Dimopoulos, Meletios Α.

Background:Despite recent advances, multiple myeloma (MM) remains incurable, and new treatment options are needed to continue to improve patient outcomes. This is the first randomized, phase 3 trial of an anti‐CD38 antibody in combination with pomalidomide (P) and dexamethasone (d) in RRMM.Aims:The primary objective of this phase 3 trial (NCT02990338) was to demonstrate progression free survival (PFS) improvement of isatuximab (Isa), a novel anti‐CD38 monoclonal antibody targeting a specific epitope, combined with Pd versus (vs) Pd in RRMM.Methods:Patients (pts) with RRMM who received ≥2 prior lines, including lenalidomide (len) and a proteasome inhibitor (PI), refractory to last therapy were enrolled. IsaPd arm received Isa 10 mg/kg IV weekly for first 4 weeks (wks), then every 2 wks. Both arms received approved schedules of pom and dex (4 mg PO days 1–21; 40 mg [20 mg if >75 yrs] PO or IV weekly) every 28 days until progression or unacceptable toxicity.Results:307 pts (154 IsaPd, 153 Pd) were randomized and analyzed (ITT). Patient characteristics were well balanced across arms. Median age: 67 (36–86) yrs; median prior lines of therapy: 3 (2–11); estimated GFR: <60 ml/min in 33.9% pts; 92.5% refractory to len, 75.9% to PI; and 19.5% pts had high‐risk cytogenetics. At median follow‐up of 11.6 months (mos), median PFS was 11.5 mos IsaPd vs 6.5 mos Pd; HR 0.596 (95% CI 0.44–0.81), P = 0.001. PFS benefit was consistent across all major subgroups. ORR (≥PR) was 60.4% IsaPd vs 35.3% Pd, P < 0.0001. VGPR rate or better was 31.8% IsaPd vs 8.5% Pd, and MRD negativity (NGS, 10−5) was seen in 5.2% IsaPd pts vs 0% Pd. At analysis date, overall survival (OS) was immature (99 events) but a trend to OS improvement in IsaPd (vs Pd) was observed (HR 0.687; 95% CI 0.461–1.023). Median treatment duration was 41 wks IsaPd vs 24 wks Pd; median Isa infusion (inf.) duration was 3.3 h at 1st inf. and 2.8 h at subsequent inf. Grade ≥3 AEs were observed in 86.8% IsaPd vs 70.5% Pd; 7.2% IsaPd and 12.8% Pd pts discontinued due to AEs; 7.9% IsaPd and 9.4% Pd pts died due to AEs. Inf. reactions were reported in 38.2% (2.6% grade 3–4) IsaPd. Grade ≥3 infections were seen in 42.8% IsaPd and 30.2% Pd, grade ≥3 neutropenia in 84.9% (febrile 11.8%) IsaPd and 70.1% (febrile 2.0%) Pd.Summary/Conclusion:Isatuximab in combination with pomalidomide and dexamethasone significantly improved PFS and ORR vs pomalidomide and dexamethasone, with a manageable safety profile. Isatuximab in combination with pomalidomide and dexamethasone is an important new treatment option for the management of RRMM.

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.

