The International Staging System for multiple myeloma recently underwent a second revision (R2-ISS) to include gain/amplification of 1q21 and account for the additive prognostic significance of multiple high-risk features. The phase 3 ICARIA-MM (isatuximab-pomalidomide-dexamethasone vs. pomalidomide-dexamethasone) and IKEMA (isatuximab-carfilzomib-dexamethasone vs. carfilzomib-dexamethasone) studies provide large datasets for retrospectively validating the prognostic value of the R2-ISS in relapsed/refractory multiple myeloma. Of 609 pooled patients, 68 (11.2%) were reclassified as R2-ISS stage I, 136 (22.3%) as R2-ISS stage II, 204 (33.5%) as R2-ISS stage III, 55 (9.0%) as stage IV, and 146 (24.0%) "Not classified". Median progression-free survival was shorter among those reclassified as R2-ISS stage II (HR 1.52, 95% CI 0.979-2.358), stage III (HR 2.59, 95% CI 1.709-3.923), and stage IV (HR 3.51, 95% CI 2.124-5.784) versus stage I. Adding isatuximab led to longer progression-free survival versus doublet therapy (adjusted HR 0.544 [95% CI 0.436-0.680]), with a consistent treatment effect observed across all R2-ISS stages. This is the first study to validate the R2-ISS with novel agents, including anti-CD38 monoclonal antibodies, and to show that R2-ISS, as a prognostic scoring system, can be applied to patients with relapsed/refractory multiple myeloma.

• MeSH
• Dexamethasone therapeutic use   administration & dosage   MeSH
• Adult MeSH
• Antibodies, Monoclonal, Humanized * therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Multiple Myeloma * pathology   drug therapy   mortality   diagnosis   MeSH
• Oligopeptides therapeutic use   MeSH
• Prognosis MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Neoplasm Staging * MeSH
• Thalidomide analogs & derivatives   therapeutic use   administration & dosage   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Randomized Controlled Trial MeSH
• Validation Study MeSH
• Names of Substances
• carfilzomib MeSH Browser
• Dexamethasone MeSH
• Antibodies, Monoclonal, Humanized * MeSH
• isatuximab MeSH Browser
• Oligopeptides MeSH
• pomalidomide MeSH Browser
• Thalidomide MeSH

• MeSH
• Leukemia, Myeloid, Acute * drug therapy   MeSH
• CD28 Antigens MeSH
• CD3 Complex immunology   MeSH
• ADP-ribosyl Cyclase 1 * antagonists & inhibitors   metabolism   MeSH
• Antibodies, Monoclonal, Humanized * therapeutic use   MeSH
• Humans MeSH
• Membrane Glycoproteins MeSH
• Antibodies, Bispecific therapeutic use   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• T-Lymphocytes immunology   metabolism   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• CD28 Antigens MeSH
• CD3 Complex MeSH
• ADP-ribosyl Cyclase 1 * MeSH
• CD38 protein, human MeSH Browser
• Antibodies, Monoclonal, Humanized * MeSH
• isatuximab MeSH Browser
• Membrane Glycoproteins MeSH
• Antibodies, Bispecific MeSH

The primary and prespecified updated analyses of ICARIA-MM (clinicaltrial gov. Identifier: NCT02990338) demonstrated improved progression-free survival (PFS) and a benefit in overall survival (OS) was reported with the addition of isatuximab, an anti-CD38 monoclonal antibody, to pomalidomide-dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma. Here, we report the final OS analysis. This multicenter, randomized, open-label, phase III study included patients who had received and failed ≥2 previous therapies, including lenalidomide and a proteasome inhibitor. Between January 10, 2017, and February 2, 2018, 307 patients were randomized (1:1) to isatuximab-pomalidomide-dexamethasone (Isa-Pd; N=154) or Pd (N=153), stratified based on age (<75 vs. ≥75 years) and number of previous lines of therapy (2-3 vs. >3). At data cutoff for the final OS analysis after 220 OS events (January 27, 2022), median follow-up duration was 52.4 months. Median OS was 24.6 months (95% confidence interval [CI]: 20.3-31.3) with Isa-Pd and 17.7 months (95% CI: 14.4- 26.2) with Pd (hazard ratio=0.78; 95% CI: 0.59-1.02; 1-sided P=0.0319). Despite subsequent daratumumab use in the Pd group and its potential benefit on PFS in the first subsequent therapy line, median PFS2 was significantly longer with Isa-Pd versus Pd (17.5 vs. 12.9 months; log-rank 1-sided P=0.0091). In this analysis, Isa-Pd continued to be efficacious and well tolerated after follow-up of approximately 52 months, contributing to a clinically meaningful, 6.9-month improvement in median OS in patients with relapsed/refractory multiple myeloma.

