Recovery of uninvolved heavy/light chain pair immunoparesis in newly diagnosed transplant-eligible myeloma patients complements the prognostic value of minimal residual disease detection

Abstract

Immunoparesis (IP) in multiple myeloma (MM) patients can be measured by classic assessment of immunoglobulin (Ig) levels or by analysis of the uninvolved heavy/light chain pair of the same immunoglobulin (uHLC) by the Hevylite® assay. In this study we evaluate the prognostic value of recovery from IP measured by classic total Ig and uHLC assessment in newly diagnosed MM transplant-eligible (NDMM-TE) patients with intensive treatment and its association with minimal residual disease (MRD). Patients were enrolled and treated in the PETHEMA/GEM2012MENOS65 trial and continued in the PETHEMA /GEM2014MAIN trial. Total Ig (IgG, IgA and IgM) and uHLC were analyzed in a central laboratory at diagnosis, after consolidation treatment and after the first year of maintenance. MRD was analyzed by next-generation flow cytometry after consolidation (sensitivity level 2x10-6). We found no differences in progression-free survival (PFS) between patients who recovered and patients who didn't recover from IP after consolidation when examining classic total Ig and uHLC. However, after the first year of maintenance, in contrast to patients with classic IP, patients with recovery from uHLC IP had longer PFS than patients without recovery, with hazard ratio of 0.42 (95% confidence interval [CI]: 0.21-0.81; P=0.008). Multivariate analysis with Cox proportional-hazards regression models confirmed recovery from uHLC IP after the first year of maintenance as an independent prognostic factor for PFS, with an increase in C-statistic of 0.05 (95% CI: -0.04 to 0.14; P<0.001) when adding uHLC IP recovery. Moreover, we observed that MRD status and uHLC IP recovery affords complementary information for risk stratification. In conclusion, recovery from uHLC IP after 1 year of maintenance is an independent prognostic factor for PFS in NDMM-TE patients who receive intensive treatment. Immune reconstitution, measured as recovery from uHLC IP, provides complementary prognostic information to MRD assessment (clinicaltrials gov. Identifiers: NCT01916252 and NCT02406144).

Figure 1.

Flowchart showing patients analyzed and not analyzed from diagnosis to post-consolidation and from diagnosis to after the first year of maintenance for classic immunglobulin G and for uninvolved heavy/light chain. IgG: immunoglobulin G; uHCL: uninvolved heavy/light chain.

Figure 2.

Progression-free survival according to immunoparesis recovery after the first year of maintenance. (A) Progression-free survival for classic immunglobulin G (IgG) immunoparesis recovery and (B) for uninvolved heavy/light chain (uHLC) immunoparesis recovery. HR: hazard ratio (95% confidence interval).

Figure 3.

Progression-free survival according to minimal residual disease status after consolidation and uninvolved heavy/light chain immunoparesis recovery after the first year of maintenance. (A) Progression-free survival (PFS) of the 4 combinations of minimal residual disease MRD (positive or negative) and uninvolved heavy/ light chain (uHLC) immunoparesis (IP) (recovery or no recovery). (B) Comparison of PFS of patients with both favorable factors (MRD-negative & uHLC IP recovery), patients with only 1 favorable factor (MRD-negative or uHLC IP recovery) and patients with both unfavorable factors (MRD-positive & absence uHLC IP recovery). -ve: negative; +ve: positive, rec: recovery.