Pomalidomide, Bortezomib and Dexamethasone in Multiple Myeloma Patients Double Refractory to Lenalidomide and Anti-CD38 Monoclonal Antibodies: A Multicentric Italian Retrospective Study

Background: Drug refractoriness negatively impacts outcome of relapsing multiple myeloma (MM) patients (pts). Increased use of continuous Lenalidomide (Len) and anti-CD38 Monoclonal Antibodies (MoAb) since the 1° line, will increase rates of pts double refractory (DR) to anti-CD38 MoAb+Len after 1 or 2 lines of therapy (LoT).For these pts, especially those with early progression (<12 months) from therapy initiation, salvage treatments available in daily practice - like PVD (pomalidomide, bortezomib, dexamethasone) - are limited. Furthermore most clinical trial leading to their approval did not include anti-CD38 MoAb+Len DR pts. In the OPTIMISMM study, Len-refractory pts treated with PVD had a median PFS of 9.5 months, with longer PFS in Len-refractory pts treated after 1 LoT (17.8 months). None of the pts enrolled in the OPTIMISMM trial were previously exposed to anti-CD38 MoAb, thus data on PVD outcomes in MoAb+Len DR MM pts are limited. Aims: To explore the real-life outcome of PVD in a population of MM pts DR to IMIDs and anti-CD38 MoAbs after 1 or 2 LoT. Methods: We retrospectively reviewed data of 74 MM pts DR to MoAb+Len after 1 or 2 LoT, consecutively treated with PVD regimen according to on-label schedule across 20 Italian centers. The study received ethics committee approval, all pts provided informed consent. Categorical variables were described as counts and percentage, quantitative ones as median and interquartile range (IQR). OS and PFS were estimated by Kaplan-Meier method. Pts were considered responsive if achieving ≥ partial remission (PR) according to IMWG criteria. To evaluate the effect of best response on disease progression, PFS was defined as the time between date of best response and progression or death. The effect of predictors on PFS was evaluated by Cox regression model. All statistical analyses were performed using Stata 18 Results: Characteristics of the cohort of pts at time of PVD starting were: median age 74 years (IQR: 66-76), isotype distribution was 58% IgG, 27% IgA, and 15% light chain, ISS and R-ISS stages I/II/III were distributed as follows 13.8%/31%/55.2% and 5.5%/48.6%/45.9%. FISH data, collected before starting PVD, were available for 42 pts (57%), with 31 pts (42%) having high-risk abnormalities such as t(4;14), t(14;16), del(17p) and gain/ampl(1q21). Nine pts (12,2%) had extramedullary disease. PVD was started for symptomatic relapse in 77% (57 pts), while in 23% (17 pts) for biochemical relapse. All pts were MoAb+Len DR when starting PVD: 56 pts (75,6%) became MoAb+Len DR after receiving Daratumumab-Lena-Dexamethasone (DRd) as 1° LoT until progression, whereas 18 patients (24%) became MoAb+Len DR after receiving DRd in 2° LoT following bortezomib-based 1° LoT (10 pts after VTD followed by transplant without maintenance, and 8 pts after VMP). Median time from diagnosis to PVD starting was 21 months (IQR: 11-34 months), 36 pts (48.6%) were in early progression in course of DRd (<12 months from DRd starting). After a median follow up of 5.7 months (IQR: 3.6-12.8), median number of PVD cycles was 6 (IQR: 4-10). The median time to best response was 2.9 months (IQR: 1.8-4.5 months). The overall response rate was 75% (CR 20%, VGPR 27%, PR 28%). The median PFS after PVD initiation was 8 months (95%CI: 5.7-10.8 months) for the whole cohort and 7 months (95%CI: 5.3-10.8 months) for pts DR after 1 LoT. Univariate analysis found no significant association between PFS and time from diagnosis to PVD initiation or the number of LoT before acquiring DR status (1 vs 2)(all p-values > 0,7). There is a positive association between response to PVD and outcome (p=0.021), with longer PFS in pts with ≥VGPR vs <VGPR (HR= 3.1; 95%CI: 1.3-6.9; p=0.008). Toxicity profile was consistent with OPTISMM data. Median OS was 17.8 months (95%CI: 12.2-not reached). Conclusions: To our knowledge, this is the first study exploring the outcome of PVD regimen in a real-life population of MM pts becoming double refractory to IMIDs and anti-CD38 MoAb after 1 or 2 LoT. In this setting, PVD proved safe and achieved a significant response rate. Nonetheless, the duration of response and survival were limited, highlighting the need for more extensive access to innovative therapies, especially in the setting of double refractory pts with early relapse after exposure to both IMIDS and anti-CD38 MoAb in 1 or 2 LoT.