Heavy+light chain monitoring correlates with clinical outcome in multiple myeloma patients

Abstract

Novel anti-myeloma agents have improved patient response rates, which are historically based on reductions of the M-protein. These methods can be inaccurate for quantifying M-proteins at low concentrations. We compared the consistency and clinical impact of response assignment by electrophoretic and heavy+light chain (HLC) immunoassays post-consolidation in 463 newly diagnosed patients. The two methods gave similar assignments in patients with partial (PR; 79% agreement) or complete response (⩾CR; 92%). However, in patients achieving very good PR (VGPR) there was poor concordance between methods (45%). Median progression-free survival (PFS) for standard VGPR patients was 34.5 months; HLC responses stratified these patients further into PR, VGPR and ⩾CR, with median PFS of 21.3, 28.9 months and not reached, respectively; P<0.001. At this time, abnormal HLC ratios had better concordance with multiparametric flow cytometry (sensitivity 10^-4) (37 and 34% positive, respectively), compared to immunofixation (62% positive). In addition, HLC-pair suppression was identified in 38% of patients and associated with shorter PFS (30.6 months vs not reached; P<0.001). We conclude that HLC monitoring could augment electrophoretic assessments in patients achieving VGPR. The prognostic significance of HLC responses might partly depend on the patients' ability to recover their immune system, as determined by normalisation of HLC measurements.

Figure 1

IMWG and HLC responses at the end of consolidation therapy associate with outcome. Forest plot showing hazard ratios (HR) and 95% confidence intervals (95% CI) for VGPR vs CR responses, using either IMWG or HLC assessment. Hazard ratios (95% CI) were calculated by Cox regression univariate analysis.

Figure 2

HLC responses further stratify standard VGPR and CR patients. (a) In 225 patients at VGPR by IMWG at the end of consolidation therapy, HLC assessment identified patients at ⩽PR, VGPR and ⩾CR, with median PFS of 21.3, 28.9 months and not reached, respectively. (b) In 141 patients at ⩾CR by IMWG, HLC identified patients at VGPR and ⩾CR, with median PFS of 35.1 months and not reached, respectively. HR refers to hazard ratio of patients at VGPR vs ⩾CR. Log rank test: P⩽0.05 indicates statistical significance. Red line: ⩽PR; green line: VGPR; blue line: ⩾CR. Number of patients (event) for each arm is shown.

Figure 3

IMWG and HLC models for response assessment at the end of consolidation therapy stratify patients for progression-free survival (PFS). (a) PFS for IMWG response categories was 31.0 months for ⩽VGPR and not reached for ⩾CR. (b) PFS for HLC responses was 28.7 months for ⩽VGPR and not reached for ⩾CR. Red line: ⩽VGPR; blue line: ⩾CR. HR refers to hazard ratio of patients at ⩽VGPR vs ⩾CR. Log rank test: P⩽0.05 indicates statistical significance. Number of patients (event) for each arm is shown. Akaike information criterion (AIC) and C-statistic for each model are shown.

Figure 4

MRD assessment by serum immunofixation (IFE), HLC ratio and multiparametric flow cytometry (MFC). (a) In 327 patients with matched data by all methods at the end of consolidation therapy, 62% patients had a positive IFE, 37% an abnormal HLC ratio and in 34% patients there was presence of malignant plasma cells in the bone marrow as determined by seven-colour MFC.

Figure 5

Prognostic significance of multiparametric flow cytometry (MFC) assessment at different levels of response. Detection of disease using MFC associated with shorter PFS in patients at (a) VGPR and (b) ⩾CR by IMWG response criteria. Using HLC response assignment, a positive MFC result had no prognostic value for (c) patients at VGPR; however in (d) those at ⩾CR, disease detection by MFC associated with shorter PFS. HR: hazard ratio. Log rank test: P⩽0.05 indicates statistical significance. Red line: MFC positive; Blue line: MFC negative. Number of patients (event) for each arm is shown.

Figure 6

HLC-pair suppression at the end of consolidation therapy associates with poorer outcome. (a) Patients with HLC-pair suppression had shorter PFS compared to patients with no suppression (median PFS 30.6 months vs not reached, respectively). (b) In patients at ⩾CR by IMWG assessment, those with severe HLC-pair suppression had shorter PFS compared to all other patients (median PFS 22.9 months vs not reached, respectively). HR: hazard ratio. Log rank test: P⩽0.05 indicates statistical significance. Red line: HLC-pair suppression; Blue line: no or moderate HLC-pair suppression. Number of patients (event) for each arm is shown.