Background:Maintenance therapy (MT) in NDMM has been increasingly used to prolong duration of response achieved by ASCT. TOURMALINE‐MM3 is a phase 3, double‐blind, placebo‐controlled study, where ixazomib improved PFS, and is the first study to evaluate the impact of MT on HRQoL post ASCT in NDMM (Dimopoulos et al., Lancet 2019;393:253). HRQoL is an important consideration during MT in NDMM patients with minimal disease burden post ASCT (Anderson et al., Leukemia 2008;22:231).Aims:To assess HRQoL in patients randomized to ixazomib vs. placebo MT in TOURMALINE‐MM3.Methods:In TOURMALINE‐MM3, NDMM patients post ASCT were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo. HRQoL was assessed by EORTC QLQ‐C30 (overall/subscale score range, 1–100) at screening, the start of every cycle (1–26), end of treatment, every 4 weeks until start of next line of therapy after progression and twice thereafter. MM‐specific symptoms were assessed by EORTC QLQ‐MY20 (subscale score range, 1–100) at screening, the start of every 3 cycles between cycles 1–25, end of treatment, every 4 weeks until start of next line of therapy after progression and twice thereafter. For both instruments, higher scores for global and functional domains indicate better HRQoL, while higher scores on symptom scales represent higher levels of symptomatology. Change from study entry in subscale scores, defined in terms of 30 four‐week intervals, was analyzed using a linear mixed‐effects model among patients who reported HRQoL outcomes at study entry and completed at least one post‐study entry assessment.Results:Characteristics at study entry were well balanced between ixazomib (n = 386) and placebo (n = 251) arms; median age: 58 years; ECOG performance status 0–1: 97%; 79% had at least a very good partial response post ASCT at study entry. At study entry, least squares (LS) mean scores for ixazomib vs. placebo on the EORTC QLQ‐C30 were: Global Health Status/QoL, 69.8 vs. 69.1; Physical Functioning, 82.1 vs. 82.0; Pain, 25.3 vs. 25.7; Nausea/Vomiting, 2.3 vs. 2.0; Diarrhea, 5.9 vs. 6.0; and on the EORTC QLQ‐MY20 were: Disease Symptoms, 20.3 vs. 19.2; Peripheral Neuropathy, 25.0 vs. 25.6. Compliance with study assessments, averaged across cycles, was high in the treatment phase (≥94%) and similar between treatment groups.Changes in subscale scores across the 4‐week intervals were generally similar between the ixazomib and placebo groups, with treatment differences not reaching the established minimal important difference (MID) of 10 in MM (Kvam et al., Eur J Haematol 2011;87:330). LS mean (95% CI) score changes at interval 24 (week 96) for ixazomib vs. placebo on the EORTC QLQ‐C30 included: Global Health Status/QoL, –0.4 (–3.4, 2.7) vs. 1.8 (–1.7, 5.2); Physical Functioning, 0.7 (–1.8, 3.1) vs. 3.0 (0.3, 5.8); Pain, 4.1 (0.5, 7.7) vs. –1.4 (–5.5, 2.7); and on the EORTC QLQ‐MY20 were: Disease Symptoms, 5.1 (2.4, 7.9) vs. 0.8 (–2.3, 3.8); Peripheral Neuropathy, –0.7 (–5.1, 3.7) vs. –6.2 (–11.1, –1.3). EORTC QLQ‐C30 Nausea/Vomiting and Diarrhea subscales, while consistently worse for ixazomib than placebo (LS mean [95% CI] change at interval 24, 5.0 [3.0, 7.0] vs. 1.0 [–1.3, 3.3] and 4.0 [1.1, 6.8] vs. 0.5 [–2.8, 3.8], respectively), were in line with the ixazomib toxicity profile; treatment differences did not exceed the MID.Summary/Conclusion:In addition to improvements in PFS with ixazomib, HRQoL was maintained during the protocol‐defined treatment period in both arms, and active treatment with ixazomib did not have an adverse impact on HRQoL.

Background:A.R.R.O.W. demonstrated superior progression‐free survival (PFS) with once‐weekly carfilzomib (K, 70 mg/m2) and dexamethasone (Kd70) vs twice‐weekly K (27 mg/m2) and dexamethasone (Kd27) in relapsed and refractory (RRMM) patients (pts), regardless of age. For a comprehensive measure of fitness, frailty scales were developed incorporating age, comorbidities, and functional status (Palumbo Blood 2015;125:2068–74; Facon Blood 2015;126:4239).Aims:Here, we assessed post‐hoc pt outcomes by frailty status.Methods:PFS and safety were assessed by treatment arm and a frailty algorithm which incorporated age, Charlson Comorbidity Index derived from medical history, and ECOG performance status; pts with frailty scores of 0, 1, or ≥2 were classified as fit, intermediate, or frail, respectively. PFS was assessed using the Kaplan‐Meier method. Safety was assessed in pts who received ≥1 treatment dose.Results:The distribution of pts by frailty status was generally balanced between treatment arms (Table). Once‐weekly Kd70 vs twice‐weekly Kd27 resulted in median PFS for fit, intermediate, and frail pts of 15.7 vs 5.7 months (hazard ratio [HR] 0.53 [95% confidence interval (CI), 0.33–0.86]), 11.1 vs 7.7 months (HR 0.81 [95% CI, 0.55–1.19]), and 10.3 vs 6.6 months (HR 0.76 [95% CI, 0.49–1.16]), respectively.Rates of grade ≥3 treatment‐emergent adverse events (TEAEs) of interest were similar between treatment arms across frailty subgroups (Table). In the once‐weekly Kd70 subgroups, there was no grade ≥3 peripheral neuropathy and grade ≥3 cardiac failure rates were ≤4%.Summary/Conclusion:Once‐weekly Kd70 resulted in PFS benefits vs twice‐weekly Kd27, regardless of frailty level. These results support weekly Kd70 as a treatment option for fit and frail RRMM pts.image

