Abstract Background: Despite significant advances in therapy, multiple myeloma (MM) remains an incurable disease thus far. Patients with high-risk cytogenetic profiles represent a particular challenge, given their more aggressive disease course and poor response to treatment. While innovative treatment approaches like CAR T-cell therapy and bispecific antibodies are becoming standard in many countries, their availability in Russia remains limited. Therefore, we present Russia's first real-world use of a quadruplet regimen in high-risk newly diagnosed MM (NDMM) patients to achieve the deepest possible therapeutic response within the limitations of currently available treatment options. Methods: Twelve high-risk NDMM patients who received Dara-RVd at the Blokhin National Medical Research Center of Oncology, from 2024 to 2025 were included in the study. All patients received induction therapy with Dara-RVd, followed by an MRD-adaptive strategy and autologous stem cell transplantation (ASCT). Tandem or allogeneic SCT were not performed. Depending on post-ASCT MRD status, patients received lenalidomide maintenance therapy, if MRD negativity was achieved. In patients, who remained MRD-positive post-ASCT, consolidation therapy was administered. If patients remained MRD-positive after consolidation therapy, they proceeded to dual-agent maintenance therapy (D-R). The median follow-up was 15 months, the median age – 59 years (33–60). Nine patients had high cytogenetic risk. Three patients presented with extramedullary disease at diagnosis, while four patients had myeloma-related nephropathy that did not require renal replacement therapy. All patients received pneumococcal vaccination prophylaxis. Antitumor treatment was administered alongside supportive therapy (sulfamethoxazole-trimethoprim, acyclovir), immunoglobulin infusions, osteomodifying agents. Clinical responses were assessed according to the International Myeloma Working Group 2016 criteria. Risk stratification was based on cytogenetic abnormalities (amp1q, del17p, t(4;14), t(14;16)). Circulating tumor cells (CTCs) were evaluated using the EuroFlow protocol. We also conducted a patient survey, in which respondents emphasized the importance of receiving the most effective treatment option providing complete disease remission while maintaining a high quality of life. Results: All patients completed 4 Dara-RVd cycles of induction therapy. The overall response rate was 83% (6 patients achieved PR, 2 achieved VGPR). Two patients experienced disease progression and were switched to the Isa-PACE regimen, while two patients have not yet been evaluated. All patients are currently alive. CTCs were quantified in 8 out of 12 patients, with a median level of 0.048% (0.001–0.200%). MRD-negative status (10-5) after induction was achieved by 7 out of 10 patients, while 3 remained MRD-positive. Seven patients underwent stem cell harvesting (etoposide 750 mg/m2)combined with short-acting filgrastim without routine plerixafor administration. The median of apheresis – 3 procedures, CD34+ x 106 – 5,21 cells/kg, with a median interval of 31 days from last course to apheresis. Six patients proceeded to ASCT. Post-ASCT MRD negativity was observed in 6 patients: 5 maintained their MRD-negative status achieved after induction, and 1 patient converted from MRD-positive to MRD-negative. In all cases, the MRD level remained at the 10⁻⁵ threshold without further deepening of response. The median duration of MRD-negative remission is 11.3 months (6 – 17). Maintenance therapy is ongoing, guided by MRD status. Clinically significant adverse events (grade 3, CTCAE v.5.0) included secondary immunodeficiency in 4 patients, while upper and lower respiratory tract infections occurred in 8 out of 12 patients. Additionally, neuropathy grades 2–3 with pain syndrome were observed in 5 patients, attributed primarily to the use of generic medications, resulting in dose reductions and loss of dose intensity in 5 cases. According to patient-reported outcomes assessed via the visual analog scale, symptomatic improvement was noted in 10 out of 12 patients. Conclusion: In the context of limited access to CAR T-cell and bispecific therapies in Russia, early use of Dara-RVd with MRD-adaptive strategies shows high efficacy, including high-risk NDMM patients. This quadruplet-based approach may shift the treatment paradigm, though careful monitoring for complications like hypogammaglobulinemia is essential.
Kamyshanov et al. (Mon,) studied this question.