Next-generation sequencing identifies driver mutations in refractory non-secretory multiple myeloma, aiding diagnosis

Diagnosing Multiple Myeloma (MM), a plasma cell malignancy, relies on detecting M-protein and abnormal free light chain ratios. However, a subset of patients presents with non-secretory MM, where these traditional markers are absent, making definitive diagnosis challenging and often delaying appropriate treatment. Differentiating non-secretory MM from other lymphoproliferative disorders like lymphoplasmacytic lymphoma can be particularly difficult, highlighting a critical diagnostic gap that impacts patient management and outcomes.

A 62-year-old man presented with leukocytosis and 25.5% plasma cell-like cells in peripheral blood. Initial workup showed no M-protein and a normal κ/λ free light chain ratio. Bone marrow biopsy revealed increased plasma cells, positive for CD138 but negative for both κ and λ chains, leading to a challenging diagnosis of non-secretory MM. After remission induction and autologous peripheral blood stem cell transplantation, the patient relapsed one year later with refractory disease. To confirm the diagnosis and guide further treatment, next-generation sequencing was performed on a bone marrow sample obtained at relapse.

Next-generation sequencing (NGS) of the patient's bone marrow sample at relapse provided crucial diagnostic and prognostic information. The analysis revealed multiple characteristic mutations in known MM driver genes: IRF4, TRAF2, and TRAF3. Additionally, a 1q gain was identified, which is a common cytogenetic abnormality associated with MM. These specific genetic alterations are highly indicative of Multiple Myeloma and are frequently linked to aggressive disease and poor prognosis. The presence of these mutations was consistent with the patient's clinical course, which involved refractory disease despite various chemotherapies. This case demonstrates how NGS can resolve diagnostic ambiguities in challenging presentations.

Next-generation sequencing revealed multiple driver gene mutations, including IRF4, TRAF2, and TRAF3, alongside a 1q gain, all characteristic of multiple myeloma.