Background:Deepened response has been associated with prolonged progression‐free (PFS) and overall survival in multiple myeloma, including in the maintenance therapy setting. In the Myeloma XI trial, post‐ASCT maintenance with lenalidomide vs observation resulted in improved responses in 15.8% vs 11.0% of patients (pts) and a median PFS of 56.9 vs 30.1 months (Jackson et al, ASH 2017). In the phase 3, double‐blind, placebo‐controlled TOURMALINE‐MM3 study (NCT02181413), post‐ASCT maintenance therapy with the oral proteasome inhibitor (PI) ixazomib vs placebo resulted in a 39% improvement in PFS (median 26.5 vs 21.3 months; HR 0.72; 95% CI: 0.58–0.89; p = 0.002), with a favorable safety profile (Dimopoulos et al, Lancet 2019). We report improvements in depth of response and the impact on outcomes in TOURMALINE‐MM3.Aims:To evaluate the rates and timing of response improvement during ixazomib vs placebo maintenance and the impact on PFS in TOURMALINE‐MM3.Methods:Pts who had achieved ≥partial response (PR) to induction therapy with a PI and/or immunomodulatory drug followed by single ASCT were randomized 3:2 to receive ixazomib (N = 395) or placebo (N = 261) on day 1, 8, and 15 of 28‐d cycles for up to 2 years or until progressive disease or unacceptable toxicity. Randomization was stratified by induction regimen, pre‐induction ISS stage, and post‐ASCT response (complete response [CR] or very good PR [VGPR] vs PR). Ixazomib dose was 3 mg in cycles 1–4 and 4 mg from cycle 5 if tolerated in cycles 1–4. Minimal residual disease (MRD) was assessed at screening by flow cytometry (10–5 sensitivity). The primary endpoint was PFS per independent review committee (IRC). Other endpoints included rate of response improvement in pts enrolled in VGPR or PR.Results:At study entry, 60 (15%), 213 (54%), and 89 (23%) pts in the ixazomib arm and 54 (21%), 152 (58%), and 35 (13%) in the placebo arm had CR, VGPR, and PR, respectively, by IRC. Deepening responses were seen in 139/302 (46%) ixazomib vs 60/187 (32%) placebo pts with VGPR/PR at enrollment (relative risk [RR] 1.41, 95% CI 1.1–1.8, p = 0.004), including 92/213 (43%) vs 48/152 (32%) VGPR to CR (RR 1.37, p = 0.025) and 47/89 (53%) vs 12/35 (34%) PR to VGPR/CR (RR 1.54, p = 0.063). On Kaplan‐Meier analysis of time to best deepened response in VGPR/PR pts (Figure), 24‐month rates of deepening response were 54.2% vs 41.4%, and there was a 38.4% improvement in the chance of deepening response over time with ixazomib vs placebo (HR 1.384, p = 0.034). A pooled analysis across arms among pts enrolled in VGPR/PR showed that deepening response vs no improvement was associated with prolonged PFS (median not reached vs 15.9 months; HR 0.245, 95% CI 0.184–0.325, p < 0.0001). Analysis by treatment arm showed that, in VGPR/PR pts with deepening response, 24‐month PFS rates were 77.4% vs 68.3% with ixazomib vs placebo (medians not reached; HR 0.875; 12.5% risk reduction; 95% CI 0.52–1.47; p = 0.615); in VGPR/PR pts without deepening response 24‐month PFS rates were 33.4% vs 23.6% (median 17.9 vs 14.1 months; HR 0.780; 22% risk reduction; 95% CI 0.59–1.03; p = 0.080). Baseline MRD status was a strong predictor of deepening response; deepening responses were seen in 63% (78/124) vs 32% (94/293) of MRD‐ vs MRD+ pts enrolled in VGPR/PR.Summary/Conclusion:Post‐ASCT maintenance with ixazomib resulted in a significantly higher rate of deepening response vs placebo; deepening response was associated with prolonged PFS. Ixazomib resulted in non‐significant PFS benefit vs placebo in VGPR/PR pts with and without deepening response; prolonged follow‐up would be needed to confirm these results.image

