Isa-PACE in the treatment of functionally high-risk multiple myeloma: Intermediate results.

Abstract Introduction. The VRd regimen with autologous hematopoietic stem-cell transplantation (auto-HSCT) is the standard treatment for newly diagnosed multiple myeloma (NDMM) in Russia. However, some patients already during induction therapy show progression, classified as functionally high risk (FHR). In the absence of chimeric antigen receptor T-cell (CAR-T) therapy in Russia, the Isa-PACE (isatuximab + cisplatin, doxorubicin, cyclophosphamide, and etoposide) combination is considered a potential bridge therapy to auto-HSCT. The role of intermediate positron emission tomography/computed tomography (PET/CT) as an early diagnostic tool for patients with FHR MM remains poorly understood but highly relevant. Methods. This single-center, prospective study was conducted from 2024 to 2025 at the National Research Medical Center of Oncology named after N.N. Blokhin. Nine patients with NDMM who were candidates for auto-HSCT were included in the study. All patients were male and non-frail, with a median age of 57 years (range 47-66). Cytogenetic risk stratification was based on gain of 1q, deletion of 17p, translocations t(4;14), t(14;16), t(14;20), the MRD status (10-5), was determined by flow cytometry (ELISA). Only two patients had high cytogenetic risk myeloma. Results. All patients received 4 courses of VRd as induction therapy with the achievement of >PR and subsequent collection of PBSCs. By the stage of auto-HSCT, all had disease progression (PFS 6 months (4-10), the median time from the moment of achieving the best response to progression is 2 months (1-6)). In pre-therapeutic PET/CT patients showed high levels of SUVmax in the most active tumor site (median -7.83 (4.25–19.26)), indicating a link between high metabolic activity and the risk of early disease progression on the first line of treatment. At the same time, 6/9 patients had a recurrence of the disease only due to PET/CT data, in 3/9 – according to PET/CT data and immunochemical analysis. As further therapy, all patients received 1-3 cycles (median 2) of Isa-PACE. The overall response rate (ORR) after Isa-PACE treatment was 78% (n=7/9): CR with MRD-negative status- 6, VGPR with MRD positive status- 1 and PD was detected in 2 patients. Patients who achieved CR (n=6) proceeded to auto-HSCT. In July 2025, the median follow-up time was 16 months (range 10.5-31.9), all patients maintain sustained MRD-negative status, with complete remission of disease. The median progression-free survival was not reached. In patients refractory to both first- and second-line regimens, PET/CT revealed that the patient who later died of disease progression had extensive paramedullary involvement, highlighted by a large sternal plasmacytoma (SUVₘₐₓ 21.56). The other progressing patient likewise demonstrated a heavy overall tumor burden, which likely contributed to suboptimal treatment response. Grade 3-4 adverse events during Isa-PACE treatment included febrile neutropenia in two patients, thrombocytopenia in eight, anemia in six, and HPV infections in nine. Five patients experienced a loss of therapy intensity due to grade 3-4 AE. All patients continue to receive maintenance therapy with isatuximab and lenalidomide, while maintaining MRD-negative status. After achieving MRD-negative complete remission for >12 months, patients will be switched to continued lenalidomide maintenance until progression or intolerable toxicity. An auto-HSCT will be planned for a patient who achieves VGPR. One patient with disease progression after four lines of therapy (VRD, IsaPACE, DaraKd, EloPD) was treated with bispecific BCMA antibody therapy, resulting in the achievement of VGPR. Unfortunately, one patient died due to further disease progression despite treatment. Conclusion. In patients with FHR MM, the combination of Isa-PACE allowed achieving an overall response of 78% and a complete metabolic response in 67% of cases. The regimen demonstrates a manageable toxicity profile and can be considered an effective bridge to autologous hematopoietic stem cell transplantation (auto-HSCT). Further follow-up will be necessary to assess long-term survival and validate the ability to discontinue therapy. Intermediate assessment of PET/CT imaging effectively reflected the response to treatment and identified the need for treatment intensification. Expanding the sample size will help to clarify the prognostic significance of this approach and aid in stratifying patients with NDMM.