Minimal residual disease monitoring and immune profiling in multiple myeloma in elderly patients

Abstract

Key Points• MRD monitoring is one of the most relevant prognostic factors in elderly MM patients, irrespective of age or cytogenetic risk.• Second-generation MFC immune profiling concomitant to MRD monitoring also helped to identify patients with different outcomes.The value of minimal residual disease (MRD) in multiple myeloma (MM) has been more frequently investigated in transplant-eligible patients than in elderly patients. Because an optimal balance between treatment efficacy and toxicity is of utmost importance in patients with elderly MM, sensitive MRD monitoring might be particularly valuable in this patient population. Here, we used second-generation 8-color multiparameter-flow cytometry (MFC) to monitor MRD in 162 transplant-ineligible MM patients enrolled in the PETHEMA/GEM2010MAS65 study. The transition from first-to second-generation MFC resulted in increased sensitivity and allowed us to identify 3 patient groups according to MRD levels: MRD negative (<10 25; n 5 54, 34%), MRD positive (between <10 24and ‡10 25 ; n 5 20, 12%), and MRD positive ( ‡10 24 ; n 5 88, 54%). MRD status was an independent prognostic factor for time to progression (TTP) (hazard ratio [HR], 2.7; P 5 .007) and overall survival (OS) (HR, 3.1; P 5 .04), with significant benefit for MRDnegative patients (median TTP not reached, 70% OS at 3 years), and similar poorer outcomes for cases with MRD levels between <10 24 and ‡10 25 vs ‡10 24 (both with a median TTP of 15 months; 63% and 55% OS at 3 years, respectively). Furthermore, MRD negativity significantly improved TTP of patients >75 years (HR, 4.8; P < .001), as well as those with high-risk cytogenetics (HR, 12.6; P 5 .01). Using second-generation MFC, immune profiling concomitant to MRD monitoring also contributed to identify patients with poor, intermediate, and favorable outcomes (25%, 61%, and 100% OS at 3 years, respectively; P 5 .01), the later patients being characterized by an increased compartment of mature B cells. Our results show that similarly to transplant candidates, MRD monitoring is one of the most relevant prognostic factors in elderly MM patients, irrespectively of age or cytogenetic risk. This trial was registered at www.clinicaltrials.gov as #NCT01237249. (Blood. 2016;127(25):3165-3174)

Current Review on High-Risk Multiple Myeloma

“…In recent years, reaching minimal residual disease (MRD) negativity has also become an important treatment milestone in MM, as studies have repeatedly demonstrated positive prognostic outcomes in patients who are MRD negative [57][58][59]. The PETHEMA/ GEM group has also published two recent publications showing better survival outcomes in MRD negative high-risk patients than those who were MRD positive [60,61].…”

Diagnosis of Plasma Cell Dyscrasias and Monitoring of Minimal Residual Disease by Multiparametric Flow Cytometry

“…We (submitted] and others 120 have clearly established that the more events that are acquired, the more sensitive the assay becomes, and the higher the predictive value for PFS. In most clinical laboratories, the detection sensitivity of MFC to identify neoplastic PCs in the bone marrow ranges from 10 −4 (1 in 10,000 cells) to 10 −5 (1 in 100,000 cells).…”

“…55,115–118 Due to the long latency between drug development and the approval to be considered as therapeutic options, the measurement of MRD by MFC as an independent method to predict PFS and OS for patients diagnosed with PCD has been employed. 119,120 All flow cytometric studies to date have strongly correlated the measurement of MRD with PFS and OS at the Day 100 time point, reducing from years to months the time required to reach meaningful clinical outcomes. 121–124 …”

Is immunotherapy here to stay in multiple myeloma?

“…22 Furthermore, by using 8-color flow cytometry to simultaneously assess MRD and characterize patients’ immune profile, we were able to show that a few MRD positive cases - those showing a strong recovery of the normal B-cell lymphopoiesis - have similar outcomes to those of MRD negative patients. 23 This suggests that despite MRD positivity, the intact immune surveillance was profitable in these patients. Finally, we have observed that MM patients attaining long-term survival (i.e., progression-free survival [PFS] for more than 10 years) showed a unique immune profile with a higher number of effector cells (T cells, NK cells, DCs, normal PCs), and a lower number of Tregs, underlying the importance of an active immune system to control disease evolution.…”