Relapse from MRD Negativity As Indication for Treatment in Multiple Myeloma - the Remnant Study
Authors: Askeland Frida Bugge , Rasmussen Anne-Marie , Schjesvold Fredrik 
Published: February 2021

Background: Early intervention can reduce the rate of progression and improve overall survival (OS) in smouldering multiple myeloma (SMM) patients (pts) (1, 2). The most powerful predictor of prognosis in active MM is whether pts achieve minimal residual disease (MRD) negativity in bone marrow with treatment (3), however treating MRD relapse has not been evaluated in a randomized fashion. The REMNANT study will evaluate whether treating MRD relapse after first line (1.L) treatment prolongs progression free survival (PFS) and OS for MM pts versus treating relapse after 1.L. treatment at progressive disease (PD) (4). To establish a homogenous group of MRD negative pts after 1.L treatment including autologous stem cell transplantation (ASCT), pts are enrolled at diagnosis and treated with Norwegian standard of care (SOC) 1.L treatment. MRD negative pts will move on to the randomized part.
Methods: The REMNANT study is an academic, multicenter, open-label, randomized phase II/III study of NDMM pts eligible for ASCT (see Figure 1). 391 pts across Norway will be included in the phase II part of the study and receive SOC 1.L treatment according to Norwegian national guidelines; VRd (V: 1,3 mg/m2 SC Days 1, 4, 8, 11; R: 25 mg PO Days 1-14; d: 20 mg PO Days 1, 2, 4, 5, 8, 9, 11, 12) for 4 pre-transplant induction and 4 post-transplant consolidation cycles (all 21-d cycles). After induction pts will undergo tandem or single ASCT, depending on toxicity and response to first ASCT. The primary endpoint of the phase 2 part of the study is the number of pts who achieve MRD negative (Euroflow NGF 10 -5) complete response (CR) 30-45 days post consolidation. Safety evaluations and pts-reported outcome assessment will be measured. Pts (176) achieving MRD negative CR will be randomly assigned in a 1:1 ratio to receive 2.L treatment at MRD reappearance (arm A) or at progressive disease (PD) as defined by the IMWG criteria (4) (arm B). Randomization will be stratified by R-ISS stage at diagnosis and single vs tandem ASCT. Pts in arm A will be followed with MRD assessment every 4 month and start 2.L treatment at loss of MRD negative CR. Pts in arm B will be followed up by standard criteria and start 2.L treatment at PD. Both arms will receive the same 2.L treatment; KdD (all 28-d cycles) (K: 70mg/m2 iv Days 1,8,15 d: 40 mg Days 1, 8, 15, 22 D: 1800 mg SC Days 1, 8, 15 during C 1-2, Days 1, 8 during cycle 3-6, Day 1 from cycle 7,). 2.L treatment will continue until disease progression, unacceptable AEs or patient withdrawal. In arm A MRD Euroflow will be assessed after 6 and 18 months of 2L therapy. In arm B MRD Euroflow will be assessed if &gt;CR is achieved but not before 6 months of 2 L therapy, and again after 12 consecutive months. The co-primary endpoint is progression and death by any cause (PFS) and death by any cause alone (OS). Secondary endpoints includes TTNT and the proportion pf pts who achieve MRD negative CR during 2.L treatment in arm A and arm B, safety evaluations and pts-reported outcome.
The trial is approved and will start enrollment Q3 2020.
1. Mateos MV, Hernandez MT, Giraldo P, de la Rubia J, de Arriba F, Corral LL, et al. Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial. Lancet Oncol. 2016;17(8):1127-36.
2. Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, et al. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. 2020;38(11):1126-37.
3. Munshi NC, Avet-Loiseau H, Rawstron AC, Owen RG, Child JA, Thakurta A, et al. Association of Minimal Residual Disease With Superior Survival Outcomes in Patients With Multiple Myeloma: A Meta-analysis. JAMA Oncol. 2017;3(1):28-35.5.
4. Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-e46.

Disclosures
Schjesvold: Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, Takeda: Honoraria; Celgene, Amgen, Janssen, Oncopeptides: Research Funding; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, Takeda: Consultancy.

OffLabel Disclosure:
Carfilzomib-dexamethason-daratumumab (KdD) as second line treatment