Isatuximab, Pomalidomide, and Dexamethasone (IsaPd) As Salvage Therapy for Patients with Multiple Myeloma: Multicenter, Retrospective Clinical Experience with 262 Cases Outside of Controlled Clinical Trials

This preliminary study investigates the real-world efficacy and safety of Isatuximab (Isa) combined with pomalidomide (P) and dexamethasone (d) (IsaPd) as a salvage therapy for relapsed/refractory multiple myeloma (RRMM) patients treated outside of controlled clinical trials according to marketing approval.

A cohort of 262 RRMM patients from 50 Italian centers received at least one cycle of IsaPd as salvage treatment between January 2021 and June 2024. To qualify as responsive, patients were required to achieve at least a partial remission (PR). At the initiation of IsaPd therapy, 143 patients (54.6%) were males, with 14.1% classified as stage III according to the International Staging System (ISS). The median number of prior therapies was 2 (range 2-7), with 24.8% of patients exhibiting refractory disease. Furthermore, 38.9% of patients had undergone autologous stem cell transplant (ASCT), and 16.8% had prior exposure to daratumumab. Cytogenetic data from FISH analysis data were available for 142 patients (54.2%), with 69.7% showing favorable cytogenetic profiles, while 30.3% were categorized as high-risk due to aberrations such as t(4;14), t(14;16), and del(17p). As of June 2024, all patients were evaluable for response. The median number of IsaPd cycles administered was 11 (range 1–37). The overall response rate (ORR) was 73.7%, including 11 stringent complete responses (sCR, 4.2%), 28 complete responses (CR, 10.7%), and 77 very good partial responses (VGPR, 29.4%). Significant grade 3/4 adverse events included neutropenia (56.1%), anemia (14.1%), and thrombocytopenia (16.4%). Infection rates were 48%, with pneumonia occurring in 26.7% of cases. After a median follow-up of 23.5 months (range 1-35), disease progression or death occurred in 105 patients, yielding a median progression-free survival (PFS) of 15.4 months. Univariable analyses showed no significant impact on PFS from age, gender, number of previous therapies, or prior ASCT. However, elevated LDH (HR=1.8; P=0.004), high-risk cytogenetic abnormalities (HR=2.57; P<0.0001), refractory disease (HR=1.52; P=0.02), ISS stage III (HR=2.48; P<0.0001) and previous daratumumab exposure (HR=2.12; P<0.0001) were associated with a significantly shorter PFS. Cox multivariable analysis identified high-risk cytogenetic abnormalities (HR=2.87; P<0.0001), elevated LDH (HR=2.35; P=0.003), and previous daratumumab exposure (HR=2.44; P=0.003) as independent prognostic factors for PFS. The 2-year-overall survival (OS) probability was 66.3%. Univariable analyses identified elevated LDH (HR=2.3; P=0.01), high-risk cytogenetic abnormalities (HR=1.92; P=0.042), creatinine clearance <60 ml/min (HR=1.52; P=0.02), ISS stage III (HR=2.51; P<0.0001), prior daratumumab exposure (HR=1.95; P=0.013), and more than 2 previous therapies (HR=1.57; P=0.041) as adverse prognostic factors. In Cox multivariable analysis, high-risk cytogenetic abnormalities (HR=2.12;P=0.023), elevated LDH (HR=3.3; P=0.001) and creatinine clearance <60 ml/min (HR=2.48;P=0.007) maintained independent prognostic significance for OS. Previous daratumumab exposure was trendily associated with OS (HR=2.48; P=0.07).

In conclusion, this comprehensive real-world study confirms the safety and efficacy of IsaPd as a viable salvage therapy for RRMM who have undergone at least two treatment regimens. The ORR of 73.7% is noteworthy. Nonetheless, when making therapeutic decisions on the IsaPd triplet regimen, a number of prognostic factors that have a detrimental effect on outcomes should be taken into account.