, while 2.5% and 4.9% of 65-74 and 18-64 year old patients were hospitalized, respectively (Table). IR per 1000 PYRs [95% CI] among the 14 carfilzomib-treated MM patients hospitalized for any cardiac event during the carfilzomib treatment period was 89.7 (49.0; 150.5) - see Figure for IRs of specific cardiac events. Conclusions: Among carfilzomib-treated patients in a US claims database, hospitalization for a cardiac event was uncommon (~5%) and does not exceed what has been observed in MM patients. Patients at highest risk for cardiac hospitalizations had a history of amyloidosis or chronic renal failure. Additional analyses in much larger populations are needed to better understand risk factors for these events. Disclosures Chari: Array Biopharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Research Funding. Aggarwal:Amgen: Employment, Equity Ownership. Mezzi:Amgen Inc.: Employment, Equity Ownership. Wang:Amgen Inc.: Employment, Equity Ownership. Kim:Amgen Inc.: Employment, Equity Ownership. Zhu:Amgen Inc.: Consultancy. Braunlin:Amgen Inc.: Employment, Equity Ownership. Werther:Amgen Inc.: Employment, Equity Ownership. Mikhael:Abbvie: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Onyx: Research Funding.

Background:Carfilzomib (CFZ) combined with dexamethasone is approved to treat patients (pts) with relapsed and/or refractory multiple myeloma (RRMM), with CFZ given once‐weekly at 70 mg/m2 (Kd70 QW) or twice‐weekly at 56 mg/m2 (Kd56 BIW). No randomized trials have directly compared Kd70 QW with Kd56 BIW.Aims:We performed a post hoc comparison between pts who received Kd56 BIW in the ENDEAVOR trial and pts who received Kd70 QW in the A.R.R.O.W. or CHAMPION‐1 trials.Methods:Data were analyzed from 3 trials of CFZ in RRMM: A.R.R.O.W. (240 pts in Kd70 QW arm; 2–3 prior therapies and refractory to most recent therapy), CHAMPION‐1 (104 pts received Kd70 QW; 1–3 prior therapies), and ENDEAVOR (464 pts in Kd56 BIW arm; 1–3 prior therapies). Pts who received Kd70 QW in A.R.R.O.W. and CHAMPION‐1 were pooled and compared with pts who received Kd56 BIW in ENDEAVOR. As study populations slightly varied among the 3 trials, an analysis of safety and efficacy was performed in a subgroup of pts who received 2–3 prior therapy lines and were not refractory to bortezomib (BTZ). Also, we performed regression analyses (controlling for age, ISS stage, BTZ and lenalidomide refractory status, and number of prior regimens) among all pts in the trials who received Kd70 QW or Kd56 BIW.Results:Among BTZ non‐refractory pts with 2–3 lines of prior therapy, median progression‐free survival (PFS) was 12.1 months (95% CI 8.4–14.3) for Kd70 QW (n = 146) and 14.5 months (95% CI 10.2–NE) for Kd56 BIW (n = 217), and the overall response rate (ORR) was 69.9% (95% CI 61.7–77.2) for Kd70 QW and 72.4% (95% CI 65.9–78.2) for Kd56 BIW. The rate of grade ≥3 adverse events (Kd70 QW vs Kd56 BIW) was 67.6% and 85.3%; among adverse events of interest, the grade ≥3 rate was 1.4% and 5.1% for cardiac failure, 3.4% and 6.0% for renal failure, and 5.5% and 15.7% for hypertension. Kd70 QW represents a convenient and well‐tolerated treatment modality for pts with RRMM. In a Cox proportional hazards model, the hazard ratio for PFS (Kd70 QW vs Kd56 BIW) was 0.91 (95% CI 0.69–1.19), and in a logistic regression model the odds ratio for ORR (Kd70 QW vs Kd56 BIW) was 1.12 (95% CI 0.74–1.69).Summary/Conclusion:This post hoc analysis suggests that once‐weekly Kd70 has a comparable benefit‐risk profile to twice‐weekly Kd56.© 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 ASCO Annual Meeting. All rights reserved.