Impact of Etiological Cytogenetic Abnormalities on the Depth of Immunoparesis and Survival in Newly Diagnosed Multiple Myeloma

Immunoparesis is associated with poor survival in myeloma (MM). We demonstrate that the etiologic cytogenetic abnormality influences the degree and clinical impact of immunoparesis in newly diagnosed patients in a large clinical trial. As the depth of IgM immunoparesis impacts survival for hyperdiploid patients, this may be used to further risk-stratify this cytogenetic subgroup of patients for future clinical decisions. Introduction/Background: Immunoparesis, or low polyclonal immunoglobulin levels, is commonly seen in multiple myeloma (MM), and is associated with poor clinical outcomes. MM can be divided into subgroups with distinct biology and outcomes based on etiologic cytogenetic abnormalities. These include hyperdiploidy and translocations of t(11;14), t(4;14), t(14;16), and t(14;20), with the latter 3 associated with high-risk disease. We hypothesized that the different etiologic cytogenetic abnormalities drive bone marrow microenvironmental changes, resulting in different degrees of immunoparesis, and subgroup-dependent effects on clinical outcomes. Materials and Methods: We performed a retrospective review of 985 newly diagnosed patients enrolled in the Myeloma IX and XI trials. Immunoglobulin levels, survival outcomes, and infection rates were evaluated for each cytogenetic subgroup. Results: A significant proportion of patients with high-risk t(4;14), t(14;16), or t(14;20) had suppressed polyclonal immunoglobulins compared to standard-risk patients with hyperdiploidy or t(11;14). The clinical impact of immunoparesis depended on the cytogenetic subgroup, with the degree of IgM suppression effecting progression-free and overall survival only in the hyperdiploid subgroup. There was no significant difference in infection rates amongst the etiologic subgroups. Conclusion: These findings demonstrate that the etiologic cytogenetic subgroup influences the degree and clinical impact of immunoparesis. This suggests that the underlying cytogenetic abnormality affects remodeling of the bone marrow plasma cell niche, resulting in suppressed normal plasma cell function, and low immunoglobulin levels.