Characterisation of immunoparesis in newly diagnosed myeloma and its impact on progression-free and overall survival in both old and recent myeloma trials

Abstract

We measured immunosuppression at myeloma diagnosis and assessed the impact on survival in 5826 UK myeloma trial patients. Polyclonal immunoglobulin levels were below normal in 85% of patients and above normal in only 0.4% of cases for IgA, 0.2% for IgM and no cases for IgG. Immunoparesis had a greater impact in recent trials: median overall survival (OS) was up to 3 years longer for patients without immunoparesis compared to the old trials, less than 1 year longer. Median progression-free survival (PFS) was 39%, 36% and 57% longer for patients with normal IgG, IgA and IgM levels, respectively. The depth of IgM suppression, but not the depth of IgG or IgA suppression, was prognostic for survival: the most severely suppressed IgM tertile of patients OS was 0.9 years shorter than those in the top tertile, and 2.6 years shorter than OS of those with normal IgM levels (p = .007). The degree of suppression of polyclonal IgM levels below normal was associated with worse PFS (p = .0002). Infection does not appear to be the main mechanism through which immunoparesis affects survival. We hypothesise that IgM immunoparesis impacts through a combination of being associated with more aggressive disease and reduced immune surveillance against relapse.

Risk factors for infections in newly diagnosed Multiple Myeloma patients: A Danish retrospective nationwide cohort study

“…Immunoparesis has been suggested as an unfavorable prognosis in newly diagnosed MM patients . To evaluate whether immunoparesis has significant importance for survival, we further analyzed the survival of patients after the diagnosis of pneumonia or sepsis (Figures and ).…”

“…Immunoparesis has been suggested as an unfavorable prognosis in newly diagnosed MM patients. [12][13][14] To evaluate whether immunoparesis has significant importance for survival, we further analyzed the survival of patients after the diagnosis of pneumonia or sepsis (Figures 3 and 4). We found no significant difference in the survival of patients with immunoparesis or without quantitative immunoparesis of 25% after a diagnosis of pneumonia or sepsis (P = 0.18 and P = 0.95, respectively).…”

“…10 Our group has recently shown that ISS-III and high LDH level at MM diagnosis are independent risk factors for blood stream infections (BSI). 11 Immunoparesis (hypogammaglobulinemia) is present in 90% of newly diagnosed MM patients and has in some studies been associated to poor progression-free survival (PFS) and overall survival (OS), [12][13][14] whereas in the Danish population-based study, immunoparesis could not be associated with a poorer OS. 15 Previously, immunoparesis in MM patients has been regarded as an important risk factor for infection with encapsulated bacteria.…”

Polyclonal Immunoglobulin Recovery after Autologous Stem Cell Transplantation Is an Independent Prognostic Factor for Survival Outcome in Patients with Multiple Myeloma

“…The reason for this might be that the patients with R-ISS stage I responded well and most of them achieved CR and subsequent Ig recovery, while patients with R-ISS stage III or high risk may suffered a long time enough to cause clonal evolution and normal plasma cells might be more strongly suppressed, and thus humoral immune recovery was more difficult to occur. As support for this hypothesis, several studies have reported that patients with R-ISS stage III and adverse cytogenetic abnormalities were more likely to have suppression of Ig at diagnosis [15,16]. Further studies are needed to elucidate the mechanism of immunosuppression and the relationship between cytogenetic abnormality of MM cells and its inhibitory effects on normal plasma cells.…”

“…On the other hand, most patients present with immunoparesis at diagnosis, which is shown to be another important prognostic factor associated with PFS and OS [14][15][16]. Since subsequent treatment itself induces humoral and cellular immunodeficiency, the balance between treatment intensity and immune recovery is a crucial issue for improving the long-term disease stability.…”