Isatuximab in combination with carfilzomib and dexamethasone in 1q21+ patients with relapsed/refractory multiple myeloma: Long-term outcomes in the Phase 3 IKEMA study.

Gain/amplification of 1q21 (≥3 copies), a chromosomal abnormality frequently observed in multiple myeloma, can negatively affect prognosis, due to its involvement in resistance to anti-myeloma therapy and disease progression. In this updated subgroup analysis of the randomized, Phase 3 IKEMA study (NCT03275285) in relapsed/refractory multiple myeloma (RRMM), we evaluated progression-free survival (PFS) and depth of response with the anti-CD38 antibody isatuximab plus carfilzomib-dexamethasone (Isa-Kd) versus Kd, in 1q21+ patients and related subgroups, at long-term follow-up (44.2 months). Our analysis included patients with 1q21+ (≥3 copies, with/without high-risk chromosomal abnormality [HRCA]), isolated 1q21+ (≥3 copies, without HRCA), gain(1q21) (3 copies, with/without HRCA), and amp(1q21) (≥4 copies, with/without HRCA). PFS benefit was achieved with Isa-Kd versus Kd in patients with 1q21+ (HR 0.58, 95% CI: 0.37-0.92), with isolated 1q21+ (HR 0.49, 95% CI: 0.27-0.92), with gain(1q21), or amp(1q21), consistent with the overall population and prior interim 1q21+ subgroup analyses. Median PFS with Isa-Kd versus Kd was 25.8 versus 16.2 months in 1q21+ patients and 38.2 versus 16.2 months in patients with isolated 1q21+. Clinically meaningful, higher rates of very good partial response or better, complete response or better (≥CR), minimal residual disease (MRD) negativity, and MRD negativity and ≥CR were reached with Isa-Kd versus Kd in patients with 1q21+, isolated 1q21+, gain(1q21), or amp(1q21). In Isa-Kd and Kd, the MRD negativity and ≥CR rate was 29.3% versus 15.4% in 1q21+ patients, 36.2% versus 12.9% in patients with isolated 1q21+, 27.9% versus 13.5% in patients with gain(1q21), and 31.3% versus 20.0% in patients with amp(1q21), respectively. In conclusion, addition of Isa to Kd in triplet combination therapy has shown PFS benefit and deeper responses, compared with Kd, in 1q21+ patients at higher risk of progression, including patients with isolated 1q21+, gain(1q21), and amp(1q21), thus supporting Isa-Kd an effective treatment option for patients with RRMM.

Isatuximab plus carfilzomib and dexamethasone in patients with early versus late relapsed multiple myeloma: IKEMA subgroup analysis.

Patients with multiple myeloma (MM) who experience early relapse within 12 months of therapy initiation are considered functional high-risk and represent an unmet need, needing better therapies to improve outcomes. The final IKEMA (clinicaltrials gov. identifier: NCT03275285) progression-free survival (PFS) analysis confirmed the significant PFS improvement reported at interim analysis with isatuximab (Isa) plus carfilzomib and dexamethasone (Kd; Isa-Kd) versus Kd in patients with relapsed MM (updated median PFS: 35.7 vs. 19.2 months; hazard ratio [HR] =0.58, 95% confidence interval [CI]: 0.42- 0.79). This IKEMA subgroup analysis examined efficacy and safety of Isa-Kd versus Kd in patients who experienced early (n=61 [Isa-Kd], n=46 [Kd]) vs. late relapse (n=104 [Isa-Kd], n=72 [Kd]). As expected, more aggressive features in baseline characteristics were observed in early relapse patients. Consistent with IKEMA overall population results, median PFS (early relapse: 24.7 vs. 17.2 months, HR=0.662, 95% CI: 0.407-1.077; late relapse: 42.7 vs. 21.9 months, HR=0.542, 95% CI: 0.355- 0.826), minimal residual disease negativity (MRD-) (early relapse: 24.6% vs. 15.2%; late relapse: 37.5% vs. 16.7%), and MRD- complete response (≥CR) rates (early relapse: 18.0% vs. 10.9%; late relapse: 30.8% vs. 13.9%) were higher with Isa-Kd versus Kd, respectively, in both early and late relapse patients. Grade ≥3, serious treatment-emergent adverse events, and death rates were higher in the late relapse Isa-Kd arm. However, the numbers of deaths were low and treatment exposure was significantly longer in Isa-Kd versus Kd late relapse patients. These results support the addition of Isa to Kd as standardof- care therapy for relapsed and/or refractory MM regardless of relapse timing.

