Early Versus Late Autologous Stem Cell Transplant in Newly Diagnosed Multiple Myeloma: Long-Term Follow-up Analysis of the IFM 2009 Trial
Authors: Perrot Aurore , Lauwers-Cances Valerie , Cazaubiel Titouan , Facon Thierry , Caillot Denis , Clement-Filliatre Lauriane , Macro Margaret , Decaux Olivier , Belhadj Karim , Mohty Mohamad , Karlin Lionel , Eisenmann Jean Claude , Tiab Mourad , Orsini Frederique , Touzeau Cyrille , Leleu Xavier , Avet-Loiseau Herve , Munshi Nikhil C. , Anderson Kenneth , Richardson Paul G. , Moreau Philippe , Attal Michel 
Published: November 2020

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 2nd 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 1st progression were included in the IFM 2009-02 PCD trial (NCT02244125, Garderet L et al, Blood 2018). The choice of 2nd 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 1st 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&lt;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 2nd line. Among these pts, 76.7% (201/262) in RG and 22.6% (49/217) in TG received an ASCT at 1st relapse; 40.1% (105/262) and 46.5% (101/217) respectively received a pomalidomide-based 2nd line. Only 14 and 12 pts received carfilzomib- and daratumumab-based 2nd 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&lt;0.001), PFS2 (HR [95CI] 0.27 [0.20-0.37] p&lt;0.001) and OS (HR [95CI] 0.35 [0.25-0.49] p&lt;0.001) were longer in pts achieving MRD negativity, in comparison with those who did not. The incidence of invasive 2nd primary cancer was not significantly different between the 2 groups (p=0.38); of note, 2nd 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 2nd primary malignancy. At 1st 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.

Disclosures
Perrot: Amgen, BMS/Celgene, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Clement-Filliatre:BMS/Celgene: Honoraria. Macro:gsk: Honoraria; janssen: Honoraria, Other: travel accomodation, Research Funding; sanofi: Honoraria; takeda: Honoraria, Other: travel accomodation, Research Funding. Karlin:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene: Other: Personal fees; Sanofi: Honoraria; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Touzeau:Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Sanofi: Honoraria, Research Funding. Leleu:AbbVie: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Oncopeptide: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; BMS-celgene: Honoraria. Munshi:C4: Current equity holder in private company; Janssen: Consultancy; Adaptive: Consultancy; Legend: Consultancy; Amgen: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; BMS: Consultancy; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Anderson:Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Moreau:Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria. Attal:BMS/Celgene, Sanofi: Consultancy, Honoraria, Research Funding.