Efficacy and Tolerance of Isatuximab, Cyclophosphamide, Bortezomib, and Dexamethasone (Isa-CBD) Induction Chemotherapy in Newly Diagnosed, Transplant Eligible Multiple Myeloma: Report of the Phase 2 Multi-Centre, Open Label Canadian Myeloma Research Group (CMRG)-008 Prospective Clinical Trial
Authors: Kotb Rami , White Darrell , Bhella Sita , McCurdy Arleigh , Sandhu Irwindeep , Mian Hira , Stakiw Julie , Othman Ibraheem , Su Jiandong , Khan Aniba , Gul Engin , Reece Donna 
Published: December 2023

Background: The previous standard Canadian approach to autologous stem cell transplantation (ASCT) included CyBorD induction and single-agent lenalidomide maintenance until progression (Cote J, et al. ASH 2022: abstract 117). In an effort to improve outcomes, the current Canadian Myeloma Research Group (CMRG)–008 trial aimed to assess the efficacy and tolerance of a regimen of isatuximab-CyBorD (Isa-CyBorD) induction, stem cell mobilization/collection, high-dose melphalan with ASCT, followed by continuous maintenance with isatuximab and lenalidomide in newly diagnosed multiple myeloma (NDMM) patients eligible for transplant. We now report the first planned analysis of Isa-CyBorD induction and stem cell mobilization and collection.

Methods: This is a multi-centre phase 2 prospective study conducted in 8 centres in which transplant-eligible NDMM (TE-NDMM) patients received isatuximab added to four cycles of standard induction CyBorD chemotherapy (cyclophosphamide 300 mg/m 2 PO, bortezomib 1.5 mg/m 2 SC, and dexamethasone 40 mg PO, all given on days 1, 8, 15 and 22 of a 28-day cycle along with isatuximab 10 mg/kg IV days 1, 8, 15 and 22 of cycle 1 and days 1 and 15 of cycles 2-4). Isatuximab premedication also included acetaminophen, H2-antagonist (ranitidine) or proton pump inhibitor and montelukast. No thromboprophylaxis required per protocol. After the completion of induction treatment, subjects achieving ≥ stable disease (SD) proceeded to mobilization and collection of hematopoietic stem cells (SCs) per local institutional standards. Eligible patients with successful SC collection then proceeded to high-dose melphalan 200 mg/m 2 followed by ASCT. Maintenance treatment commenced at 100 days (+/- 7 days) post-ASCT and continued until disease progression. Maintenance treatment consisted of 28-day cycles of isatuximab (10 mg/kg IV on days 1, 8, 15 and 22 of cycle 1; days 1 and 15 of cycles 2-3; then day 1 of each subsequent cycle) administered with lenalidomide (10 mg daily on days 1-21).

Results: Between December 2022-January 2023, 71 patients with ECOG ≤ 2 were enrolled: 25 females, 46 males; median age 61 years (range: 31-73); 46.5%, 35.2% and 18.3% were ISS stages I, II and III, respectively. High-risk cytogenetics were documented in 20.6% of evaluable patients (13/63).

All completed Isa-CyBorD induction therapy. The treatment was well-tolerated with rare grade 3 - 4 adverse events: neutropenia (8.2%), anemia (8.2%) and febrile neutropenia (4.1%). Common side-effects (All grades combined, ≥20%) included nausea (50%), constipation (28%), fatigue (28%), peripheral neuropathy (27% - all ≤ grade 2 with no dose holds for neuropathy), insomnia (24%), diarrhea (22%), infusion-related reaction (22%).

Response assessment at the end of induction was available for 57 pts by the data cut-off date (June 1 st, 2023). All patients had clinical improvement with no primary progressive disease. Complete response (CR), very good partial response (VGPR) and partial response (PR) were documented in 7%, 52.6% and 33.3%, respectively. Four patients (7%) had &lt;50% improvement of M-protein (SD).

Three patients did not proceed to stem cell transplantation due to patient / physician choices. SC mobilization utilized cyclophosphamide in 10 (15.4%) and plerixafor in 12 (18.5%) patients; mobilization was successful in all 65 patients mobilized so far with 1-3 apheresis (median 2). The median number of CD34+ cells collected was 5.3 x10^6/kg (range: 2.25-7.28).

Conclusion: Isa-CyBorD with weekly bortezomib is an effective induction therapy in patients with NDMM (93% ≥ PR with no progression and no mobilization failures). The treatment was well-tolerated with a side-effect profile comparable to our Canadian prior experience with CyBorD alone. All patients who proceeded to mobilization had successful collection of adequate number of SCs. Further follow-up is ongoing to assess long-term outcomes with this approach.