IRd Regimen Shows No Significant Advantage in Frail Patients With NDMM Compared With IDd Regimen

Multiple myeloma (MM) is a disease that primarily affects patients with a median age of 69 years at diagnosis. Unlike younger patients with MM, older patients are highly heterogeneous regarding toxicity- and relapse-related treatment discontinuation as well as geriatric assessment of frailty. Authors of a study published in eClinicalMedicine analyzed the efficacy and safety of ixazomib-based frontline therapies in frail patients with newly diagnosed MM (NDMM) that was defined by the International Myeloma Working Group (IMWG) frailty score. The treatments analyzed were ixazomib, lenalidomide, and dexamethasone (IRd) and ixazomib, pegylated liposomal doxorubicin, and dexamethasone (IDd) followed by ixazomib and dexamethasone (Id) maintenance therapy.

This prospective, multicenter, non-randomized concurrent controlled study included patients aged 65 years and older with NDMM who were considered to be frail. Frailness was determined if patients had a IMWG frailty score equal to or greater than 2 or a Mayo frailty index (combination of age ≥ 70, ECOG-PS ≥ 2, and NT-proBNP ≥ 300 ng/L simultaneously). Further, patients had to have a disease measured with evaluable serum monoclonal protein of blood (IgG ≥10 g/L, others ≥5 g/L), urine (≥200 mg/24 h), or serum-free light chain greater than or equal to 10 mg/dL, or by the presence of measurable extramedullary plasmacytoma. In addition, patients were not included in the study if they had allergies to any of formulation of the drugs that were examined, had prior cardiovascular and cerebrovascular events or conditions within 15 days before enrollment, or received live attenuated vaccine within 4 weeks before drug administration.

The total 120 enrolled patients were assigned to receive either the IRd regimen (n = 60) or IDd regimen (n = 60). The IRd regimen consisted of 4 mg of oral ixazomib (administered on days 1, 8, and 15), 25 mg of oral lenalidomide (administered on days 1-14; 10 mg were recommended depending on the patients’ creatinine clearance, resulting in postponement until creatinine clearance was improved), and 20 mg of oral dexamethasone (administered on days 1, 8, 15, and 22) in a 28-day cycle. Similarly, the IDd regimen consisted of 4 mg of oral ixazomib (administered on days 1, 8, and 15) and 20 mg of oral dexamethasone (administered on days 1, 8, 15, and 22) in a 28-day cycle; however, 40 mg of intravenous liposomal doxorubicin was administered on day 1 in place of lenalidomide. Patients that achieved a response better than very good partial response (VGPR) moved on to receive 2 more cycles, whereas those who achieved a partial response (PR) or minimal response (MR) received 4 more cycles as consolidation therapy.

The primary endpoint for the study was overall response rate (ORR) with different induction regimens (defined as the proportion of patients who achieved partial response [PR] or above according to IMWG criteria). Key secondary end points were progression-free survival (PFS), overall survival (OS), early death (defined as death within 60 days of enrollment), health-related quality of life (QoL), toxicity-related discontinuation of treatment, and relative dose intensity (RDI).

The results indicated that the ORR during induction was comparable in the IRd and IDd groups, with a higher CR in the IRd group. The ORR was approximately 82% (95% CI: 0.719-0.915) in the IRd group and 77% (95% CI: 0.660-0.834) in the IDd group, with a respective 15 (25%) and 7 (12%) patients having a CR, 22 (37%) and 24 (40%) patients with a VGPR, and 12 (20%) and 15 (25%) patients with a PR. Further, there was no statistical difference in efficacy between the 2 groups, according to the authors. In addition, of the 22 patients who achieved CR, 18 (82%) were included in the minimal residual disease (MRD) analysis, and 11 (50%) of them were MRD-negative.

