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.
- MeSH
- Dexamethasone MeSH
- Antibodies, Monoclonal, Humanized therapeutic use MeSH
- Humans MeSH
- Multiple Myeloma * MeSH
- Antineoplastic Combined Chemotherapy Protocols therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
CONTEXT: Anti-CD38 antibody Isa in combination with Kd is approved in various countries for relapsed multiple myeloma (MM) patients after ≥1 prior therapy based on primary interim analysis (IA) of the Phase 3 IKEMA study (NCT03275285). OBJECTIVE: To report updated efficacy and safety results from IKEMA. Setting and Main Outcome Measures: This prespecified analysis (179 patients randomized to Isa-Kd, 123 to Kd) evaluated progression-free survival (PFS) (primary endpoint) at 159 PFS events, PFS2, minimal residual disease negativity (MRD-) rate, complete response (CR) rate, MRD- and CR rates in all patients, and safety. INTERVENTIONS: Isa 10 mg/kg was given IV weekly for 4 weeks and then every 2 weeks; Kd (20/56 mg/m2, twice weekly, 3/4 weeks) was administered in both arms. RESULTS: At cutoff (14-Jan-2022), with a 44-month median follow-up, 49 (27.4%) patients in Isa-Kd and 11 (8.9%) in Kd were still on treatment. Updated PFS, consistent with IA results, demonstrated significant benefit in favor of Isa-Kd (vs. Kd): HR=0.58 (95.4%CI=0.42-0.79; 35.7 vs. 19.2 months); PFS2 HR=0.68 (95%CI=0.50-0.94; 47.2 vs. 35.6 months). Primary PFS analysis, per FDA request/sensitivity analysis for other countries (censoring PFS events occurring >8 weeks after last valid assessment), was 41.7 versus 20.8 months (HR=0.59, 95%CI=0.42-0.83). With additional follow-up and using Hydrashift Isa immunofixation assay to rule out potential Isa interference in CR determination, final CR rate (Isa-Kd vs. Kd) was 44.1% versus 28.5% (OR=2.09, 95%CI=1.26-3.48); ORR was 86.6% versus 83.7%; MRD- was reached in 33.5% versus 15.4% patients (OR=2.78, 95%CI=1.55-4.99); and the rate of MRD- CR patients was 26.3% versus 12.2% (OR=2.57, 95%CI=1.35-4.88). Safety profiles in both arms remain consistent with prior IKEMA findings. Serious TEAEs were reported in 70.1% of Isa-Kd versus 59.8% Kd patients. The most common any-grade non-hematologic TEAEs in Isa-Kd were infusion reaction (45.8%), diarrhea (39.5%), hypertension (37.9%), and upper respiratory tract infection (37.3%). CONCLUSIONS: These results show unprecedented mPFS, CR, MRD-, and MRD- CR rates in non-lenalidomide containing regimens with benefits maintained through subsequent therapies and a manageable safety profile. Moreover, PFS analysis using FDA censoring rules showed consistent results with the IA. Our findings support Isa-Kd as a standard-of-care treatment for relapsed MM patients.
- MeSH
- Dexamethasone therapeutic use MeSH
- Progression-Free Survival MeSH
- Antibodies, Monoclonal, Humanized MeSH
- Humans MeSH
- Neoplasm Recurrence, Local * drug therapy MeSH
- Multiple Myeloma * drug therapy MeSH
- Oligopeptides MeSH
- Antineoplastic Combined Chemotherapy Protocols * adverse effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Randomized Controlled Trial MeSH
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.
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.