• MeSH
• Survival Analysis MeSH
• Drug Resistance, Neoplasm MeSH
• Dexamethasone * administration & dosage   MeSH
• Adult MeSH
• Antibodies, Monoclonal, Humanized * administration & dosage   therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Multiple Myeloma * drug therapy   mortality   pathology   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Recurrence MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Thalidomide * analogs & derivatives   administration & dosage   MeSH
• Treatment Outcome 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 III MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Dexamethasone * MeSH
• Antibodies, Monoclonal, Humanized * MeSH
• isatuximab MeSH Browser
• pomalidomide MeSH Browser
• Thalidomide * MeSH

Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with ≥3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received ≥3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade ≥3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies.

• MeSH
• Transplantation, Autologous MeSH
• Dexamethasone therapeutic use   MeSH
• Phenylalanine * analogs & derivatives   MeSH
• Proteasome Inhibitors MeSH
• Humans MeSH
• Melphalan * analogs & derivatives   MeSH
• Multiple Myeloma * diagnosis   drug therapy   MeSH
• Antibodies, Monoclonal * MeSH
• Neoplasms, Plasma Cell * MeSH
• Neutropenia * MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   MeSH
• Hematopoietic Stem Cell Transplantation * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Randomized Controlled Trial MeSH
• Geographicals
• United States MeSH
• Names of Substances
• daratumumab MeSH Browser
• Dexamethasone MeSH
• Phenylalanine * MeSH
• Proteasome Inhibitors MeSH
• Melphalan * MeSH
• melflufen MeSH Browser
• Antibodies, Monoclonal * MeSH

Melphalan flufenamide (melflufen), a first-in-class, alkylating peptide-drug conjugate, demonstrated clinical benefit in combination with dexamethasone in triple-class refractory multiple myeloma (MM). The phase I/IIa ANCHOR study evaluated melflufen (30 or 40 mg) and dexamethasone (40 mg with daratumumab; 20 mg followed by 40 mg with bortezomib; dose reduced if aged ≥75 years) in triplet combination with daratumumab (16 mg/kg; daratumumab arm) or bortezomib (1.3 mg/m2; bortezomib arm) in patients with relapsed/refractory MM refractory to an immunomodulatory agent and/or a proteasome inhibitor and who had received one to four prior lines of therapy. Primary objectives were to determine the optimal dose of melflufen in triplet combination (phase I) and overall response rate (phase IIa). In total, 33 patients were treated in the daratumumab arm and 23 patients received therapy in the bortezomib arm. No dose-limiting toxicities were reported at either melflufen dose level with either combination. With both triplet regimens, the most common grade ≥3 treatment-emergent adverse events were thrombocytopenia and neutropenia; thrombocytopenia was the most common treatment-emergent adverse event leading to treatment discontinuation. In the daratumumab arm, patients receiving melflufen 30 mg remained on treatment longer than those receiving the 40-mg dose. In the daratumumab arm, the overall response rate was 73% and median progression-free survival was 12.9 months. Notably, in the bortezomib arm, the overall response rate was 78% and median progression-free survival was 14.7 months. Considering the totality of the data, melflufen 30 mg was established as the recommended dose for use with dexamethasone and daratumumab or bortezomib for future studies in relapsed/refractory MM.

• MeSH
• Bortezomib therapeutic use   MeSH
• Dexamethasone therapeutic use   MeSH
• Phenylalanine * analogs & derivatives   MeSH
• Humans MeSH
• Melphalan * analogs & derivatives   MeSH
• Multiple Myeloma * diagnosis   drug therapy   MeSH
• Antibodies, Monoclonal * MeSH
• Neoplasms, Plasma Cell * MeSH
• Neutropenia * chemically induced   MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   MeSH
• Aged MeSH
• Thrombocytopenia * MeSH
• Check Tag
• Humans MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase I MeSH
• Clinical Trial, Phase II MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Bortezomib MeSH
• daratumumab MeSH Browser
• Dexamethasone MeSH
• Phenylalanine * MeSH
• Melphalan * MeSH
• melflufen MeSH Browser
• Antibodies, Monoclonal * MeSH

