Salvage Autologous Stem Cell Transplant for the Treatment of First Relapse Multiple Myeloma: Evidence of Its Clinical Role from a Multicenter Italian Study

Background: Salvage autologous stem cell transplant (sASCT) has been indicated as possible therapeutic option at first (1^st) relapse, alternative to continuous treatment with novel agent combinations in selected Multiple Myeloma (MM) patients (pts). Particularly, MM pts who are eligible for a transplant procedure at the time of relapse and who have prolonged progression free survival (PFS) after the 1^st ASCT - i.e. at least 36 or 18 months, respectively, with or without Lenalidomide (Len) maintenance - are those who could benefit most from sASCT. There are limited data regarding the frequency of choice for sASCT in the current therapeutic scenario and the outcome of sASCT when incorporating novel Len-based triplets KRd (Carfilzomib-Lenalidomide-Dexamethasone) and DaraRd (Daratumumab-Lenalidomide-Dexamethasone) as induction regimens before sASCT.

Aims: To explore the real-life use, efficacy, and outcome of sASCT preceded by novel agent-based re-induction therapy in a population of unselected Len-sensitive MM population in the 1^st relapse.

Patients and methods: We planned a retrospective multicenter study, approved by local ethic committees, aimed at identifying MM Len-sensitive pts in the 1^st relapse addressed to sASCT. On a final cohort of 663 MM pts addressed in 22 Italian centers to Len-based triplets salvage therapy from 2017 to December 2022, sASCT after Len-based re-induction was the therapy of choice for 123 pts (18.6%), while the remaining 540 pts (81,4%) were addressed to continuous Len-based triplets until progression or unacceptable toxicity.

The rate of pts addressed to sASCT at the time of the 1^st relapse was distributed as follows: 81 pts out of 512 pts (15.8%) received sASCT in the time window 2017-2019, 42 pts out 151 (27.8%) between 2020-2022 (p=0.001). Table 1 summarizes patients' characteristics and treatment history details. In our series 1^st ASCT was performed without Len maintenance. All pts entering the analysis received re-induction treatment before sASCT as well as continuous therapy with DaraRd or KRd according to standard schedule and doses. sASCT consisted of Melphalan 200 mg/m² as a conditioning regimen followed by infusion of ≥2*10⁶ CD34* cells per kg body weight. The option to perform maintenance therapy following sASCT was chosen by the attending physician. The response was assessed according to IMWG criteria. Compared with pts treated with continuous Len-based triplets, those addressed to sASCT were younger (62 vs 68 years, p<0.001), with a longer time from diagnosis (3.9 vs 2.5 years, p<0.001), and they received a higher rate of prior ASCT (80.5% vs 53.8%, p<0.001). Regarding the sASCT program, KRd was the most common choice for the re-induction phase (102 pts, 82.9%), DaraRd was used in the remaining 21 pts (17.1%). The median number of cycles before sASCT was 6 (range 4-10), and maintenance after transplant was performed only in 18 pts (14.9%). sASCT was associated with an overall response rate (ORR) of 94.3% (116 pts), with 78% (96 pts) of very good partial response or better (≥VGPR), and 35.5% (43 pts) of CR. No case of transplant-related mortality was documented. After a median follow-up of 33.6 months (IQR 21.3-51.8), the median PFS of pts addressed to sASCT was 36.6 months, with 24-month PFS of 75% (95%CI 65-82%)(Figure 1). When a multivariable Cox regression model was carried out including 1^st ASCT, the best response to 1^st line therapy and ≥36 months PFS after 1^st line therapy, as well as the number of re-induction KRd/DaraRd cycles as covariates, only PFS ≥36 months after 1^st-line therapy retained an independent statistically significant association with a reduced progression/death risk after sASCT (HR=0.5, 95%CI; 0.2-1.0, p=0.049). The median overall survival (OS) was not yet reached with a 2-year OS of 89% (95%CI: 81-93%).

Conclusions: This study on 663 consecutive MM cases in the first relapse showed that salvage transplants retained a significant role in the current clinical management of MM, accounting for around 19% of selected salvage strategies. The incorporation of the highly active combinations KRd and DaraRd used as re-induction regimens before sASCT was associated with a significantly high rate of deep and long-lasting response, representing a possible alternative strategy to continuous therapy with Len-based triplets. The major benefit of Len-based triplets followed by sASCT was related to prolonged remission after first-line therapy.