Efficacy and safety of isatuximab plus bortezomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma ineligible/with no immediate intent for autologous stem cell transplantation

Abstract

Patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem cell transplantation (ASCT) have lower survival rates and may benefit from frontline regimens that include novel agents. This Phase 1b study (NCT02513186) evaluated preliminary efficacy, safety, and pharmacokinetics (PK) of isatuximab, an anti-CD38 monoclonal antibody, combined with bortezomib-lenalidomide-dexamethasone (Isa-VRd) in patients with NDMM ineligible for/with no intent for immediate ASCT. Overall, 73 patients received four 6-week induction cycles of Isa-VRd, then maintenance with Isa-Rd in 4-week cycles. In the efficacy population (n = 71), the overall response rate was 98.6%, with 56.3% achieving a complete response or better (sCR/CR), and 36/71 (50.7%) patients reaching minimal residual disease negativity (10^-5 sensitivity). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 79.5% (58/73) of patients but TEAEs leading to permanent study treatment discontinuation were reported in 14 (19.2%) patients. Isatuximab PK parameters were within the previously reported range, suggesting that VRd does not alter the PK of isatuximab. These data support additional studies of isatuximab in NDMM, such as the Phase 3 IMROZ study (Isa-VRd vs VRd).

Fig. 1. Study design.

^aPre-medications included diphenhydramine 25–50 mg IV (or equivalent), dexamethasone 20 mg IV/PO, H2 antagonists, acetaminophen 650–1000 mg PO, montelukast 10 mg PO (or equivalent). The use of montelukast was strongly recommended in Cycle 1, optional from Cycle 2 onward. ^bIsa 10 mg/kg diluted and administered IV from a fixed-volume infusion bag containing 250 mL of 0.9% sodium chloride solution. ^c20 mg/day in patients >75 years old. ASCT autologous stem cell transplant, d dexamethasone, h hour, IR infusion reaction, Isa isatuximab, IV intravenously, min minute, MRD minimal residual disease, NDMM newly diagnosed multiple myeloma, ORR overall response rate, PD progressive disease, PK pharmacokinetics, PO orally, QW once weekly, Q2W every other week, R lenalidomide, SC subcutaneous, V bortezomib. At the time of protocol amendment 08 (21 December 2018) implementation, a new cohort (Part B) was included and a new fixed-volume infusion method was tested, including all patients from Part A who had already received Isa using weight-based infusion with the earliest switch at Cycle 19 (Maintenance C15). With the implementation of protocol amendment 11 in October 2021, the schedule of Isa administration in the maintenance phase for both cohorts was changed from every 2 weeks to every 4 weeks (on day 1 of each cycle). This change allowed for alignment with several Isa Phase 3 studies where this switch was implemented in the frontline setting. In trials without the transplant procedure included, this switch is done after at least 12 months of treatment. At the time of this switch, all ongoing 43 (58.9%) patients had received triplet maintenance with Isa every 2 weeks in combination with lenalidomide and dexamethasone for at least 18 months (at least 24 months of treatment in total, as the induction phase duration is 6 months). This study also included a cohort of patients treated with Isa combined with bortezomib, cyclophosphamide, and dexamethasone (Isa-VCd), but safety and efficacy of the Isa-VCd cohort will be published separately.

Fig. 2. Best overall response in the efficacy population (n = 71)^a.

^aData adjusted by incorporating results from 8 (Part A) or 21 (Part B) patients whose samples underwent HYDRASHIFT 2/4 isatuximab IFE testing, an immunofixation test assessing serum M-protein without isatuximab interference. The HYDRASHIFT 2/4 isatuximab IFE assay was launched by Sebia in Europe in February 2021 and approved by FDA in November 2021. CR complete response, IFE immunofixation electrophoresis, sCR stringent complete response, VGPR very good partial response.

Fig. 3. MRD- by BOR in the efficacy population (n = 71)^a.

A At a sensitivity level of 10⁻⁵. B At a sensitivity level of 10⁻⁶. ^aMRD was determined by NGF and NGS methods, and MRD- rate was determined by combining both methods in the case of at least 1 method yielding negative results and the other method showing no positive result at the same time. BOR data adjusted by incorporating results from 8 (Part A) or 21 (Part B) patients whose samples underwent testing with HYDRASHIFT 2/4 isatuximab IFE test, an immunofixation test assessing serum M-protein without isatuximab interference. The HYDRASHIFT 2/4 isatuximab assay was launched by Sebia in Europe in February 2021 and approved by FDA in November 2021. BOR best overall response, CR complete response, MRD- minimal residual disease negativity, NGF next-generation flow cytometry, NGS next-generation sequencing, sCR stringent complete response, VGPR very good partial response.

Fig. 4. Median PFS at 10⁻⁵.

A In the efficacy population. B by MRD status^a. ^aMRD was determined by NGF and NGS methods, and MRD negativity rate was determined by combining both methods in the case of at least 1 method yielding negative results and the other method showing no positive result at the same time. CI confidence interval, d dexamethasone, Isa isatuximab, MRD minimal residual disease, NC not calculable, PFS progression-free survival, R lenalidomide, V bortezomib.

Fig. 5. Median OS at 10⁻⁵.

A In the efficacy population. B by MRD status^a. ^aMRD was determined by NGF and NGS methods, and MRD- rate was determined by combining both methods in the case of at least 1 method yielding negative results and the other method showing no positive result at the same time. d dexamethasone, Isa isatuximab, MRD- minimal residual disease negativity, NC not calculable, OS overall survival, R lenalidomide, V bortezomib.