We performed real world evidence (RWE) analysis of daratumumab, lenalidomide and dexamethasone (Dara-Rd) versus lenalidomide and dexamethasone (Rd) treatment in relapsed/refractory multiple myeloma patients (RRMM). In total, 240 RRMM patients were treated with Dara-Rd from 2016 to 2022 outside of clinical trials in all major Czech hematology centers. As a reference, 531 RRMM patients treated with Rd were evaluated. Patients' data were recorded in the Czech Registry of Monoclonal Gammopathies (RMG). Partial response (PR) or better response (ORR) was achieved in significantly more patients in Dara-Rd than in Rd group (91.2% vs. 69.9%; p < 0.001). The median progression free survival (PFS) was 26.9 months in the Dara-Rd and 12.8 months in the Rd group (p < 0.001). Median overall survival (OS) was not reached in the Dara-Rd compared to 27.2 months in the Rd group (p = 0.023). In patients with 1-3 previous treatment lines, there was significant PFS benefit of Dara-Rd compared to Rd (median PFS not reached vs. 13.2 months; p < 0.001). In patients with > 3 previous treatment lines, there was no significant PFS benefit of Dara-Rd treatment (7.8 months vs. 9.9 months; p = 0.874), similarly in patients refractory to PI + IMIDs (11.5 months vs. 9.2 months; p = 0.376). In RWE conditions, the median PFS in RRMM patients treated with Dara-Rd is shorter when compared to clinical trials. In heavily pretreated RRMM patients, efficacy of Dara-Rd treatment is limited; best possible outcomes of Dara-Rd are achieved in minimally pretreated patients.

• Keywords
• Multiple myeloma, Relapse, Response rate, Treatment,
• MeSH
• Dexamethasone adverse effects   MeSH
• Lenalidomide therapeutic use   MeSH
• Humans MeSH
• Multiple Myeloma * diagnosis   drug therapy   MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• daratumumab MeSH Browser
• Dexamethasone MeSH
• Lenalidomide MeSH

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
• Names of Substances
• carfilzomib MeSH Browser
• Dexamethasone MeSH
• Antibodies, Monoclonal, Humanized MeSH
• isatuximab MeSH Browser

BACKGROUND: Given the incurable nature of multiple myeloma (MM), efforts are made to improve the efficacy of anti-CD38 monoclonal antibodies via combinations with other potentially synergistic therapies. This Phase 1/2 trial (NCT03194867) was designed to determine whether cemiplimab (anti-PD-1) enhances the anti-myeloma activity of isatuximab (anti-CD38) in patients with relapsed and refractory multiple myeloma (RRMM), to confirm the feasibility of the combination, determine its efficacy, and further evaluate its safety. METHODS: Patients received isatuximab 10 mg/kg once weekly for 4 weeks followed by every 2 weeks (Isa), or isatuximab 10 mg/kg plus cemiplimab 250 mg every 2 (Isa + CemiQ2W) or every 4 weeks (Isa + CemiQ4W). RESULTS: Overall, 106 patients with RRMM treated with a median of 4 prior lines were included; 25.5% had high-risk cytogenetics, 63.2% were refractory to proteasome inhibitors and immunomodulatory agents, 26.4% were previously exposed to daratumumab, and 84.0% were refractory to their last treatment line. There were no major changes in the safety or pharmacokinetic profile of isatuximab with the addition of cemiplimab. As assessed by investigators, four patients (11.8%) in the Isa arm, nine patients (25.0%) in the Isa + CemiQ2W arm, and eight patients (22.2%) in the Isa + CemiQ4W arm were responders. Though response rates were numerically higher in cemiplimab-containing arms, differences were not statistically significant and did not translate to improved progression-free or overall survival after a median follow-up of 9.99 months. CONCLUSION: Our results suggest a marginal benefit by adding cemiplimab to isatuximab, despite demonstration of target engagement, without additional observed safety issues.

• MeSH
• Dexamethasone therapeutic use   MeSH
• Antibodies, Monoclonal, Humanized adverse effects   MeSH
• Humans MeSH
• Multiple Myeloma * drug therapy   MeSH
• Antineoplastic Agents * therapeutic use   MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase I MeSH
• Clinical Trial, Phase II MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• cemiplimab MeSH Browser
• Dexamethasone MeSH
• Antibodies, Monoclonal, Humanized MeSH
• isatuximab MeSH Browser
• Antineoplastic Agents * MeSH

• MeSH
• Dexamethasone therapeutic use   MeSH
• Antibodies, Monoclonal, Humanized therapeutic use   MeSH
• Humans MeSH
• Neoplasm Recurrence, Local drug therapy   MeSH
• Multiple Myeloma * drug therapy   MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Letter MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• carfilzomib MeSH Browser
• Dexamethasone MeSH
• Antibodies, Monoclonal, Humanized MeSH
• isatuximab MeSH Browser

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.

• Keywords
• CD38, elderly, isatuximab, monoclonal antibody, multiple myeloma,
• 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
• Names of Substances
• Dexamethasone MeSH