The treatment of patients primary refractory or with sub-optimal response to d-VTD induction: An italian real-life Study Free

Despite the improvement in the treatment of multiple myeloma (MM) patients, there is still a consistent fraction of patients who have a primary refractory MM (PRMM) or relapse early during treatment. Up to now in Italy the treatment for newly diagnosed transplant eligible (TE) patients is settled by Daratumumab-Bortezomib-Thalidomide-Dexamethasone (D-VTD) induction; however, there is a significant proportion of patients who progressed or have a sub-optimal response whose outcome is dismal. Even though these patients are now suitable to be enrolled in clinical trials with novel immunotherapies like CAR-T cell and bispecific antibodies, the treatment of these cases outside clinical trials is not clearly established.

With this background, the aim of this study is to retrospectively and prospectively evaluate the efficacy of the current standard second-line treatments in real-life settings for fit patients who progressed or have a sub-optimal response (≥partial response) to D-VTD induction and are not suitable to receive ASCT frontline.

Between1^th January 2022 to 30^th June 2025, 88 patients (51% males) followed in 18 Italian centers were included in this study. The median age was 62 years (37-72). Considering baseline features, 31/81 (38.3%) had high LDH levels and 32/87 (37%) were ISS III. In 58 cases FISH analysis was available and 35/58 (60.4%) cases were high-risk (HR) [including t(4,14), t(14,16), del17p and +1q], with 18 patients displaying ≥2 HR alterations. By R-ISS and R2-ISS, 32% (19/59) and 22.7% (10/44) were R-ISS III and R2-ISS IV, respectively. Finally, 7 cases had extramedullary disease at diagnosis (8.1%). After a median number of 4 cycles of D-VTD, all patients switched to a second line treatment, in 55/86 (64%) cases due to progressive disease (56% symptomatic, 44%, biochemical), in 21/86 (24.4%) due to sub-optimal response, while in 10/86 (11.6%) due to refractory disease. In the remaining two cases, this info was not available. As second line treatment, most patient received KRD as salvage (73/88, 83%), followed by intensive chemo-based (VD/KRD-PACE) regimens in 8 cases (9.1%), other Lenalidomide-based combinations in 4 cases (4.5%) and Isa-KD in 3 cases (3.4%). The overall response rate to second line treatment was 74%, with ≥VGPR rate of 53.2% and 16.2% of CR/sCR.

With a median follow up of 15 months, the median PFS was 17 months, and the median OS has not been reached (12-months OS: 79%). Considering HR disease prognostic factors, an inferior PFS was observed in patients with baseline HR cytogenetic (8.4 months vs not reached, p=0.073) and at relapse high LDH levels (6.8 months vs not reached, p=0.0009), β2 microglobulin >3.5mg/dL (4.9 months vs not reached, p=0.0005) and albumin <3.5g/dL, (6.8 months vs 24 months, p=0.082). Notably, patients with decreased renal function (eGFR<45ml/min) showed reduced PFS (3.8 months vs not reached, p<0.0001).

Considering the reason to switch to second-line therapy, the treatment in case of refractory disease showed dismal outcome compared to progressive disease and sub-optimal response (3.6 months vs 14 months vs not reached, p=0.0001). In addition, in case of progressive disease, the patients treated due to biochemical relapse were characterized by longer PFS compared to symptomatic relapse (24 months vs 5.5 months, p=0.036). Achieving a high-quality response (≥VGPR) was associated with an improved PFS compared to PR or less (not reached vs 4.7 months and 2.5 months, respectively, p<0.0001).

Finally, treatment with KRD showed a promising PFS of 24 months compared to the other combinations (8.8 months), although not statistically significant (p=0.44). Those patients who received at least an autologous stem cell transplantation (ASCT) (33/88, 37.5%) displayed a significantly better PFS compared those who did not receive ASCT (not reached vs 4.5 months, p<0.0001), with no significant differences between single (n=22) and tandem (n=11) ASCT (p=0.8).

To our knowledge, this is the first study aiming to evaluate the outcome of patient's refractory or with sub-optimal response to D-VTD. The data herein presented confirmed the dismal prognosis of these functional high-risk cases, especially in case of symptomatic and aggressive relapse. However, a significant proportion of patients can be rescued by the second line treatment, particularly with KRD reinduction and ASCT.