Minimal residual disease (MRD) evaluation by next-generation flow-cytometry is being established as a valuable indicator of treatment efficacy and a surrogate marker of progression-free survival (PFS) among patients with newly diagnosed multiple myeloma (NDMM).^{1, 2} The key question lies in the feasibility of adjusting our therapeutic approach according to the MRD results.There are several ongoing trials that use the MRD status as their primary endpoint or formulate the consolidation/maintenance therapeutic strategy based on the MRD status, such as the PERSEUS³ and the MASTER⁴ trials (Table 1). The primary results of the MASTER trial are encouraging, as none of the 27 MRD-negative patients who have entered the observation phase have relapsed during a short-term median follow up of 5 months. 

In this context, we administered four cycles of carfilzomib (20/56 weekly), lenalidomide and dexamethasone (KRd) as consolidation regimen in 40 consecutive transplant-eligible patients with NDMM who had not achieved MRD negativity, assessed by Euroflow, following autologous stem cell transplant (ASCT). None of the included patients had received induction with KRd. At the end of consolidation, 79% had improved their response status, whereas 25 patients achieved MRD negativity at the level of 10^-5. Among them, 19 performed also a fluorodeoxyglucose positron emission tomography–computed tomography (FDG PET/CT) scan; all but one were negative.

During the last ASH meeting, the early results of the ongoing phase 2 CONPET study were presented.⁵The study team led by Fredrik H. Schjesvold applied a PET/CT – guided consolidation approach. NDMM patients, who had received induction treatment and ASCT and had achieved at least a very good partial response, were examined with FDG PET/CT. Those with positive results received 4 cycles of consolidation with KRd (carfilzomib 20/36 biweekly). Among the 14 evaluable patients, 9 showed improvement in PET/CT, although only 3 were converted from positive to completely negative.

Pending the final results from studies with risk-adapted strategies and the long-term outcomes, it seems that MRD, probably in combination with PET/CT, has the potential to guide tailored decisions for treatment intensification after ASCT.

Table 1. Clinical studies implementing an adaptive, MRD-based strategy

References 

1.              Paiva B, Puig N, Cedena MT, et al.Measurable Residual Disease by Next-Generation Flow Cytometry in Multiple Myeloma. J Clin Oncol 2019 Nov 26:JCO1901231.

2.              Avet-Loiseau H, Ludwig H, Landgren O, et al.Minimal Residual Disease Status as a Surrogate Endpoint for Progression-free Survival in Newly Diagnosed Multiple Myeloma Studies: A Meta-analysis. Clin Lymphoma Myeloma Leuk 2020 Jan; 20(1):e30-e37.

3.              Sonneveld P, Broijl A, Gay F, et al.Bortezomib, lenalidomide, and dexamethasone (VRd) ± daratumumab (DARA) in patients (pts) with transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): A multicenter, randomized, phase III study (PERSEUS). Journal of Clinical Oncology 2019; 37(no. 15_suppl).

4.              Costa L, Chhabra S, Godby K, et al.Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRd) Induction, Autologous Transplantation and Post-Transplant, Response-Adapted, Measurable Residual Disease (MRD)-Based Dara-Krd Consolidation in Patients with Newly Diagnosed Multiple Myeloma (NDMM). Blood 2019; 134(Supplement_1):860.

5.              Nordberg Nørgaard J, Abildgaard N, Lysén A, Revheim M, Connelly J, Schjesvold F. Krd Consolidation in Myeloma Patients with a Positive PET-CT after Standard First Line Treatment: A Phase II Study (CONPET). Blood 2019; 134(Supplement_1):3172.

Ioannis Ntanasis-Stathopoulos and Maria Gavriatopoulou

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece

Email: mariagabria@gmail.com