Isatuximab Plus Carfilzomib and Dexamethasone in East Asian Patients With Relapsed Multiple Myeloma: Updated IKEMA Subgroup Analysis.

BACKGROUND: The Phase 3 IKEMA study (NCT03275285) demonstrated isatuximab (Isa) in combination with carfilzomib (K) and dexamethasone (d) significantly improved progression-free survival (PFS) in patients with relapsed multiple myeloma (MM) compared with Kd. A post-hoc analysis of East Asian patients in IKEMA evaluated the efficacy and safety of Isa-Kd versus Kd in this population and was previously published. PATIENTS AND METHODS: Patients with relapsed MM who had received 1 to 3 prior lines of therapy were randomized 3:2 to receive Isa-Kd or Kd. The primary endpoint was PFS, and key secondary endpoints included rate of very good partial response or better (≥VGPR), complete response (CR) rate, and minimal residual disease (MRD) negativity. Of the IKEMA overall population, 46 patients were of East Asian descent. This is an updated analysis of the efficacy and safety of Isa-Kd in East Asian patients, including data through 14 January 2022. RESULTS: Isa-Kd continued to demonstrate improved efficacy and safety versus Kd in East Asian patients with relapsed MM, with improved PFS, rate of ≥VGPR, CR rate, and MRD negativity, that was consistent with the overall IKEMA population. The rate of Grade ≥3 treatment-emergent adverse events was also consistent with the prior analysis and overall IKEMA population. CONCLUSION: Based on the results of this analysis, Isa-Kd is a novel treatment option for East Asian patients with relapsed MM.

Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: updated results from IKEMA, a randomized Phase 3 study.

Longer-term outcomes with the anti-CD38 antibody isatuximab in combination with carfilzomib-dexamethasone (Isa-Kd) were evaluated in the randomized Phase 3 trial IKEMA (NCT03275285), in a prespecified, follow-up analysis of progression-free survival (PFS, primary study endpoint), final complete response (CR) using Hydrashift Isa immunofixation assay, minimal residual disease (MRD) negativity, and safety. Enrolled patients had relapsed/refractory multiple myeloma (1-3 prior treatment lines). Isa 10 mg/kg was administered intravenously weekly in cycle 1 then biweekly. Efficacy analyses were performed in the intent-to-treat population (Isa-Kd: n = 179, Kd: n = 123) and safety evaluated in treated patients (Isa-Kd: n = 177, Kd: n = 122). Consistent with the primary interim analysis, the addition of Isa to Kd prolonged PFS (HR 0.58, 95.4% CI: 0.42-0.79; median PFS 35.7 [95% CI: 25.8-44.0] vs 19.2 [95% CI: 15.8-25.0] months). PFS benefit was observed with Isa-Kd across subgroups, including patients with poor prognosis. The stringent CR/CR rate was 44.1% vs 28.5% (odds-ratio: 2.09, 95% CI: 1.26-3.48), the MRD negativity rate 33.5% vs 15.4% (odds-ratio: 2.78, 95% CI: 1.55-4.99) and the MRD negativity CR rate 26.3% vs 12.2%, with Isa-Kd vs Kd. The safety profile of Isa-Kd was similar to that reported in the prior interim analysis. These findings further support Isa-Kd as a standard-of-care treatment for relapsed multiple myeloma patients.Clinical trial information: ClinicalTrials.gov, NCT03275285.

