Blood-Based Mass Spectrometry MRD Tracking (M-InSight) in Multiple Myeloma Patients from Clinical Trial NCT02513186
Authors: Di Stefano Luciano , Mouktadi Zarouki , Vimard Victor , Moreau Sarah , Mace Sandrine , Klippel Zandra K. , Bonifay Vincent , Rougé Dubroc Caroline , Sonigo Pierre 
Published: December 2023

Multiple Myeloma (MM) is a type of cancer of the bone marrow characterized by an anormal growth of the number of plasma cells, which produce a monoclonal antibody (M-protein). Measurable residual disease (MRD) is an important prognostic factor in multiple myeloma to evaluate the depth of treatment response which is widely used in clinical trials. MRD is therefore monitored using techniques that measure the number of tumor cells in the bone marrow (BM). On top of being invasive for the patient, BM-MRD might not represent accurately the disease burden because of the heterogeneous nature of a single area measure in the BM. With new drugs and treatment regimen guided by MRD soon, collecting samples at more frequent timepoints is critical to evaluate the depth of response, thus the need of less invasive sampling becomes evident. To overcome all these difficulties, M-InSight (Sebia), a cutting-edge mass spectrometry (MS) technique that allows quantitation of the M-protein in blood has been developed. MS is used to sequence the M-protein then select and quantifies clonotypic peptides from the variable (CDR) region which are used to track the M-protein level of MM patients.
The high sensitivity of M-InSight enables the quantification of M-protein at much lower concentrations than current blood techniques used for diagnostic, which makes it possible to track low level M-protein and potentially detect a relapse before the apparition of new symptoms.
The main objective of this study was to show that M-insight can monitor MRD in blood samples of MM patients treated by isatuximab during the maintenance phase.
Samples from 15 newly diagnosed non eligible for transplantation MM patients from a Sanofi clinical trial (NCT02513186) were chosen to monitor MRD by M-InSight. All patients were selected from the VRDI Part B (bortezomib, lenalidomide, dexamethasone) consisting of evaluating the preliminary efficacy (complete response [CR] rate) of isatuximab administered at the selected dose in combination with bortezomib based regimen. The treatment period included 4 induction cycles (24-week duration), followed by a maintenance period consisting of 4 weeks cycles until progression, unacceptable AE, or patient willingness to discontinue. M-InSight was used to sequence the M-protein (collected predose at Day 1 of Cycle 1) and to measure M-protein concentration in the serum samples collected during the maintenance phase. Results were compared to SPEP, IFE and MRD at 10-6 sensitivity by clonoSEQ®️ (Adaptive Biotechnologies).
After 4 cycles of induction, all patients had Very Good Partial Response. Rate of 9/15 CR, 5/15 VGPR and 1 sCR was observed as the best overall response. NGS MRD data were obtained for 14 patients of which 8 reached MRD negativity at 10 -6 sensitivity. 4 of the remaining 6 patients relapsed during maintenance.
Clonotypic peptides were identified in all 15 patients from the baseline sample. A total of 302 serum samples collected during maintenance were analyzed. M-protein quantification was highly concordant with the one obtained by SPEP when available (Pearson R=0.78, p&lt;0.01). 100% of patients that were MRD positive by NGS 10 -6 were MS-MRD positive and could be quantified by M-InSight. 60% of patients that were MRD negative by NGS 10 -6 were still positive and quantifiable by M-InSight, suggesting higher sensitivity. The remaining 40% was negative by both NGS and MS. M-insight was able to monitor the disease on 5 patients that had sustained MRD (consecutive MRD negativity) and stable M-protein levels (no increase or decrease of M-protein by 2-fold for 2 consecutive time points). All 4 patients that developed PD had an increase of M-protein of at least 2-fold in 2 consecutive time points showing that M-InSight was able to provide an earlier detection of relapse, when SPEP was still negative for 3 of these. Only one patient had unmeasurable M-protein concentration, staying unmeasurable for 1 year and negative by NGS MRD. The lowest M-protein concentration measured by M-InSight was 0.01 mg/dL (10 mg/dL).
This study shows that MRD monitoring on blood is feasible using an ultra-sensitive technique, avoiding invasive bone-marrow aspiration. M-InSight shows accurate monitoring of the depth and kinetics of response to treatment thanks to frequent timepoints. M-InSight can track low level of M-protein in CR patients and detect early relapse.