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The Role of Monoclonal Antibodies in the First-Line Treatment of Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma.

ABSTRACT: Elderly transplant-ineligible (NTE) patients represent the majority of patients affected by multiple myeloma (MM). Elderly patients are a highly heterogeneous population, with large variability in health and functional status. Thus, choosing their optimal treatment is challenging. A wide range of first-line treatments is available, and novel-agent combinations, including monoclonal antibodies (mAbs), have recently entered clinical practice. The combination of the anti-CD38 mAb daratumumab with bortezomib, melphalan and prednisone (Dara-VMP) or lenalidomide and dexamethasone (Dara-Rd) demonstrated impressive advantages in terms of progression-free survival and minimal residual disease negativity, as compared to VMP and Rd, without safety concerns. Another anti-CD38 mAb, isatuximab, is showing encouraging results, and new isatuximab-based combinations might enter clinical practice in the future. Nevertheless, available data come from clinical trials with selected patient populations and, to date, the manageability of these regimens in real-life patients or in frail patients remains unknown. Frailty-tailored treatments, including mAbs, are under evaluation in preliminary studies. In this review, we analyze recently approved mAb-based treatments for NTE newly diagnosed MM patients and new combinations under evaluation, focusing on the efficacy and safety of these regimens and on open issues regarding the choice of therapy for elderly patients.

SUBMITTER: Bonello F

PROVIDER: S-EPMC7823261 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The Role of Monoclonal Antibodies in Smoldering and Newly Diagnosed Transplant-Eligible Multiple Myeloma.

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Oral ixazomib, lenalidomide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma.

Project description:Continuous lenalidomide-dexamethasone (Rd)-based regimens are among the standards of care in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. The oral proteasome inhibitor ixazomib is suitable for continuous dosing, with predictable, manageable toxicities. In the double-blind, placebo-controlled TOURMALINE-MM2 trial, transplant-ineligible NDMM patients were randomized to ixazomib 4 mg (n = 351) or placebo (n = 354) plus Rd. After 18 cycles, dexamethasone was discontinued and treatment was continued using reduced-dose ixazomib (3 mg) and lenalidomide (10 mg) until progression/toxicity. The primary endpoint was progression-free survival (PFS). Median PFS was 35.3 vs 21.8 months with ixazomib-Rd vs placebo-Rd, respectively (hazard ratio [HR], 0.830; 95% confidence interval, 0.676-1.018; P = .073; median follow-up, 53.3 and 55.8 months). Complete (26% vs 14%; odds ratio [OR], 2.10; P < .001) and ≥ very good partial response (63% vs 48%; OR, 1.87; P < .001) rates were higher with ixazomib-Rd vs placebo-Rd. In a prespecified high-risk cytogenetics subgroup, median PFS was 23.8 vs 18.0 months (HR, 0.690; P = .019). Overall, treatment-emergent adverse events (TEAEs) were mostly grade 1/2. With ixazomib-Rd vs placebo-Rd, 88% vs 81% of patients experienced grade ≥3 TEAEs, 66% vs 62% serious TEAEs, and 35% vs 27% TEAEs resulting in regimen discontinuation; 8% vs 6% died on study. Addition of ixazomib to Rd was tolerable with no new safety signals and led to a clinically meaningful PFS benefit of 13.5 months. Ixazomib-Rd is a feasible option for certain patients who can benefit from an all-oral triplet combination. This trial was registered at www.clinicaltrials.gov as #NCT01850524.

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A simplified frailty scale predicts outcomes in transplant-ineligible patients with newly diagnosed multiple myeloma treated in the FIRST (MM-020) trial.

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Project description:BackgroundPatients with high-risk, newly diagnosed multiple myeloma (HR-NDMM) who are ineligible for autologous stem cell transplant (ASCT) have limited first-line treatment options. Recent meta-analyses evaluating the impact of incorporating daratumumab in the backbone regimen on progression-free survival (PFS) have found mixed results in these patients.Materials and methodsA pooled analysis of patient-level data for ASCT-ineligible patients with HR-NDMM [ie, del(17p), t(4;14), t(14;16)] from the MAIA and ALCYONE trials; stratified by study identifier and adjusting for cytogenetic abnormality subtype, baseline performance status, International Staging System stage, myeloma type, and renal impairment; was conducted. Impact of daratumumab on PFS and rates of complete response or better (≥CR), minimal residual disease (MRD)-negative CR, very good partial response or better (≥VGPR), and overall response (ORR) was compared to control.ResultsAmong 101 patients in the daratumumab and 89 patients in the control cohort, median follow-up was 43.7 months. Daratumumab reduced the risk of progression or death by 41% (adjusted hazard ratio for PFS [95% confidence interval (CI)] = 0.59 [0.41-0.85]) versus control. At 36 months, the estimated proportion of patients who did not progress and were still alive was 41.3% in the daratumumab and 19.9% in the control cohort. Rates of ≥CR (41.6% vs. 22.5%), MRD-negative CR (24.8% vs. 5.6%), ≥VGPR (75.2% vs. 46.1%), and ORR (92.1% vs. 74.2%) were higher for daratumumab versus control.ConclusionThese findings demonstrate that incorporation of daratumumab in frontline treatment regimens reduced the risk of progression or death and improved response rates among ASCT-ineligible HR-NDMM patients.