Isatuximab Plus Carfilzomib and Dexamethasone Versus Carfilzomib and Dexamethasone in Patients with Relapsed Multiple Myeloma: IKEMA Subgroup Analysis by Prior Transplantation.

In the era of highly active novel agents for multiple myeloma (MM), the role, ideal timing, and impact of transplantation on further therapy after relapse remains a matter of debate. The impact of prior transplantation on treatment benefit from monoclonal antibodies in patients with relapsed/refractory MM (RRMM) is largely unknown. Few Phase 3 studies of monoclonal antibody combinations with proteasome inhibitors or immunomodulatory agents have reported outcomes according to transplantation status. This subgroup analysis examined efficacy and safety in patients from the Phase 3 IKEMA study with and without previous transplantation. IKEMA (NCT03275285) was a randomized, open-label, multinational, parallel-group Phase 3 study that investigated isatuximab (Isa), an anti-CD38 monoclonal antibody, combined with carfilzomib and dexamethasone (Isa-Kd; experimental group) versus Kd (control group) in 302 patients with RRMM and 1 to 3 prior lines of therapy. Patients were randomized in a 3:2 ratio to either Isa-Kd or Kd, with stratification by number of prior lines (1 versus more than 1) and Revised International Staging System (R-ISS) stage (I or II versus III versus not classified). Treatment was given until progressive disease, unacceptable adverse events, or patient choice. Of the 302 randomized patients in IKEMA, 185 (61.3%) had received a prior transplant, comprising 116 of 179 (64.8%) patients in the Isa-Kd arm and 69 of 123 (56.1%) patients in the Kd arm. After a median follow-up of 20.6 months, median progression-free survival (PFS) in patients with prior transplant was not reached with Isa-Kd versus 19.15 months with Kd (hazard ratio [HR] = 0.60; 99% confidence interval [CI], 0.31-1.16). After a median follow-up of 20.8 months, median PFS in patients without prior transplant was not reached with Isa-Kd versus 18.99 months with Kd (HR = 0.44; 99% CI, 0.18-1.05). The overall response rate in patients with prior transplant was 87.9% (Isa-Kd) versus 85.5% (Kd). More patients in the Isa-Kd arm achieved a complete response or better compared with the Kd arm (43.1% versus 29.0%). The overall response rate in patients without prior transplant was 84.1% (Isa-Kd) versus 79.6% (Kd). More patients in the Isa-Kd arm achieved a complete response or better compared with the Kd arm (33.3% versus 25.9%). The minimal residual disease negativity rate was higher with Isa-Kd versus Kd in patients with (31.9% versus 13.0%) and without prior transplantation (25.4% versus 13.0%). In patients with prior transplant, Grade 3 or higher treatment-emergent adverse events (TEAEs) were more common with Isa-Kd; however, no increases in serious TEAEs or definitive treatment discontinuations were seen versus Kd. Among patients without prior transplant, serious treatment-related TEAEs were similar, and there were fewer TEAEs leading to definitive discontinuation with Isa-Kd. The most common Grade 3 or higher TEAEs in patients with and without prior transplant were hypertension and pneumonia. For patients who underwent prior transplantation, Isa-Kd is an effective treatment option. Overall, these data demonstrate that Isa-Kd represents a standard of care for patients with RRMM, regardless of prior transplant status.

Isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma patients with high-risk cytogenetics: IKEMA subgroup analysis.