Further, after a median follow-up period of 34.2 months (95% CI: 31.2-37.4), 38 patients (63%) in the IRd group and 50 patients (83%) in the IDd group had PFS events. Of the 38 patients from the IRd group who had PFS events, 10 (26%) were deaths—9 due to infection, including 3 which were COVID-19-related, and 1 due to myocardial infarction—and 28 (74%) were disease progression events. Of the 50 patients in the IDd group who had PFS events, 13 (26%) were death—7 due to infection, 1 due to myocardial infarction, 6 due to toxicity—or withdrawal-related treatment discontinuation, and 37 (74%) were disease progression events.The median PFS for all patients was 18.5 months (95% CI: 15.4-21.6), and 21.6 months (95% CI: 20.0-23.2) and 13.9 months (95% CI: 7.7-20.1) in the IRd and IDd groups, respectively, with the PFS being notably longer in the IRd group.

A total of 28 patients discontinued IRd treatment and 33 discontinued IDd treatment prior to the initiation of maintenance therapy. Further, in the IRd group, the median RDI for induction treatment was 0.87 (0.74-0.93) for ixazomib, 0.89 (0.77-0.93) for lenalidomide, and 0.88 (0.76-0.93) for dexamethasone, and in the IDd group, the median RDI was 0.82 (0.72-0.90) for ixazomib, 0.82 (0.70-0.89) for liposomal doxorubicin, and 0.82 (0.72-0.89) for dexamethasone. Because of infections, gastrointestinal toxicity, or peripheral neuropathy, ixazomib dose reduction occurred in 3% (n = 2) of patients in the IRd group and 15% (n = 9) in the IDd group. In addition, lenalidomide dose reductions were seen in 7% of patients in the IRd group, with infrequent dose withholdings, according to the investigators.

Maintenance treatment was initiated in approximately 53% of patients (n = 32) in the IRd group and 45% (n = 27) in the IDd group. Maintenance treatment discontinuation was primarily due to disease progression, toxicity, or the onset of other diseases. Among those who received subsequent therapy, a higher proportion in the IRd group received a daratumumab-containing regimen compared to the IDd group.

Hematological and non-hematological adverse events (AEs) of grade 3 or higher were reported in both the IRd and IDd groups, with infections (21%) and gastrointestinal AEs (13%) being the most common non-hematological AEs. Serious adverse events (SAEs) occurred in a minority of patients (IRd group: n = 11, 18%; IDd group: n = 15, 25%), with only 4 SAEs resulting in non-treatment-related deaths.

A total of 970 questionnaires were obtained from patients, with the median number of questionnaires per patient being 9 (range: 1-33). The baseline QoL score was 76.6 (IQR: 50.0-83.3) for those in the IRd group and 67.2 (IQR: 16.6-83.3) for those in the IDd group. The scores of the IRd group and the IDd group increased to 165.2 and 157.2, respectively, after 8 cycles of induction treatment with improvement in the QoL during induction treatment being statistically significant (P < 0.001) and clinically relevant after induction Cycle 2. According to the investigators, the improvement in QoL continued to increase over time during following induction cycles.

Limitations of the study include its non-randomized design resulting in potential biases of baseline disease characteristics between the 2 groups, differences in subsequent therapies between groups which could influence the OS analysis, and the inability to accurately assess frailty in NDMM patients due to the varied scoring systems. Further, the study authors note that the results could not conclusively determine in regard to ORR if 1 regiment was inferior to the other.

Although the results don’t indicate strongly whether 1 regimen over the other, the IRd group demonstrated longer PFS and OS, and overall, the results indicate the IMWG frailty score can be helpful in guiding treatment decisions for frail NDMM patients. The study authors suggest that results should be validated by larger randomized trials to strengthen statistical significance and minimize potential confounding factors.

Reference

Bao L, Wang Y, Liu P, et al. Ixazomib-based frontline therapy followed by ixazomib maintenance in frail elderly newly diagnosed with multiple myeloma: a prospective multicenter study. eClinicalMedicine. 2024;68:102431. doi:10.1016/j.eclinm.2024.102431