| S-EPMC9256027 | biostudies-literature

Continuous treatment with lenalidomide and low-dose dexamethasone in transplant-ineligible patients with newly diagnosed multiple myeloma in Asia: subanalysis of the FIRST trial.

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Carfilzomib, lenalidomide, and dexamethasone plus transplant in newly diagnosed multiple myeloma.

Project description:In this phase 2 multicenter study, we evaluated the incorporation of autologous stem cell transplantation (ASCT) into a carfilzomib-lenalidomide-dexamethasone (KRd) regimen for patients with newly diagnosed multiple myeloma (NDMM). Transplant-eligible patients with NDMM received 4 cycles of KRd induction, ASCT, 4 cycles of KRd consolidation, and 10 cycles of KRd maintenance. The primary end point was rate of stringent complete response (sCR) after 8 cycles of KRd with a predefined threshold of ?50% to support further study. Seventy-six patients were enrolled with a median age of 59 years (range, 40-76 years), and 35.5% had high-risk cytogenetics. The primary end point was met, with an sCR rate of 60% after 8 cycles. Depth of response improved over time. On intent-to-treat (ITT), the sCR rate reached 76%. The rate of minimal residual disease (MRD) negativity using modified ITT was 70% according to next-generation sequencing (<10-5 sensitivity). After median follow-up of 56 months, 5-year progression-free survival (PFS) and overall survival (OS) rates were 72% and 84% for ITT, 85% and 91% for MRD-negative patients, and 57% and 72% for patients with high-risk cytogenetics. For high-risk patients who were MRD negative, 5-year rates were 77% and 81%. Grade 3 to 4 adverse events included neutropenia (34%), lymphopenia (32%), infection (22%), and cardiac events (3%). There was no grade 3 to 4 peripheral neuropathy. Patients with NDMM treated with KRd with ASCT achieved high rates of sCR and MRD-negative disease at the end of KRd consolidation. Extended KRd maintenance after consolidation contributed to deepening of responses and likely to prolonged PFS and OS. Safety and tolerability were manageable. This trial was registered at www.clinicaltrials.gov as #NCT01816971.

| S-EPMC7714092 | biostudies-literature

Survival, health care resource utilization and expenditures of first-line treatments for multiple myeloma patients ineligible for transplant in Taiwan.

Project description:BackgroundWe aimed to provide real-world information on survival, health care resource utilization (HCRU), and expenditures related to various first lines of therapy (1LOTs) in newly diagnosed multiple myeloma (NDMM) patients who were transplant ineligible (TI).Patients and methodsFrom the Taiwan National Health Insurance Database (2008-2016), we identified 1,511 NDMM-TI patients who had received 1LOT since June 2012. We categorized 1LOT regimens into four groups: bortezomib (V)+thalidomide (T), V, T, and non-V/T. Patients' characteristics were collected. The overall survival (OS), event-free survival (EFS), frequencies of HCRU (hospitalization, visiting outpatient and emergency departments), and related expenditures within one year after commencement of the 1LOT were evaluated and compared.ResultsThe mean age of the included patients was 71.3 (SD 10.7) years, and 40.4% of patients had a CCI score ≥3. Most patients (747; 49.4%) were in the V+T group and, after adjusting for covariates, had a significantly longer OS (median, 22.2 months) and EFS (9.1 months) than those in the T group (12.6 and 4.5 months, respectively) and the non-V/T group (12.2 and 3.2 months, respectively), but they were mostly comparable with patients in the V group (23.8 and 6.6 months, respectively). Compared to those in the V+T group, patients in the T and non-V/T groups had 29% and 39% fewer outpatient visits and 15% and 24% lower total expenditure, respectively.ConclusionOur real-world data consolidate evidence for the effectiveness of bortezomib-containing regimens as the 1LOT in NDMM-TI patients at the expense of more outpatient visits and higher total costs.

| S-EPMC8153459 | biostudies-literature

Ixazomib-based induction regimens plus ixazomib maintenance in transplant-ineligible, newly diagnosed multiple myeloma: the phase II, multi-arm, randomized UNITO-EMN10 trial.

Project description: Not available

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