Suppression of the noninvolved pair of the myeloma isotype correlates with poor survival in newly diagnosed and relapsed/refractory patients with myeloma

Abstract

Heavy light chain (HLC) assays allow precise measurement of the monoclonal and of the noninvolved polyclonal immunoglobulins of the same isotype as the M-protein (e.g., monoclonal IgAκ and polyclonal IgAλ in case of an IgAκ myeloma), which was not possible before. The noninvolved polyclonal immunoglobulin is termed 'HLC-matched pair'. We investigated the impact of the suppression of the HLC-matched pair on outcome in 203 patients with multiple myeloma, a phenomenon that likely reflects the host's attempt to control the myeloma clone. Severe (>50%) HLC-matched pair suppression was identified in 54.5% of the 156 newly diagnosed patients and was associated with significantly shorter survival (45.4 vs. 71.9 months, P = 0.019). This correlation was statistically significant in IgG patients (46.4 vs. 105.1 months, P = 0.017), but not in patients with IgA myelomas (32.9 vs. 54.1 months, P = 0.498). At best response, HLC-matched pair suppression improved only in patients with ≥VGPR, indicating partial or complete humoral immune reconstitution during remission in those with excellent response. Severe HLC-matched pair suppression retained its prognostic impact also during follow-up after first response. In the 47 pretreated patients with relapsed/refractory disease, a similar correlation between severe HLC suppression and survival was noted (22.8 vs. not reached, P = 0.028). Suppression of the polyclonal immunoglobulins of the other isotypes than the myeloma protein correlated neither with HLC-matched pair suppression, nor with outcome. Multivariate analysis identified severe HLC-matched pair suppression as independent risk factor for shorter survival, highlighting the impact of isotype specific immune dysregulation on outcome in multiple myeloma.

Figure 1

(A) Overall survival in 156 newly diagnosed patients (100 IgG and 56 IgA) with and without severe HLC‐matched suppression (45.4 vs. 71.9 months, P = 0.019). (B) Overall survival in 100 IgG patients with and without severe HLC‐matched suppression (46.4 vs. 105.1 months, P = 0.017). (C) Overall survival in 56 IgA patients with and without severe HLC‐matched suppression (32.9 vs. 54.1 months, P = 0.498). (D) Overall survival in patients without polyclonal immunoglobulin suppression (n = 22), with IgA/IgG or IgM suppression only (n = 37) or with IgG/IgA and IgM suppression (n = 97) (median 69.5 vs. 66.9, vs. 53.5 months, P = 0.646) using values just below the normal range provided no additional values (P = 0.25).

Figure 2

(A) Overall survival in 90 newly diagnosed patients with FISH data available. No risk factor (median: 120.0 months), high risk cytogenetics only (median: 84.2 months), severe HLC‐matched pair suppression only (median: 80.9 months), and both, high risk cytogenetics and severe HLC‐matched pair suppression (median: 32.9 months, P = 0.002). (B) HLC‐matched pair suppression in newly diagnosed patients at baseline and at best response according to response category. HLC‐matched pair suppression improved significantly only in patients with VGPR or better (P < 0.001). (C) Overall survival after achievement of best response in newly diagnosed patients with and without severe HLC‐matched pair suppression (49.0 vs. 71.9 months, P = 0.035). (D) Overall survival in relapsed/refractory patients with and without HLC‐matched pair suppression (median. 22.8 vs. not reached months, HR: 4.632, CI: 1.034–20.751, P = 0.028) and separately in patients with severe HLC‐matched pair suppression and IgG (median: not reached) or IgA (median: 21.5 months) myeloma.