INTRODUCTION: The presence of high-risk chromosomal abnormalities [t(4;14), del(17p), and t(14;16)] has been linked with inferior outcomes in patients with multiple myeloma (MM). A prespecified interim analysis of the Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) + carfilzomib (K) and dexamethasone (d; Isa-Kd) significantly improved progression-free survival (PFS) versus Kd in patients with relapsed MM. This prespecified subgroup analysis of IKEMA examined efficacy and safety in patients with high-risk cytogenetics. METHODS: High-risk cytogenetics was assessed by central laboratory and patients were classified as high risk if abnormalities were present in ≥1 of the following: del(17p): 50% cutoff; t(4;14), and/or t(14;16): 30% cutoff. RESULTS: Of the randomized patients, 23.5% (Isa-Kd) and 25.2% (Kd) had ≥1 high-risk chromosomal abnormality. A PFS benefit was seen in favor of Isa-Kd for patients with standard-risk (HR 0.440; 95% CI 0.266-0.728) and high-risk cytogenetics (HR 0.724; 95% CI 0.361-1.451). Grade ≥3 treatment-emergent adverse events (TEAEs) were more common with Isa-Kd (85.7%) versus Kd (63.3%) in patients with high-risk cytogenetics; however, the incidence of serious TEAEs (64.3% vs. 66.7%) was similar. CONCLUSIONS: Isa-Kd is a new treatment option for the difficult-to-treat subgroup of patients with relapsed MM and high-risk cytogenetics.

Isatuximab plus carfilzomib and dexamethasone versus carfilzomib and dexamethasone in elderly patients with relapsed multiple myeloma: IKEMA subgroup analysis.

In this subgroup analysis of the randomized, Phase 3 IKEMA study (NCT03275285), we evaluated efficacy and safety of the anti-CD38 monoclonal antibody isatuximab (Isa) in combination with carfilzomib-dexamethasone (Isa-Kd) versus Kd in older (≥70 years of age, n = 86) and younger (<70 years, n = 216) patients with relapsed multiple myeloma (MM). Patients received Isa 10 mg/kg intravenously weekly for 4 weeks, then every 2 weeks in the Isa-Kd arm, and approved schedule of carfilzomib (twice weekly) and dexamethasone in both study arms. Primary endpoint was progression-free survival (PFS); key secondary efficacy endpoints included rates of overall response (ORR), very good partial response or better (≥VGPR), minimal residual disease negativity (MRD-), and complete response (CR). Addition of Isa to Kd resulted in improved PFS in elderly patients (hazard ratio, 0.36 [95% CI, 0.18-0.75]) consistent with the significant PFS improvement observed in the overall IKEMA population. Treatment with Isa-Kd improved depth of response versus Kd, with higher rates of ≥VGPR (73.1% vs. 55.9%), MRD- (23.1% vs. 11.8%), and CR (38.5% vs. 23.5%). Although the incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was higher in Isa-Kd, the incidence of serious TEAEs was similar between arms. Fewer elderly patients definitively discontinued treatment due to TEAEs in Isa-Kd than Kd: 11.8% versus 23.5%. In conclusion, Isa-Kd provides a consistent benefit versus Kd in elderly patients, with a manageable safety profile, and represents a new treatment option for patients with relapsed MM, independent of age.

Depth of response and response kinetics of isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma.

