Early rescue intervention with daratumumab, pomalidomide and dexamethasone (DPd) in high-risk smoldering myeloma (HR-SMM) patients included in the GEM-CESAR treated with carfilzomib, lenalidomide and dexamethasone (KRd)- autologous stem cell transplantation (ASCT)-krd-rd

Abstract

Abstract Background: Early treatment of HR-SMM has been shown to delay progression to symptomatic myeloma. In the phase II GEM-CESAR trial, 90 patients received early intensive therapy with KRd x6 induction, high-dose meplhalan (HDM)-ASCT, KRd consolidation (2 cycles), and 2 years of Rd maintenance. The primary endpoint— minimal residual disease (MRD) negativity post-ASCT—was achieved in 62% of patients, and sustained MRD negativity at 4 years was observed in 31%. After 70 months, the time to progression (TTP) was 94%, and overall survival (OS) reached 92%, supporting a potential curative strategy (Mateos MV et al., JCO 2024). A secondary endpoint was the evaluation of time to biochemical progression (TTBP); patients experiencing BP had the option to receive rescue therapy with DPd to prevent progression to myeloma. Patients and study design: BP was defined as: i) biochemical relapse from complete response (CR) or ii) biochemical progressive disease according to the IMWG criteria or iii) ultrasensitive MRD relapse defined by the reappearance of MRD confirmed at least 2 months apart. Patients who accepted to be included in this trial received continuous therapy with 4-weeks cycles consisting of Daratumumab 1,800 mg sc at the conventional schedule, Pomalidomide 4 mg vo days 1-21 and Dexamethasone 40 mg (20 in older than 75) QW. Aims: i) To evaluate the biochemical relapse/progression patterns after treatment with KRd-ASCT-KRd-Rd; ii) Efficacy in terms of response rate after DPd rescue therapy; iii) progression-free survival (PFS) and OS from the BP; and iv) safety profile. Results: A total of 43 out of 90 patients experienced BP: 12 patients (28%) with biochemical progression, 22 patients (51%) with relapse from CR, and 9 patients (21%) with ultrasensitive MRD relapse. The median time to biochemical progression (TTBP) was 53 months, with no differences across the three types of BP. Baseline characteristics were no different to those who have not experienced BP. However, the achievement of MRD negativity at the key time points significantly impacted on the BP: MRD negativity rates after ASCT, at the end of maintenance, and at 4 years post-ASCT were 35.7%, 30.2%, and 12.5% in patients who experienced BP, compared to 64.3%, 69.8%, and 87.5% in those who did not (p < 0.0001). Twenty-nine of the 43 patients in BP agreed to participate in the early rescue intervention study with DPd, and 28 were evaluable for response. The median bone marrow plasma cell infiltration at inclusion was 10%, and the median TTBP in this subgroup was 55 months. After a median of 28 cycles of DPd, the ORR was 89.3%, including sCR/CR in 50%, very good partial repsonse (VGPR) in 25%, partial response (PR) in 14.3%, and 10.7% of patients maintained stable disease (SD). 14 patients were evaluable for MRD one year after initiating DPd therapy with 6 (43%) achieving MRD negative (NGF 10-5). Notably, all these MRD-negative patients had experienced either relapse from CR or ultrasensitive MRD relapse; none of the patients with biochemical progression achieved MRD negative. After a median follow up of 45 months since BP (range: 3.3-70.3), 9 patients have progressed to myeloma being the 50 m-TTP rate of 74%. Of note, none of the patients included with ultrasensitive MRD relapse have so far progressed to MM. 50 m-OS rate is 85% with three patients dying because of disease progression. Safety profile of DPd was acceptable. Neutropenia was the most frequent hematological adverse event (AE) reported overall in 73% and G3-4 in 67%; however, G3-4 febrile neutropenia occurred in only 10% of the patients. Respiratory infections were the most frequent non-hematological AEs, in 57% and G3-4 in 35%. The most frequent reason for discontinuation was progressive disease in 7 patients and only 2 patients discontinued because of infections. No toxic deaths occurred. Conclusion: The achievement of MRD negativity at key time points—particularly after transplant and at the end of maintenance—was predictive of BP. Early rescue intervention with DPd was safe and effective; however, further studies are needed to better define which patients truly benefit from this approach and to determine the optimal timing for intervention.