Goldschmidt, Hartmut

Abstract Both the phase 3 MAIA and ALCYONE studies demonstrated significant survival benefit with the addition of daratumumab to standard-of-care Rd (Revlimid [lenalidomide] and dexamethasone; D-Rd) or to VMP (Velcade [bortezomib], melphalan, and prednisone; D-VMP), respectively, vs Rd or VMP alone in transplant-ineligible newly diagnosed multiple myeloma (NDMM). Patients with NDMM are highly susceptible to infection; therefore, gaining a greater understanding of infection incidence may help to mitigate future risk. We conducted a pooled analysis of infection incidence, timing, and management strategies from MAIA and ALCYONE. The median (range) age of the pooled population was 72 (40-93) years. Incidence was higher with D-Rd/D-VMP vs Rd/VMP for grade 3/4 (36.9% vs 22.4%) and grade 5 (3.0% vs 1.5%) infections; however, exposure-adjusted incidence rates were generally comparable between groups. Any-grade infections led to the discontinuation of study treatment in ∼2% of patients across treatment groups. Of the timing intervals explored, the highest incidence of grade 3/4 infection occurred within the first 6-month interval of study treatment initiation in both groups. Median time to the first onset of grade 3/4 infections (per Kaplan-Meier estimates) was 83.3 months and not estimable in the D-Rd/D-VMP and Rd/VMP groups, respectively. Although the rates of D-Rd/D-VMP treatment discontinuation due to infection remained low in MAIA and ALCYONE, clinicians should remain vigilant about infections throughout treatment and follow local guidelines and International Myeloma Working Group recommendations to minimize the risk of infection. These trials were registered at www.ClinicalTrials.gov as NCT02252172 (MAIA) and NCT02195479 (ALCYONE).

PURPOSE To report the results of the multicenter, open-label IRAKLIA trial (ClinicalTrials.gov identifier: NCT05405166 ) of isatuximab subcutaneous (SC) versus intravenous (IV), plus pomalidomide and dexamethasone, in relapsed/refractory multiple myeloma (MM), to our knowledge, the first phase III MM trial using an on-body injector (OBI). METHODS Patients with ≥1 prior line of therapy were randomly assigned 1:1 to Isa OBI (1,400 mg) or IV (10 mg/kg) once weekly in cycle (C)1 and then every 2 weeks, plus pomalidomide (4 mg once daily, day [D]1-21) and dexamethasone (40 mg once weekly [age ≥75: 20 mg]) and treated until progression, unacceptable toxicity, or patient request. Coprimary end points were overall response rate (ORR; noninferiority margin, 0.839) and Isa C trough (C6D1 predose; noninferiority margin, 0.8). Noninferiority of OBI versus IV was demonstrated if both coprimary end points achieved noninferiority. RESULTS IRAKLIA randomly assigned 531 patients (OBI, n=263; IV, n=268). After 12-month median follow-up, the ORR was 71.1% (OBI) and 70.5% (IV; relative risk, 1.008 [95% CI, 0.903 to 1.126]; lower CI exceeded noninferiority margin). The mean (standard deviation) C6D1 C trough was 499 (259) μg/mL (OBI) and 340 (169) μg/mL (IV). The C trough geometric mean ratio (90% CI) was 1.532 (1.316 to 1.784); lower CI exceeded noninferiority margin. Grade ≥3 treatment-emergent adverse event incidences were 81.7% (OBI) and 76.1% (IV); infusion reaction incidences were 1.5% and 25.0%. Injection site reactions occurred in 0.4% of OBI injections (all grade 1-2); 99.9% of injections completed without interruption. CONCLUSION IRAKLIA demonstrated efficacy and pharmacokinetic noninferiority between Isa OBI and IV. No unexpected safety signal was observed, with excellent local tolerability of Isa OBI. Efficacy and safety were comparable with Isa IV in ICARIA-MM, except the lower OBI infusion reaction rate. These results support potential use of the OBI, designed to improve practice efficiency.

PURPOSE Newly approved drugs and combinations treating multiple myeloma (MM) have resulted in substantial improvements in patients' survival. To deliver rapid access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to evaluate the minimal residual disease–negative complete response (MRD-CR) as an intermediate end point for progression-free survival (PFS) and overall survival (OS) in newly diagnosed (ND) transplant-eligible (NDTE) patients, ND transplant-ineligible (NDTinE) patients, and patients with relapsed/refractory (RR) MM. PATIENTS AND METHODS Individual patient data from 20 randomized multicenter trials were collected. Eleven studies (4,773 patients) with sufficient data were analyzed to evaluate whether 9- or 12-month MRD-CR classified at a 10 –5 threshold could be reasonably likely to predict the clinical benefit of new agents regarding PFS and OS. Global odds ratio (OR) was estimated using the bivariate Plackett Copula model. Supportive evaluation included correlations of the treatment effects on MRD-CR end points and PFS/OS, evaluated by both linear regression ( R 2 weighted least squared ) and Copula ( R 2 Copula ) models. RESULTS The analysis demonstrated that both 9- and 12-month MRD-CR strongly correlated with PFS at patient level in NDTE patients, NDTinE patients, and patients with RRMM. Global ORs ranged from 3.06 to 16.24, all with 95% CIs excluding 1.0. Encouraging trial-level correlations ( R 2 , 0.61-0.70) were observed by pooling three populations and were stronger ( R 2 , 0.67-0.78) in the ND population. Similar results were observed for OS. CONCLUSION Our findings provided the support for use of MRD-CR classified at a 10 –5 threshold at either 9 or 12 months after starting of the treatment, as an intermediate end point to support accelerated approvals, in future trials in NDTE patients, NDTinE patients, and patients with RRMM.

PURPOSE Outcomes for patients with newly diagnosed multiple myeloma (NDMM) are heterogenous, with overall survival (OS) ranging from months to over 10 years. METHODS To decipher and predict the molecular and clinical heterogeneity of NDMM, we assembled a series of 1,933 patients with available clinical, genomic, and therapeutic data. RESULTS Leveraging a comprehensive catalog of genomic drivers, we identified 12 groups, expanding on previous gene expression–based molecular classifications. To build a model predicting individualized risk in NDMM (IRMMa), we integrated clinical, genomic, and treatment variables. To correct for time-dependent variables, including high-dose melphalan followed by autologous stem-cell transplantation (HDM-ASCT), and maintenance therapy, a multi-state model was designed. The IRMMa model accuracy was significantly higher than all comparator prognostic models, with a c-index for OS of 0.726, compared with International Staging System (ISS; 0.61), revised-ISS (0.572), and R2-ISS (0.625). Integral to model accuracy was 20 genomic features, including 1q21 gain/amp, del 1p, TP53 loss, NSD2 translocations, APOBEC mutational signatures, and copy-number signatures (reflecting the complex structural variant chromothripsis). IRMMa accuracy and superiority compared with other prognostic models were validated on 256 patients enrolled in the GMMG-HD6 (ClinicalTrials.gov identifier: NCT02495922 ) clinical trial. Individualized patient risks were significantly affected across the 12 genomic groups by different treatment strategies (ie, treatment variance), which was used to identify patients for whom HDM-ASCT is particularly effective versus patients for whom the impact is limited. CONCLUSION Integrating clinical, demographic, genomic, and therapeutic data, to our knowledge, we have developed the first individualized risk-prediction model enabling personally tailored therapeutic decisions for patients with NDMM.

Abstract Background: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. Results: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09–1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01–1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. Conclusions: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. Impact: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.