Sustained Recovery of Uninvolved Heavy/Light Chain Pair Immunoparesis during Maintenance Discriminates Patients with Sustained Negative Minimal Residual Disease
Authors: Lakhwani Sunil , Rosiñol Laura , Puig Noemi , Pico Picos Miguel Angel , Medina-González Laura , Martinez Lopez Joaquin , Paiva Bruno , Cedena Romero Maria Teresa , Oriol Albert , Ríos Rafael , Blanchard María Jesús , Jarque Isidro , Bargay Joan , Moraleda Jose Maria , Carrillo-Cruz Estrella , Sureda Balari Anna Maria , Krsnik Isabel , Gonzalez Garcia Esther , Casado Montero Luis Felipe , Marti Tutusaus Josep Maria , Encinas Rodriguez Cristina , De Arriba Felipe , Palomera Luis , Sampol Mayol Antonia , González-Montes Yolanda , Motlló Cristina , De la Cruz Javier , Alonso Fernández Rafael , Mateos Maria-Victoria , Blade Creixenti Joan , Lahuerta Palacios Juan Jose , San Miguel Jesus , Hernández Garcia Miguel Teodoro 
Published: December 2023

Introduction. Immunoparesis (IP) or the suppression of uninvolved immunoglobulins (Ig) is a very common finding in multiple myeloma (MM) patients at diagnosis that confers worse prognosis. In addition to classic total Ig, IP can be measured by the uninvolved heavy/light chain pair of the same immunoglobulin (uHLC). Previously, we have reported that recovery of uHLC IP in a single time point (at first year of maintenance) is an independent prognostic factor in newly diagnosed MM transplant eligible (NDMM-TE) patients with intensive treatment within a clinical trial, without significant prognostic value for recovery from classic IP in that setting. Moreover, recovery of uHLC IP affords complementary information to single time point minimal residual disease (MRD) for risk stratification. Although, negative sustained MRD is the most important evolutive favorable prognostic factor in MM, some patients relapse despite achieving negative sustained MRD.
Aim. To evaluate the prognostic value of sustained uHLC IP recovery during maintenance treatment, measured by progression free survival (PFS), within a clinical trial of NDMM TE patients with intensive treatment and its potential association with sustained MRD.
Patients & Methods. Patients with newly diagnosed MM enrolled in the PETHEMA/GEM2012MENOS65 trial received six cycle VRD-GEM induction, autologous hematopoietic stem cell transplantation conditioned by melphalan or busulfan plus melphalan and consolidation with two more cycles of VRD-GEM. Afterwards, patients were enrolled in the PETHEMA/GEM2014MAIN clinical trial that randomly assigned them to maintenance with lenalidomide and low-dose dexamethasone (Rd) or Rd plus ixazomib for two years. After two years, patients who achieved negative MRD stopped the treatment and patients who did not achieve MRD negativity received three more years of Rd. We analyzed uHLC in a central laboratory at diagnosis and at the first and second year of maintenance. We consider IP at diagnosis when uHLC were under lower limit of normality (LLN) and recover IP when suppressed uHLC at diagnosis reach at least LLN plus 10%. Sustained uHLC IP recovery was defined as IP recovery in the first year of maintenance that persists in the second year of maintenance. MRD was analyzed by next generation flow cytometry (sensitivity level 2x10 -6) after consolidation and at the first and second year of maintenance. Sustained MRD was defined as a negative MRD for at least 12 months that remains negative at the second year of maintenance.
In the PETHEMA/GEM2012MENOS65 trial, 458 patients were included of which 332 patients entered the PETHEMA/GEM2014MAIN clinical trial. We included in this study 137 patients, those who reached the second year of maintenance without relapse and had samples available at any of the three time points for the uHLC analysis.
Results. We found uHLC IP in 93.7% of patients (119/127) at diagnosis, 28.1% of patients (34/121) at first year of maintenance and 46.8% of patients (51/109) at second year of maintenance. After the second year of maintenance, we found recovery from uHLC IP present at diagnosis in 48.4% of patients (46/95). Patients that recovered from uHLC IP after second year of maintenance had better PFS (p=0.015) with hazard ratio (HR) 0.27 (CI95% 0.09 - 0.84). Patients with sustained recovery from uHLC IP had better prognosis than patients without recovery at first year of maintenance [p=0.010; HR 0.16 (CI95% 0.03 - 0.78)] and patients with IP recovery at first year who lose it at second year of maintenance [p=0.002: HR 0.12 (CI95% 0.02 - 0.59)] ( Figure 1). Only five patients without recovery at first year had uHLC IP recovery at second year of maintenance, but with similar PFS than patients without recovery at both time points (p=0.441).
Sustained negative MRD for at least 12 months was present in 87/136 (64%) of patients, however we had data of IP recovery evolution in only 54 of these patients, of which 28 had sustained IP recovery. Patients with sustained negative MRD and sustained IP recovery had longer PFS than patients with sustained negative MRD without sustained IP recovery [p=0.025; HR 0.13 (CI95% 0.02 - 0.98)] ( Figure 2).
Conclusions. Sustained recovery of uHLC IP during maintenance in NDMM-TE patients with intensive treatment is a prognostic factor complementary to sustained negative MRD. Combination of both factors identify patients with very good prognosis.