Single-point and kinetics of peripheral residual disease by mass spectrometry to predict outcome in patients with high-risk smoldering multiple myeloma included in the GEM-CESAR trial

Abstract

The value of quantitative immunoprecipitation mass spectrometry (QIP-MS) to identify the M-protein is being investigated in patients with monoclonal gammopathies but no data are yet available in high-risk smoldering myeloma (HRsMM). We have, therefore, investigated QIP-MS to monitor peripheral residual disease (PRD) in 62 HRsMM patients enrolled in the GEM-CESAR trial. After 24 cycles of maintenance, detecting the M-protein by MS or clonal plasma cells by next-generation flow cytometry (NGF) identified cases with a significantly shorter median progression-free survival (mPFS) (MS: not reached vs. 1.4 years, P=0.001; NGF: not reached vs. 2 years, P=0.0002) but reaching complete response (CR) + stringent CR (sCR) did not discriminate between patients with different outcome. With NGF as a reference, the combined results of NGF and MS showed a high negative predictive value (NPV) of MS: 81% overall and 73% at treatment completion. When sequential results were considered, sustained negativity by MS or NGF was associated with a very favorable outcome with an mPFS not yet reached versus 1.66 years and 2.18 years in cases never attaining PRD or minimal residual disease (MRD) negativity, respectively. We can, thus, conclude that: 1) the standard response categories of the International Myeloma Working Group do not seem to be useful for monitoring treatment in HRsMM patients; 2) MS could be used as a valuable, non-invasive, clinical tool with the capacity of guiding timely bone marrow evaluations (based on its high NPV with NGF as a reference); and 3) similarly to NGF, sequential results of MS are able to identify a subgroup of HRsMM patients with long-term disease control. This study was registered at www.clinicaltrials.gov (clinicaltrials.gov identifier: 02415413).

Figure 1.

Percentages of patients with detectable residual disease. Percentages of patients with detectable residual disease by serum protein electrophoresis / immunofixation electrophoresis (IFE) (blue), mass-spectrometry (MS) (gray) and next-generation flow cytometry (NGF) (orange) at the 5 time-points analyzed in the trial: post-induction, after high-dose chemotherapy and autologous stem cell transplant (ASCT), post-consolidation, after one year of maintenance (M1), and at treatment completion after two years of maintenance (M2).

Figure 2.

Analysis of the combined results of mass spectrometry with serum protein electrophoresis / immunofixation electrophoresis or next-generation flow cytometry. Analysis of the combined results of mass spectrometry (MS) with serum protein electrophoresis (SPEP) / immunofixation electrophoresis (IFE) or next-generation flow cytometry (NGF) post-autologous stem cell transplant (ASCT) and after 24 cycles of maintenance. Percentages of concordant and discordant results, sensitivity, specificity, positive predictive value (PPV) and negative predictive values (NPV) of MS considering SPEP/IFE (A) and NGF (B) as a reference.

Figure 3.

Progression-free survival after autologous stem cell transplant and at treatment completion after two years of maintenance. Progression-free survival (PFS) after autologous stem cell transplant (ASCT) (left) and at treatment completion after two years of maintenance (right) according to the results of (A) serum protein electrophoresis / immunofixation electrophoresis in all patients, (B) next-generation flow cytometry (NGF) in patients in complete response (CR) or stringent CR (sCR) and massspectrometry. MRD: minimal residual disease; PRD: peripheral residual disease; PFSb: biochemical PFS; mPFS: median PFS; HR: Hazard Ratio.

Figure 4.

Landmark analysis of progression-free survival. Landmark analysis of progression-free survival (PFS) based on (A) minimal residual disease (MRD) or (B) peripheral residual disease (PRD) kinetics from randomization to treatment completion after 24 months of maintenance. PFSb: biochemical PFS; mPFS: median PFS. *P≤0.05, **P≤0.01, ***P≤0.001.