Assessing the Utility of Monitoring IgA Multiple Myeloma Patients with Quantitative Serum IgA Levels

Background: IgA monoclonal proteins (M-proteins), unlike IgG M-proteins, often migrate in the beta region on serum protein electrophoresis (SPEP) which can lead to underestimation of their size due to the co-migration with physiologic proteins. In IgA multiple myeloma (MM), the utility of quantitative IgA levels in assessing disease response in comparison to SPEP is not well studied.

Methods: We retrospectively analyzed the pattern of disease response and progression in newly diagnosed IgA MM patients (NDMM) diagnosed between 2004 and 2019, and an independent group of IgA MM patients on clinical trials (CTMM) with available serial serum M-proteins and IgA levels. We developed response and progression criteria using quantitative IgA levels (see table 1). We then compared the kinetics of disease response and progression using the established IMWG criteria (Kumar et al. Lancet 2016) versus our proposed IgA criteria. Kaplan Meier analysis was used to estimate the median progression free survival (mPFS) using the IMWG and IgA, where PFS was defined as the time from treatment initiation until disease progression or death.

Results: This study included a total of 494 patients [286 NDMM patients (training cohort) and 205 CTMM patients (validation cohort)]. In the NDMM and CTMM cohorts, the median M-protein at initiation of treatment was 3.3 (IQR 2.4-4.2) g/dL and 2.3 (IQR 1.3-3.2) g/dL, respectively (p<0.001), and the median IgA at diagnosis was 3080 (IQR 1895-4314) mg/dL and 2200 (IQR 1220 – 3295) mg/dL, respectively (p<0.001). In the NDMM cohort, the median time to achieve a partial response (PR) was significantly shorter if response was assessed using IMWG criteria compared to IgA criteria (32 [IQR 25-56] versus 58 [29-88] days, respectively, with p<0.001). From treatment initiation, the median time to M-protein nadir was 80 (IQR 42-144) days and to IgA nadir was 154 (IQR 90-238) days. At the onset of M-protein nadir 40% of patients still had an IgA above the upper limit of normal (ULN).

Stratification of PFS by IgA response criteria led to a clear separation in the Kaplan Meier curves for patients achieving a very good partial response (VGPR) or PR in both the NDMM (figure 1B) and CTMM (figure 1D) cohort, as opposed to stratification of PFS by IMWG response criteria (figure 1A and 1C, respectively). In the NDMM cohort, univariate analyses did not show a significant difference in PFS based on the migration of M-protein on the serum protein electrophoresis (gamma versus beta region), or age at therapy initiation. On multivariable analyses, achieving a VGPR/complete response (CR) by IgA criteria was associated with significantly improved PFS (HR 0.36, 95% CI 0.20-0.62, p<0.001) even when controlling for R-ISS at diagnosis, prior transplant, and the IMWG response. In contrast, achieving a VGPR/CR by IMWG criteria was not associated with improved PFS in the multivariable analyses.

When comparing the time to progression (TTP) using IgA to IMWG progression criteria, there was a trend towards earlier detection of progression with IgA criteria in both the NDMM cohort (median TTP 22.1 versus 26.8 months, p=0.0575) and CTMM (median TTP 13.4 versus 15.7 months, p=0.52). Of the 209 NDMM patients who met criteria for IMWG disease progression, 78 (37%) had no quantifiable M-protein at the time of progression (57 met criteria for light chain progression, 21 patients had new bone lesions or plasmacytomas), however the quantitative IgA level was above the ULN in 41 (52%) of these patients. More importantly, of the 21 patients progressing due to a new symptomatic bone lesion or plasmacytoma in the absence of a quantifiable M-protein, 14 (67%) had an IgA above the ULN.

Conclusions: In IgA MM patients, following the decline in serum M-protein may be falsely reassuring as M-protein levels decrease earlier than the quantitative IgA levels. The proposed IgA response criteria better stratify patients based on their outcomes when compared to the standard IMWG criteria and may allow for earlier detection of disease progression.