Adding isatuximab to carfilzomib, lenalidomide, and dexamethasone (KRd) significantly increases minimal residual disease negativity rates in patients with NDMM
Phase III data from the IsKia trial demonstrated that the addition of isatuximab to carfilzomib, lenalidomide and dexamethasone (KRd) in patients with newly diagnosed, transplant-eligible multiple myeloma patients significantly improved the rate of minimal residual disease (MRD) negativity versus KRd alone. Treatment with IsaKRd resulted in 77% of patients achieving MRD negativity after consolidation therapy, with no new safety signals observed.
For patients with transplant-eligible newly diagnosed multiple myeloma (NDMM), quadruplet induction with proteasome inhibitors, immunomodulatory agents, dexamethasone and an anti-CD38 monoclonal antibody followed by high-dose melphalan and autologous stem-cell transplant (MEL200-ASCT), with subsequent consolidation, is the standard of care. The phase III IsKia trial assessed the safety and efficacy of isatuximab-carfilzomib-lenalidomide-dexamethasone (IsaKRd) versus KRd alone as induction and consolidation regimen.1
Study design
In order to be eligible, patients must be <70 years old. Patients randomised to the IsaKRd arm (N= 151) received four cycles (28-day) of isatuximab (10 mg/kg IV days 1, 8, 15, 22 cycle 1, followed by 10 mg/kg days 1, 15 cycles 2-4), carfilzomib (20 mg/m2 IV day 1 cycle 1, followed by 56 mg/m2 IV days 8, 15 cycle 1 and days 1, 8, 15 cycles 2-4, lenalidomide (25 mg PO daily days 1-21), dexamethasone (40 mg PO days 1, 8, 15, 22), MEL200-ASCT and four consolidation cycles with IsaKRd at the same schedule. Patients randomised to the KRd arm (N= 151) received four KRd induction cycles, MEL200-ASCT and four KRd consolidation cycles (carfilzomib, lenalidomide and dexamethasone at the same schedule as in the IsaKRd arm). Thereafter, patients received 12 cycles (28-day) of light consolidation with reduced intensity IsaKRd or KRd (isatuximab 10 mg/kg IV on day 1, carfilzomib 56 mg/m2 IV on days 1 and 15, lenalidomide 10 mg orally on days 1-21 and dexamethasone 20 mg orally on days 1 and 15). Primary endpoint of the study was the rate of minimal residual disease (MRD) negativity by next-generation sequencing (NGS; 10-5) after consolidation in the intention-to-treat (ITT) population. MRD was tested in all patients who achieved at least a very good partial response (≥VGPR).1
Results
Patient characteristics were well balanced between the two treatment arms, median age was 60 years and approximately 20% had high-risk cytogenetics with del(17p), t(14;16) or t(4;14). After a median follow-up of 21 months in the ITT population, the rate of MRD negativity at the 10-5 cut-off after consolidation (primary endpoint) was 10% higher with IsaKRd, as compared to KRd alone (77% vs. 67%, OR 1.67; p= 0.049). When looking at the 10-6 cut-off for MRD, the difference was even more pronounced at 67% and 48%, respectively (OR 2.29; p< 0.001). Consistent MRD results were detected by next-generation flow. Interestingly, MRD negativity rates improved over time and this improvement was observed across all risk groups, including normal-risk patients, those with a single high-risk abnormality such as del(17p), t(14;16) or t(4;14), and ultra-high risk patients with two or more of these cytogenetic abnormalities or with gain(1q21) or amp(1q21). In all risk groups, MRD at the 10-5 level was comparable in patients receiving IsaKRd (77-79%), while a decline was noted in those on the KRd regimen. At the 10-6 sensitivity level, this trend was even more pronounced.1
In the IsaKRd arm, 55% of patients experienced ≥1 haematologic adverse events (AEs), as compared to 44% of patients in the KRd arm. The most frequent grade 3-4 haematologic AEs with IsaKRd vs. KRd were neutropenia (36% vs. 22%) and thrombocytopenia (15% vs. 17%). Furthermore, 41% of patients had ≥1 non-haematologic grade 3-4 AE with IsaKRd vs. 37% with KRd. Adverse events led to treatment discontinuation in 6% of patients in the IsaKRd arm and in 5% of patients in the KRd arm. Treatment-related deaths occurred in four patients with IsaKRd (2 COVID, 1 pneumonia, 1 pulmonary embolism) and one patient with KRd (septic shock).1
Enhancing convenience of intravenous isatuximab administration
In order to enhance the convenience of intravenous (IV) isatuximab administration, a phase Ib study assessed the safety and feasibility of a shorter IV infusion over 30 minutes (30-min) in patients with NDMM who are not eligible for ASCT and are still on maintenance therapy after treatment with bortezomib-based regimens (isatuximab-bortezomib-cyclophosphamide-dexamethasone [Isa-VCd] or isatuximab-bortezomib-lenalidomide-dexamethasone [Isa-VRd]. Patients were to be switched to the 30-min infusion with isatuximab at 10 mg/kg diluted in a 250 mL infusion bag of 0.9% sodium chloride. The infusion rate of the first infusion was 250 mL/hour. In the absence of infusion reactions, subsequent infusions were to be administered at an infusion rate of 500 mL/hour. Between January and May 2023, 45 patients received a total of 142 infusions; 45 first infusions with intermediate rate and 97 30-min infusions across cohorts, with a median relative isatuximab dose intensity of 99.4%. Switching occurred at a median of 46 cycles for all treated patients and proved to be well tolerated, with no infusion reactions and no infusion interruptions across cohorts.2
Conclusion
In transplant-eligible NDMM patients, the addition of isatuximab to KRd induction and consolidation significantly increased MRD negativity rates in every treatment phase and across risk groups, as compared to KRd, with no new safety concerns.1 Furthermore, results from a phase Ib trial suggest that a 30-min infusion of isatuximab is a feasible, well-tolerated, and convenient administration method for patients with multiple myeloma on isatuximab treatment for several months.2
Reference
1. Gay F, et al. Results of the Phase III Randomized Iskia Trial: Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone Vs Carfilzomib-Lenalidomide-Dexamethasone As Pre-Transplant Induction and Post-Transplant Consolidation in Newly Diagnosed Multiple Myeloma Patients. Presented at ASH 2023; Abstract LBA-4.
2. Ocio E, et al. 30-Minute Infusion of Isatuximab in Newly Diagnosed Multiple Myeloma (NDMM) Patients: Results of a Phase 1b Study. ASH 2023; Online abstract 6717.