Background:Multiple myeloma (MM) is a heterogeneous disease with varying survival outcomes depending on the presence of certain genetic abnormalities. Common abnormalities include trisomies, translocations involving the chromosome 14, and amplifications or deletions of chromosomes 1, 13, and 17. t(11;14), occurring in 15% of patients with myeloma, had been considered a standard risk abnormality, but recent data suggest inferior outcome. This is important as new therapeutic options such as the BCL‐2 inhibitor venetoclax has been shown to be particularly effective in t(11;14) patients.Aims: Primary objective: To describe the overall survival of myeloma patients with translocation t(11:14) Secondary objectives: To determine the response rates, progression free survival, time to progression, time to next treatment, duration of responses and overall survival with different regimens among patients with t(11;14), to determine the prognostic factors for overall survival among patients with t(11;14), and to identify the spectrum of co‐existing genetic abnormalities among patients with t(11;14)Methods:This was a multicenter study to identify the outcomes of patients with t(11;14), using a retrospectively assembled cohort. Patients with MM diagnosed between 2005 and 2015 with t(11;14) identified on FISH performed within six months of diagnosis, and with treatment details available and if alive, a minimum of 12 months of follow up, were enrolled.Results:The current analysis includes 848 patients; median age of 64.4 years; 60.0% male. The median follow‐up from diagnosis for the entire cohort was 46.5 months; 86.7% of the patients were alive at the last follow up. ISS stage distribution included: Stage I (35.3%), Stage II (38.9%) and Stage III (25.8%). The distribution of FISH abnormalities included: del 13q (14.5%), 1q amp (12.1%), del 17p or monosomy 17 (6.1%). Initial therapy included different regimens: 23.3% had an IMiD, 43.3% had a PI, 20.0% had both and 13.3% had no novel agent. The drug classes by line of therapy are shown in Table 1. A stem cell transplant (SCT), defined as within 12 months of start of first line treatment, was used in 39.1% of patients. The median time to next treatment (TTNT) after initial treatment was 13.7 (95% CI: 11.3 to 16.5) months. The median overall survival (OS) from diagnosis for the entire cohort was 82.5 (95% CI: 73.5 to 95.8) months; 4‐year estimates for those diagnosed from January 2005 to December 2009, and from January 2010 to December 2014 were 75.1% and 70.2%, respectively. Median OS by initial regimen is shown in Figure 1; those receiving an early SCT had median OS of 116.9 (95% CI: 85.6 to NA) months.Summary/Conclusion:This is the first study to examine the outcomes of a large group of myeloma patients with t(11;14) abnormality. Patients receiving a combination of a PI and an IMiD appear to have the best survival outcomes. Patients receiving an early SCT appear to have excellent survival with median OS approaching 10 years. Additional patients are being accrued to this study and additional analysis examining the variables affecting response duration and survival will be presented.image

e18356 Background: Carfilzomib plus dexamethasone (Kd) dosed once weekly at 70 mg/m2 (QW Kd70) was recently approved in the US for treating patients with relapsed and refractory multiple myeloma (RRMM). To assess the cost-effectiveness (CE) of QW Kd70 vs twice weekly Kd dosed at 27 mg/m2 (BIW Kd27), data from the phase 3 ARROW trial, which directly compared these regimens in patients with 2-3 prior lines of therapy were used. Methods: A partitioned survival model was developed for the CE analysis. Time to treatment discontinuation, progression-free survival, and overall survival (OS) were estimated from the ARROW trial. Long-term OS was extrapolated using Surveillance Epidemiology and End Results registry data after matching characteristics of patients in the registry and ARROW trial. Direct costs were estimated from a US health care payer perspective. Utilities collected in the ARROW trial using the five-level version of the EuroQol questionnaire (EQ-5D-5L) were applied to estimate the quality-adjusted life years (QALYs). Uncertainty was explored using sensitivity analyses. Two subgroups of patients refractory to lenalidomide or bortezomib were assessed. Main outcomes were mean life-years (LYs), QALYs, lifetime costs, and incremental cost-effectiveness ratios (ICERs). Results: For QW Kd70 and BIW Kd27, the model predicted mean LYs of 4.17 and 3.07 years, QALYs of 2.98 and 2.03 years, and mean total lifetime costs of $444,563 and $373,364, respectively. The incremental LYs gain, QALY gain, and incremental costs of QW Kd70 vs BIW Kd27 were estimated to be 1.10 years, 0.95 year, and $71,199, respectively, resulting in an ICER of $64,595 per LY gained and $75,204 per QALY gained. For patients refractory to lenalidomide and bortezomib, similar results were found with ICERs of $79,988 and $76,793, respectively. Conclusions: In line with ARROW trial results, this CE analysis showed that QW Kd70 is expected to provide considerable additional benefit in terms of LYs and QALYs gained compared with BIW Kd27. In the RRMM setting, QW Kd70 is cost-effective with ICERs below accepted willingness to pay thresholds in US and represents an efficient utilization of the health care budget.