The IKEMA study (Randomized, Open Label, Multicenter Study Assessing the Clinical Benefit of Isatuximab Combined With Carfilzomib [Kyprolis®] and Dexamethasone Versus Carfilzomib With Dexamethasone in Patients With Relapse and/or Refractory Multiple Myeloma Previously Treated With 1 to 3 Prior Lines; #NCT03275285) was a randomized, open-label, multicenter phase 3 study investigating isatuximab plus carfilzomib and dexamethasone (Isa-Kd) vs Kd in patients with relapsed multiple myeloma. This subanalysis analyzed the depth of response of Isa-Kd vs Kd. The primary end point was progression-free survival (PFS); secondary end points included overall response rate, very good partial response or better (≥VGPR) rate, complete response (CR) rate, and minimal residual disease (MRD) negativity rate (assessed in patients with ≥VGPR by next-generation sequencing at a 10-5 sensitivity level). At a median follow-up of 20.7 months, deeper responses were observed in the Isa-Kd arm vs the Kd arm, with ≥VGPR 72.6% vs 56.1% and CR of 39.7% vs 27.6%, respectively. MRD negativity occurred in 53 (29.6%) of 179 patients in the Isa-Kd arm vs 16 (13.0%) of 123 patients in the Kd arm, with 20.1% (Isa-Kd, 36 of 179 patients) vs 10.6% (Kd, 13 of 123 patients) reaching MRD-negative CR status. Achieving MRD negativity resulted in better PFS in both arms. A positive PFS treatment effect was seen with Isa-Kd in both MRD-negative patients (hazard ratio, 0.578; 95% CI, 0.052-6.405) and MRD-positive patients (hazard ratio, 0.670; 95% CI, 0.452-0.993). Exploratory analysis indicates that both current CR and MRD-negative CR rates are underestimated due to M-protein interference (potential adjusted CR rate, 45.8%; potential adjusted MRD-negative CR rate, 24.0%). In conclusion, there was a clinically meaningful improvement in depth of response with Isa-Kd. The CR rate in Isa-Kd was 39.7%. Mass spectrometry suggests that the potential adjusted CR rate could reach an unprecedented 45.8% of patients treated with Isa-Kd.

Isatuximab plus carfilzomib and dexamethasone in East Asian patients with relapsed multiple myeloma: IKEMA subgroup analysis.

In the phase 3 IKEMA study (NCT03275285), isatuximab (Isa) plus carfilzomib (K) and dexamethasone (d) significantly improved progression-free survival (PFS) in relapsed multiple myeloma (MM), compared with Kd. This IKEMA subgroup analysis evaluated efficacy and safety of Isa-Kd versus Kd among East Asian patients. Eligible patients had 1-3 prior lines of therapy and were stratified by number of prior lines and revised International Staging System. The primary endpoint was PFS. Key secondary endpoints included overall response, very good partial response or better (≥VGPR), minimal residual disease (MRD) negativity, and complete response (CR) rate. Forty-six East Asian patients (19 Japanese, 27 South Korean) were randomized to Isa-Kd (n = 25) or Kd (n = 21). Isa-Kd improved PFS (HR 0.64; 95% CI 0.23-1.76), ≥VGPR (80.0% vs 52.4%), MRD negativity rate (44.0% vs 9.5%), and CR (44.0% vs 23.8%). The rate of grade ≥ 3 treatment-emergent adverse events (TEAEs) was 79% for Isa-Kd versus 55% for Kd. The rate of serious TEAEs was 46% versus 50%, and the rate of TEAEs leading to treatment discontinuation was 4% versus 10%. Overall, Isa-Kd improved efficacy and safety versus Kd in East Asian patients with relapsed MM, consistent with the overall IKEMA population.

Isatuximab plus carfilzomib and dexamethasone versus carfilzomib and dexamethasone in relapsed multiple myeloma patients with renal impairment: IKEMA subgroup analysis.

Renal impairment (RI) is common in patients with multiple myeloma (MM) and new therapies that can improve renal function are needed. The phase III IKEMA study (clinicaltrials gov. Identifier: NCT03275285) investigated isatuximab (Isa) with carfilzomib and dexamethasone (Kd) versus Kd in relapsed MM. This subgroup analysis examined results from patients with RI, defined as estimated glomerular filtration rate <60 mL/min/1.73 m². Addition of Isa prolonged progression-free survival (PFS) in patients with RI (hazard ratio: 0.27; 95% confidence interval [CI]: 0.11-0.66; median PFS not reached for Isa-Kd versus 13.4 months for Kd [20.8-month follow-up]). Complete renal responses occurred more frequently with Isa-Kd (52.0%) versus Kd (30.8%) and were durable in 32.0% versus 7.7% of patients, respectively. Treatment exposure was longer with Isa-Kd, with median number of started cycles and median duration of exposure of 20 versus 9 cycles and 81.0 versus 35.7 weeks for Isa-Kd versus Kd, respectively. Among patients with RI, the incidence of patients with grade ≥3 treatment-emergent adverse events was similar between the two arms (79.1% in Isa-Kd vs. 77.8% in Kd). In summary, the addition of Isa to Kd improved clinical outcomes with a manageable safety profile in patients with RI, consistent with the benefit observed in the overall IKEMA study population.

