Transplant-Ineligible MM: The Phase 2 Isatuximab-Bortezomib-Lenalidomide-Dexamethasone Rest Study

Lenalidomide-dexamethasone (Rd), bortezomib-lenalidomide-dexamethasone (VRd), and bortezomib-melphalan-prednisone (VMP) are the standard therapies for newly diagnosed multiple myeloma (NDMM) patients who are ineligible for autologous stem-cell transplantation (ASCT). In two extensive phase 3 studies, the benefit of adding an anti-CD 38 monoclonal antibody (mAb) to the standard regimens of VMP and Rd was demonstrated (Facon, 2019; Mateos, 2018). Isatuximab is an anti-CD38 monoclonal antibody approved in combination with pomalidomide-dexamethasone and carfilzomib-dexamethasone to treat relapsed/refractory multiple myeloma and has also demonstrated clinical responses as combination therapy for the treatment of newly diagnosed multiple myeloma (Trudel, 2019). Since their effectiveness was discovered, corticosteroids have been the cornerstone of most myeloma-targeted therapies. Due to the paradigm of continuous treatment, the cumulative dose of corticosteroids administered to patients is substantial. Steroids diminish patients’ short- and long-term quality of life and increase their susceptibility to infection. Infections are one of the leading causes of complications and mortality during active first-line therapy, and their prevalence increases with age (Mothy, 2019).

Steroid-free and reduced corticosteroid regimens have demonstrated enhanced safety and comparable efficacy to steroid-containing regimens (O’Donnell, 2018). Rajkumar, 2010. Richardson and 2005). The study examines the efficacy of isatuximab (Isa) in combination with bortezomib (V) and lenalidomide (R) with minimal dexamethasone (d) as a first-line therapy for transplant-ineligible patients. The primary endpoint is the proportion of patients who acquire a complete response with no residual disease (Euroflow NGF 10-5) during and after 18 cycles of study treatment. Secondary endpoints include progression-free survival, overall survival, response rate, safety assessments, and patient-reported outcome. The REST study is an academic, open-label, single-arm, phase 2 study (ClinicalTrials.gov; NCT04939844) of NDMM patients ineligible for ASCT. All 28-day cycles, patients receive Isa-VRd (Isa:10 mg/kg IV Days 1, 8, 15, 22 during cycle 1, QWcycle 2-18; V:1.3 mg/m2 SC Days 1,8,15 during cycle 1-8; R:25 mg PO Days 1-21 during all cycles; d:20 mg PODays 1,8,15,22 only for the first two cycles). Recruitment concluded on January 31, 2023, with 51 patients enrolled. Table 1 contains the characteristics of the baseline. The median number of cycles initiated by patients was nine (range: 1-21), and the median duration of exposure was thirty-four weeks (range: 1-76).

One patient died from staphylococcus aureus septicemia, three were discontinued due to disease progression, and one was of inadequate compliance (after one cycle). About 23 patients developed 43 grade >3 non-hematological adverse events (AE), including infections (n=16), vasovagal syncope (n=5), bone pain (n=3), acute renal failure (n=3), diarrhea (n=3), increased transaminases (n=3), peripheral neuropathy (n=2), maculopapular rash (n=1), venous thromboembolism (n=1), reduced general condition (n=1), opiate intoxication (n=1), arthritis (n=1) and gastrointestinal hemorrhage (n=1). Due to drug toxicity or adverse events (all grade 2 or lower), two patients discontinued study treatment before cycle 19. At a median follow-up time of 8 months, the response of 39 patients was evaluated. The overall response rate was 97% (38/39 patients), and the rate of >very excellent partial response was 66.6% (26/39 patients). The safety profile of Isa-VRd in the transplant-ineligible population is tolerable, and its preliminary efficacy in transplant-ineligible NDMM is encouraging.

Source: https://library.ehaweb.org/eha/2023/eha2023-congress/386704/frida.bugge.askeland.replacing.steroids.in.transplant-ineligible.multiple.html?f=menu%3D16%2Abrowseby%3D8%2Asortby%3D2%2Ace_id%3D2489%2Aot_id%3D27922%2Atrend%3D4016%2Amarker%3D4178

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT04939844

Frida Bugge Askeland, Einar Haukås, Tobias S. Slørdahl, Anja Klostergaard, Tatjana Alexandersen, Diana Schjøll, Anna Lysén, Emil Hermansen, Fredrik Schjesvold/REPLACING STEROIDS IN TRANSPLANT-INELIGIBLE MULTIPLE MYELOMA: THE PHASE 2 ISATUXIMAB-BORTEZOMIB-LENALIDOMIDE-DEXAMETHASONE REST STUDY/Inc, M. G. (n.d.). REPLACING STEROIDS IN TRANSPLANT-INELIGIBLE MULTIPLE MYELOMA: THE… by Frida Bugge Askeland. Library.ehaweb.org. Retrieved July 14, 2023, from https://library.ehaweb.org/eha/2023/eha2023-congress/386704/frida.bugge.askeland.replacing.steroids.in.transplant-ineligible.multiple.html?f=menu%3D16%2Abrowseby%3D8%2Asortby%3D2%2Ace_id%3D2489%2Aot_id%3D27922%2Atrend%3D4016%2Amarker%3D4178