Pembrolizumab Added to First-Line Cyclophosphamide, Bortezomib and Dexamethasone in Newly Diagnosed Transplant Non-Eligible Myeloma Patients: A Phase 2A Open Label, Multi Centre Study

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.4768-4768
• Main Authors: Kotb, Rami, Gul, Engin, Abdel-Samad, Nizar, Othman, Ibraheem, Pavic, Michel, Reece, Donna E.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-153897

Background: Despite recent improvements, myeloma is still incurable. There is need to add new therapeutic tools. The combination of the proteasome inhibitor (PI) Bortezomib, an alkylator (Cyclophosphamide or Melphalan) and Dexamethasone (Dex) /Prednisone is a widely used first-line therapy. Most patients achieve a rapid response within the first two cycles. The lack of a deep response to the bortezomib-based therapy predicts an inferior outcome, a poor response to newer PIs and limited therapeutic options. Different studies highlighted the role of the PD1/PDL1 pathway in myeloma immune escape and progression. The expression of PDL1 by myeloma cells is higher in relapsed or refractory disease and on minimal residual disease cells. At least one preclinical study showed that the binding of PD1 to PDL1 expressed by the myeloma cells leads to a reverse signal that induces resistance to bortezomib and melphalan. Also, Bortezomib is known to enhance anti-myeloma immune response by different mechanisms, including stimulating myeloma cell apoptosis, sensitizing myeloma cells to natural killer cell mediated killing and enhancing antigen presentation by dendritic cells. This suggests a mutual potentiation between Pembrolizumab and Cyclophosphamide, Bortezomib and Dex (CyBorD). An early immune-based intervention is likely more beneficial. With time and disease progression, the host is more immune-compromised and the disease is more refractory with redundant escape mechanisms. The benefits of early intervention are carefully weighed against the potential risks and other available therapeutic options. The adaptive design of this CMRG-006 trial is meant to select the population with the highest need for treatment improvement while still in the early phase of therapy. We expect the combination of Pembrolizumab and CyBorD to be more effective and well tolerated. Design and Methods: Phase 2A, pilot study. Non-transplant eligible newly diagnosed myeloma patients (NTE-NDMM) will start their standard nine cycles of CyBorD (Cyclophosphamide 300 mg/m 2 PO, Bortezomib 1.5 mg/m 2 SC, and Dex 40 mg PO, all given on days 1, 8, 15 and 22 of 28-day cycle). Patients not having primary disease progression and achieving less than Very Good Partial Response (VGPR) after 2 cycles will be screened for this study during cycle 3. Eligible patients will receive Pembrolizumab 200 mg IV every 3 weeks starting with day 1 of cycle 4 (P-CyBorD). After completion of cycle nine of CyBorD, Pembrolizum