PK/PD modeling analysis for dosing regimen selection of isatuximab as single agent and in combination therapy in patients with multiple myeloma.

This analysis describes the pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that supported selection of the isatuximab (anti-CD38 monoclonal antibody) dosing regimen alongside its early clinical development in patients with relapsed/refractory multiple myeloma (RRMM). The PK/PD mathematical model characterized the variations of patient serum M-protein concentrations, the primary marker of tumor burden in multiple myeloma (MM). Three separate PK/PD models were built sequentially as data became available from phase I clinical trials. The primary PK/PD analysis was initiated using monotherapy phase I study data (n = 122), followed by analysis of data collected from phase Ib combination studies with lenalidomide and dexamethasone (Rd, n = 40) and then with pomalidomide and dexamethasone (Pd, n = 31). Using the PK/PD model, abnormal "myeloma" protein (M-protein) profiles under different isatuximab dosing regimens were simulated. Overall, simulations revealed that regimens which included a loading period of four weekly administrations followed by administration every 2 weeks thereafter (QW4-Q2W), reduced M-protein levels more than a Q2W regimen without a loading period. For isatuximab monotherapy, a 20 mg/kg dose induced greater reduction in serum M-protein levels compared with doses equal or lower than 10 mg/kg. For isatuximab in combination with either Rd or Pd, simulations yielded no substantial benefit in terms of M-protein reduction between isatuximab 10 mg/kg and 20 mg/kg. These PK/PD analyses supported the use of isatuximab 10 mg/kg QW4-Q2W in combination with Pd in the phase III trial.

Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial.

BACKGROUND: Isatuximab is an anti-CD38 monoclonal antibody approved in combination with pomalidomide-dexamethasone and carfilzomib-dexamethasone for relapsed or refractory multiple myeloma. This phase 3, open-label study compared the efficacy of isatuximab plus carfilzomib-dexamethasone versus carfilzomib-dexamethasone in patients with relapsed multiple myeloma. METHODS: This was a prospective, randomised, open-label, parallel-group, phase 3 study done at 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients with relapsed or refractory multiple myeloma aged at least 18 years who had received one to three previous lines of therapy and had measurable serum or urine M-protein were eligible. Patients were randomly assigned (3:2) to isatuximab plus carfilzomib-dexamethasone (isatuximab group) or carfilzomib-dexamethasone (control group). Patients in the isatuximab group received isatuximab 10 mg/kg intravenously weekly for the first 4 weeks, then every 2 weeks. Both groups received the approved schedule of intravenous carfilzomib and oral or intravenous dexamethasone. Treatment continued until progression or unacceptable toxicity. The primary endpoint was progression-free survival and was assessed in the intention-to-treat population according to assigned treatment. Safety was assessed in all patients who received at least one dose according to treatment received. The study is registered at ClinicalTrials.gov, NCT03275285. FINDINGS: Between Nov 15, 2017, and March 21, 2019, 302 patients with a median of two previous lines of therapy were enrolled. 179 were randomly assigned to the isatuximab group and 123 to the control group. Median progression-free survival was not reached in the isatuximab group compared with 19·15 months (95% CI 15·77-not reached) in the control group, with a hazard ratio of 0·53 (99% CI 0·32-0·89; one-sided p=0·0007). Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 136 (77%) of 177 patients in the isatuximab group versus 82 (67%) of 122 in the control group, serious TEAEs occurred in 105 (59%) versus 70 (57%) patients, and TEAEs led to discontinuation in 15 (8%) versus 17 (14%) patients. Fatal TEAEs during study treatment occurred in six (3%) versus four (3%) patients. INTERPRETATION: The addition of isatuximab to carfilzomib-dexamethasone significantly improves progression-free survival and depth of response in patients with relapsed multiple myeloma, representing a new standard of care for this patient population. FUNDING: Sanofi. VIDEO ABSTRACT.