- MeSH
- Dexamethasone adverse effects MeSH
- Humans MeSH
- Multiple Myeloma * drug therapy MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Humans MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Dexamethasone administration & dosage adverse effects MeSH
- Antibodies, Monoclonal, Humanized administration & dosage adverse effects MeSH
- Middle Aged MeSH
- Humans MeSH
- Multiple Myeloma * drug therapy immunology MeSH
- Antineoplastic Combined Chemotherapy Protocols administration & dosage adverse effects MeSH
- Aged MeSH
- Thalidomide administration & dosage adverse effects analogs & derivatives MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Letter MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
- MeSH
- Anti-Inflammatory Agents therapeutic use MeSH
- Dexamethasone therapeutic use MeSH
- Progression-Free Survival MeSH
- Antibodies, Monoclonal, Humanized therapeutic use MeSH
- Immunologic Factors therapeutic use MeSH
- Administration, Intravenous MeSH
- Drug Therapy, Combination MeSH
- Middle Aged MeSH
- Humans MeSH
- Multiple Myeloma drug therapy MeSH
- Oligopeptides therapeutic use MeSH
- Prospective Studies MeSH
- Recurrence MeSH
- Aged MeSH
- Thalidomide analogs & derivatives therapeutic use MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
Patients with relapsed/refractory multiple myeloma (RRMM) experience several relapses, and become refractory to successive therapies. In the ICARIA-MM trial (NCT02990338), isatuximab plus pomalidomide-dexamethasone prolonged median progression-free survival (PFS) in patients with RRMM. This subgroup analysis of ICARIA-MM assessed the treatment benefit of isatuximab by prior lines of therapy and refractory status. A total of 307 patients were randomized to isatuximab-pomalidomide-dexamethasone (n = 154) or pomalidomide-dexamethasone (n = 153). Isatuximab (10 mg/kg intravenously) was given weekly in the first 28-day cycle, then every other week. Standard pomalidomide-dexamethasone doses were given. PFS was assessed by prior lines and refractory status. Overall, 102 (66 %) patients receiving isatuximab-pomalidomide-dexamethasone and 101 (66 %) patients receiving pomalidomide-dexamethasone had received 2-3 prior lines; 52 (34 %) and 52 (34 %) had received >3 prior lines, respectively. Median PFS was higher with isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone for patients who received 2-3 prior lines of therapy (12.3 vs. 7.8 months) and >3 prior lines of therapy (9.4 vs. 4.3 months). Median PFS was higher with isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone for patients who were lenalidomide-refractory (11.4 vs. 5.6 months), lenalidomide-refractory at last line (11.6 vs. 5.7 months), refractory to a proteasome inhibitor (PI) (11.4 vs. 5.6 months), and double-refractory (11.2 vs. 4.8 months). Overall response rate (ORR) in patients receiving isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone was 59.0 % versus 31.4 % in lenalidomide-refractory; 60.2 % versus 32.2 % in PI-refractory; and 58.6 % versus 29.9 % in double-refractory patients. Isatuximab-pomalidomide-dexamethasone improved PFS and ORR regardless of prior lines of therapy or refractory status, consistent with the benefit in the overall population.
- MeSH
- Dexamethasone administration & dosage adverse effects MeSH
- Antibodies, Monoclonal, Humanized administration & dosage adverse effects MeSH
- Middle Aged MeSH
- Humans MeSH
- Survival Rate MeSH
- Multiple Myeloma drug therapy mortality MeSH
- Disease-Free Survival MeSH
- Prospective Studies MeSH
- Antineoplastic Combined Chemotherapy Protocols administration & dosage adverse effects MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Thalidomide administration & dosage adverse effects analogs & derivatives MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
This phase II, single-arm, multicenter study examined the efficacy and safety of coltuximab ravtansine (an anti-CD19 antibody drug conjugate) in 61 patients with histologically documented (de novo or transformed) relapsed or refractory diffuse large B-cell lymphoma who had previously received rituximab-containing immuno-chemotherapy. Patients had received a median of 2.0 (range 0-9) prior treatment regimens for diffuse large B-cell lymphoma and almost half (45.9%) had bulky disease (≥1 lesion >5 cm) at trial entry. Patients received coltuximab ravtansine (55 mg/m2) in 4 weekly and 4 biweekly administrations until disease progression or unacceptable toxicity. Forty-one patients were eligible for inclusion in the per protocol population. Overall response rate (International Working Group criteria) in the per protocol population, the primary end point, was 18/41 [43.9%; 90% confidence interval (CI:) 30.6-57.9%]. Median duration of response, progression-free survival, and overall survival (all treated patients) were 4.7 (range 0.0-8.8) months, 4.4 (90%CI: 3.02-5.78) months, and 9.2 (90%CI: 6.57-12.09) months, respectively. Common non-hematologic adverse events included asthenia/fatigue (30%), nausea (23%), and diarrhea (20%). Grade 3-4 adverse events were reported in 23 patients (38%), the most frequent being hepatotoxicity (3%) and abdominal pain (3%). Eye disorders occurred in 15 patients (25%); all were grade 1-2 and none required a dose modification. Coltuximab ravtansine monotherapy was well tolerated and resulted in moderate clinical responses in pre-treated patients with relapsed/refractory diffuse large B-cell lymphoma. (Registered at: clinicaltrials.gov identifier: 01472887).
- MeSH
- Survival Analysis MeSH
- Antigens, CD19 analysis drug effects immunology MeSH
- Lymphoma, Large B-Cell, Diffuse drug therapy immunology mortality MeSH
- Adult MeSH
- Antibodies, Monoclonal, Humanized adverse effects pharmacology therapeutic use MeSH
- Immunoconjugates therapeutic use MeSH
- Immunotherapy methods MeSH
- Middle Aged MeSH
- Humans MeSH
- Maytansine adverse effects analogs & derivatives pharmacology therapeutic use MeSH
- Rituximab therapeutic use MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Treatment Outcome MeSH
- Salvage Therapy methods MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase II MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
