Daratumumab Plus Ixazomib, Lenalidomide, and Dexamethasone As Extended Induction and Consolidation Followed By Lenalidomide Maintenance in Standard-Risk Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM) Patients (IFM 2018-01): A Phase II Study of the Intergroupe Francophone Du Myélome (IFM)
Authors: Perrot Aurore , Lauwers-Cances Valérie , Touzeau Cyrille , Decaux Olivier , Hulin Cyrille , Macro Magaret , Stoppa Anne-Marie , Chretien Marie Lorraine , Karlin Lionel , Mariette Clara , Jacquet Caroline , Roussel Murielle , Guillemot Coralie , Devlamynck Laure , Avet-Loiseau Hervé , Moreau Philippe , Attal Michel 
Published: November 2021

Abstract
Introduction
Induction therapy followed by autologous stem cell transplantation (ASCT) before maintenance is the standard of care for transplant eligible NDMM patients. The addition of daratumumab to bortezomib, thalidomide, and dexamethasone (VTD) improved response rates and reduced the risk of progression or death compared to VTD alone (Moreau et al, Lancet 2019). Other quadruplet combinations such as carfilzomib, lenalidomide, dexamethasone and daratumumab have also been evaluated, showing high response rates and high levels of MRD negativity (Landgren et al, JAMA Oncol 2021), which seems particularly suitable to high-risk patients. The replacement of bortezomib with ixazomib in an all-oral combination with lenalidomide and dexamethasone (IRD) has been demonstrated to be safe, convenient, and effective in induction and consolidation before and after ASCT (Moreau et al, Blood 2017). The more progressive response kinetics and the very safe profile of ixazomib led to consider daratumumab plus IRD (D-IRD) extended induction and consolidation in standard-risk NDMM patients. We evaluated its safety and efficacy before and after ASCT followed by lenalidomide maintenance as frontline therapy for patients with standard-risk NDMM younger than 66 years (NCT03669445).

Methods
Patients with standard-risk cytogenetic MM (defined by FISH at diagnosis according to IMWG criteria) received six 21 days-cycles of induction therapy with daratumumab 16 mg/Kg IV at days 1, 8, 15 (cycles 1-4) and days 1 and 15 (cycles 5-6) plus ixazomib 3 mg on days 1, 4, 8 and 11 plus lenalidomide 25 mg on days 1 through 14 and dexamethasone 40 mg on days 1, 8 and 15. Peripheral blood stem cells were collected after cyclophosphamide mobilization, followed by Melphalan 200 mg/m2 and ASCT. D-IRD consolidation started 2 to 3 months after ASCT and consisted in four 28 days-cycles with daratumumab at days 1 and 15, ixazomib 4 mg on days 1, 8 and 15, lenalidomide 25 mg on days 1 to 21 and dexamethasone 20 mg on days 1, 8, 15 and 22 (cycles 7-8) and days 1 and 15 (cycles 9-10). Single agent lenalidomide maintenance was administrated at 10 mg on days 1 through 21 of a 28 days-cycle during 26 cycles. The primary endpoint was the MRD-negativity after consolidation and before maintenance. MRD-negativity was assessed using NGS method with a sensitivity threshold of detection of MM cells up to 10 -6. Secondary objectives were toxicity according to NCI-CTCAE version 5.0, MRD-negativity rates at other timepoints, response rates according to 2016 IMWG criteria as well as PFS, TTP and OS.
Results
From 12/2018 to 09/2019, 45 patients were enrolled in 10 IFM centers. Median age was 57 years [28-65] and 66.7% were male. Since it was an eligibility criteria, there was no t(4;14), t(14;16) or del(17p). The distribution of ISS scores 1, 2 and 3 was as follows: 40.9%, 38.6% and 20.5%. On 45 patients who initiated the treatment, 43 completed induction, ASCT and consolidation and 42 started maintenance. All patients responded (ORR 100% [CI 92.1-100.0]) and the best response was sCR or CR in 53.4%, VGPR in 40% and PR in 6.7% of the patients. For the primary endpoint 38 patients were evaluable at 10 -6 after consolidation and the MRD-negativity rate was 39.5% ([CI 26.1-54.1]; p=0.137). At a sensitivity of 10 -5 (IMWG criteria) the MRD negativity rate was 51.4% ([CI 36.8-65.7]; p=0.005). Response rates deepen with time, regarding IMWG categories as well as MRD-negativity rates (Figure). After a median follow up of 23.6 months, 2 patients experienced disease progression. The PFS rate at 24 months was 95.2% [CI 82.1-98.8]. Serious adverse events occurred in 15 (33.3%) patients and grade 3/4 event in 28 (62.2%). The most common grade 3-4 toxicities were neutropenia (28.9%), thrombocytopenia (11.1%) and infections (15.6%). Moderate peripheral neuropathy (35.6%; no grade 3-4), gastrointestinal disorders (4.4% grade 3-4) and rash (28.9%; no grade 3-4) were also described. No deaths or secondary primary malignancies were reported to date.
Conclusion
D-IRD as extended induction prior to, and as consolidation following ASCT was safe and allows gradually deepening responses in standard-risk MM, with 39.5% of patients with MRD negativity at 10 -6 after consolidation, 2-year PFS at 95.2% and 2-year OS at 100%. MRD-negativity rates are lower than those obtained with D-VTD or D-KRD; more follow-up is needed to confirm PFS and OS data.
Figure 1 Figure 1.

Disclosures
Perrot: Abbvie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Decaux: Amgen BMS Celgene Janssen Sanofi Takeda: Honoraria. Hulin: Janssen: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Celgene/BMS: Honoraria; abbvie: Honoraria. Macro: Janssen: Honoraria, Other: Travel accomodation, Research Funding; GSK: Honoraria; Sanofi: Honoraria; Celgen/BMS: Honoraria; Takeda: Honoraria, Other: Travel accomodation, Research Funding. Karlin: Abbvie: Honoraria; Takeda: Honoraria, Other: member of advisory board; Celgene-BMS: Honoraria, Other: member of advisory board; Sanofi: Honoraria; GSK: Honoraria, Other: member of advisory board; Amgen: Honoraria, Other: travel support and advisory board ; Janssen: Honoraria, Other: member of advisory board, travel support; oncopeptide: Honoraria. Roussel: Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; BMS: Honoraria; Takeda: Consultancy; Amgen: Consultancy. Guillemot: Takeda: Honoraria. Avet-Loiseau: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau: Janssen: Honoraria; Amgen: Honoraria; Celgene BMS: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria; Oncopeptides: Honoraria.

OffLabel Disclosure:
The quadruplet Dara-Ixa-Len-Dex is not approved in newly diagnosed multiple myeloma.