Subgroup analysis of ICARIA-MM study in relapsed/refractory multiple myeloma patients with high-risk cytogenetics.

Treatment benefit in multiple myeloma (MM) patients with high-risk cytogenetics remains suboptimal. The phase 3 ICARIA-MM trial (NCT02990338) showed that isatuximab plus pomalidomide-dexamethasone prolongs median progression-free survival (mPFS) in patients with relapsed/refractory MM (RRMM). This subgroup analysis of ICARIA-MM compared the benefit of isatuximab in high-risk [defined by the presence of del(17p), t(4;14) or t(14;16)] versus standard-risk patients. The efficacy of isatuximab in patients with gain(1q21) abnormality was also assessed in a retrospective subgroup analysis. In ICARIA-MM, 307 patients received isatuximab-pomalidomide-dexamethasone (n = 154) or pomalidomide-dexamethasone (n = 153). Isatuximab (10 mg/kg intravenously) was given weekly in the first 28-day cycle, and every other week thereafter. Standard pomalidomide-dexamethasone doses were given. Isatuximab-pomalidomide-dexamethasone improved mPFS (7·5 vs 3·7 months; HR, 0·66; 95% CI, 0·33-1·28) and overall response rate (ORR, 50·0% vs 16·7%) in high-risk patients. In patients with isolated gain(1q21), isatuximab addition improved mPFS (11·2 vs 4·6 months; HR, 0·50; 95% CI, 0·28-0·88) and ORR (53·6% vs 27·6%). More grade ≥3 adverse events occurred in high-risk patients receiving isatuximab (95·7%) versus the control group (67·6%); however, isatuximab did not increase events leading to discontinuation or treatment-related mortality. Isatuximab-pomalidomide-dexamethasone provides a consistent benefit over pomalidomide-dexamethasone treatment in RRMM patients regardless of cytogenetic risk.

Isatuximab plus carfilzomib/dexamethasone versus carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma: IKEMA Phase III study design.

Although the treatment of relapsed/refractory multiple myeloma has improved dramatically over the past decade, the disease remains incurable; therefore, additional therapies are needed. Novel combination therapies incorporating monoclonal antibodies have shown significant promise. Here we describe the design of a Phase III study (NCT03275285, IKEMA), which is evaluating isatuximab plus carfilzomib and low-dose dexamethasone, versus carfilzomib/dexamethasone in relapsed/refractory multiple myeloma. The primary end point is progression-free survival. Responses are being determined by an independent review committee using 2016 International Myeloma Working Group criteria, and safety will be assessed throughout. The first patient was recruited in November 2017, and the last patient was recruited in March 2019; 302 patients have been randomized, and the study is ongoing. Clinical trial registration: NCT03275285.

Isatuximab plus pomalidomide/dexamethasone versus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma: ICARIA Phase III study design.

Treatment for relapsed/refractory multiple myeloma (RRMM) remains an unmet need. Isatuximab, an anti-CD38 monoclonal antibody has shown efficacy and tolerability as a monotherapy and combination therapy in Phase I/II studies in RRMM. Here, we describe the design of the Phase III ICARIA-MM study (NCT02990338) which will evaluate isatuximab in combination with pomalidomide (Pom) and low-dose dexamethasone (dex) (Pom/dex) versus Pom/dex alone in RRMM. Patients will be randomized in a 1:1 ratio. The primary endpoint is progression-free survival. Response will be determined by an independent response review committee using IMWG criteria (2016) and safety will be assessed throughout. Approximately 300 patients (150 in each arm) are expected to enroll. The first patient was recruited in January 2017 and accrual is ongoing.

