Introduction: The IFM 2009 study prospectively evaluated the combination of 8 cycles of lenalidomide, bortezomib and dexamethasone (RVd) versus (vs) 3 cycles of RVd plus high dose (HD) melphalan with autologous stem cell transplantation (ASCT) plus 2 consolidation RVd cycles, followed by lenalidomide maintenance for 12 months (mo) in newly diagnosed multiple myeloma (NDMM) patients (Attal M et al, NEJM 2017). RVd with transplant was associated with significantly longer progression-free survival (PFS) (primary endpoint) compared to RVd alone. Overall survival (OS) at 4 years was similar in both groups. In order to evaluate the long-term outcome in the 2 arms and the impact of 2^nd line treatments on PFS2 and OS, we performed an extension of patient follow-up (FU) of the IFM 2009 study over a period of 4 years (DB-FU-IFM 2009 / NCT03679351).

Methods: 700 NDMM patients (pts) (median age 59 years [range, 28.0-65.0]) were randomized between the 2 arms after stratification by ISS stage and FISH analysis. Patient characteristics were well-balanced, notably age, gender, ISS3, and high risk cytogenetics (defined by t(4;14), t(14;16), del(17p)). 100 patients (50 from each arm) who experienced 1^st progression were included in the IFM 2009-02 PCD trial (NCT02244125, Garderet L et al, Blood 2018). The choice of 2^nd line treatment and decision to perform an ASCT at relapse was based on investigator’s discretion. PFS2 was defined as the time from randomization to progression on next line therapy or death from any cause; second PFS as the time from date of 1^st progression to progression on next line therapy or death. This trial was previously reported with a median FU of 44 mo (Attal M et al, NEJM 2017).

Results: As of March 2020, median FU was 93 mo [range, 88-98]. As previously reported, median PFS was significantly longer in the transplant group (TG), at 47.3 mo compared to 35.0 mo in the RVd alone group (RG) (HR (95CI) 0.70 [0.59-0.83] p<0.001). 497/700 pts experienced disease progression, 270 (77.1%) pts in the RG and 227 (64.9%) pts in the TG; 262 and 217 of them respectively initiated a 2^nd line. Among these pts, 76.7% (201/262) in RG and 22.6% (49/217) in TG received an ASCT at 1^st relapse; 40.1% (105/262) and 46.5% (101/217) respectively received a pomalidomide-based 2^nd line. Only 14 and 12 pts received carfilzomib- and daratumumab-based 2^nd line regimens. Median PFS2 was similar in both groups, at 95 mo in the RG and not reached (NR) in the TG (HR [95CI] 0.96 [0.76-1.21] p=0.76). This estimate was homogeneous across ISS stage (p-value for interaction 0.26) and cytogenetic group (p-value for interaction 0.90). Median PFS2 in ISS3 and high-risk cytogenetic pts was 73 and 75 mo, and 48 and 47 mo, in the RG and TG, respectively. Second PFS was significantly increased in the RG, at 36 vs 25 mo in TG (HR [95CI] 1.41 [1.11-1.79] p=0.003). Median OS was NR in either group. At 8 years, the OS rate was 60.2% in the RG and 62.2% in the TG (HR [95CI] 1.03 [0.80-1.32] p=0.81). Minimal residual disease (MRD) was a strong predictor of outcome: PFS (HR [95CI] 0.28 [0.22-0.36] p<0.001), PFS2 (HR [95CI] 0.27 [0.20-0.37] p<0.001) and OS (HR [95CI] 0.35 [0.25-0.49] p<0.001) were longer in pts achieving MRD negativity, in comparison with those who did not. The incidence of invasive 2^nd primary cancer was not significantly different between the 2 groups (p=0.38); of note, 2^nd hematological malignancies were reported in 5/350 and 7/350 pts in RG and TG respectively.

Conclusion: RVd before and after HD melphalan and ASCT followed by one-year of lenalidomide maintenance is associated with a significantly longer PFS than RVd alone, without a significant increase of 2^nd primary malignancy. At 1^st relapse, before the systematic use of daratumumab- or carfilzomib-based combinations, almost half of the pts received pomalidomide-based treatment and about 3 quarters of pts who had not received frontline ASCT underwent delayed transplant. With a FU of almost 8 years, median OS was NR and there was no difference between the 2 strategies with respect to PFS2 and OS. MRD appears to predict outcome and might be used after induction to identify those pts who probably do not require a transplant. Quadruplets with anti-CD38 monoclonal antibodies combined with the selective use of HD therapy and transplant, followed by extended maintenance, should be considered in the future to further improve outcome. Such an approach could potentially provide a functional cure for a significant proportion of NDMM pts.