Larotaxel with Cisplatin in the first-line treatment of locally advanced/metastatic urothelial tract or bladder cancer: a randomized, active-controlled, phase III trial (CILAB).

BACKGROUND: This open-label, randomized phase III trial evaluated larotaxel/cisplatin versus gemcitabine/cisplatin as first-line treatment for locally advanced (T4b) or metastatic urothelial tract or bladder cancer. METHODS: Patients were randomized to larotaxel 50 mg/m(2) with cisplatin 75 mg/m(2) every 3 weeks (larotaxel/cisplatin) or gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 with cisplatin 70 mg/m(2) on day 1 every 4 weeks (gemcitabine/cisplatin). The primary endpoint was overall survival (OS). RESULTS: The trial was prematurely closed following the sponsor's decision to stop clinical development of larotaxel (n = 337 randomized). The larotaxel dose was reduced to 40 mg/m(2) and cisplatin to 60 mg/m(2) following a data monitoring committee safety review of the first 97 patients. At the time of analysis, the median OS was 13.7 months [95% confidence interval (CI) 11.2-17.1] with larotaxel/cisplatin and 14.3 months (95% CI 10.5 to not reached) with gemcitabine/cisplatin [hazard ratio (HR) 1.21; 95% CI 0.83-1.76; p = 0.33]. The median progression-free survival (PFS) was 5.6 months (95% CI 4.1-6.2) with larotaxel/cisplatin and 7.6 months (95% CI 6.6-9.1) with gemcitabine/cisplatin (HR 1.67; 95% CI 1.24-2.25). More myelosuppression was observed with gemcitabine/cisplatin. CONCLUSION: There was no difference in OS. Although the trial was closed prematurely, PFS appeared worse with larotaxel/cisplatin, suggesting that larotaxel/cisplatin does not improve outcomes versus cisplatin/gemcitabine.

Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group.

PURPOSE: In the randomized, multinational phase II/III trial (V325) of untreated advanced gastric cancer patients, the phase II part selected docetaxel, cisplatin, and fluorouracil (DCF) over docetaxel and cisplatin for comparison against cisplatin and fluorouracil (CF; reference regimen) in the phase III part. PATIENTS AND METHODS: Advanced gastric cancer patients were randomly assigned to docetaxel 75 mg/m2 and cisplatin 75 mg/m2 (day 1) plus fluorouracil 750 mg/m2/d (days 1 to 5) every 3 weeks or cisplatin 100 mg/m2 (day 1) plus fluorouracil 1,000 mg/m2/d (days 1 to 5) every 4 weeks. The primary end point was time-to-progression (TTP). RESULTS: In 445 randomly assigned and treated patients (DCF = 221; CF = 224), TTP was longer with DCF versus CF (32% risk reduction; log-rank P < .001). Overall survival was longer with DCF versus CF (23% risk reduction; log-rank P = .02). Two-year survival rate was 18% with DCF and 9% with CF. Overall response rate was higher with DCF (chi2 P = .01). Grade 3 to 4 treatment-related adverse events occurred in 69% (DCF) v 59% (CF) of patients. Frequent grade 3 to 4 toxicities for DCF v CF were: neutropenia (82% v 57%), stomatitis (21% v 27%), diarrhea (19% v 8%), lethargy (19% v 14%). Complicated neutropenia was more frequent with DCF than CF (29% v 12%). CONCLUSION: Adding docetaxel to CF significantly improved TTP, survival, and response rate in gastric cancer patients, but resulted in some increase in toxicity. Incorporation of docetaxel, as in DCF or with other active drug(s), is a new therapy option for patients with untreated advanced gastric cancer.