Polyclonal IgA Gammopathy Associated with Polyclonal Plasmacytosis in Patients Receiving Lenalidomide Maintenance Therapy

Lenalidomide is commonly used in the treatment of multiple myeloma both in the upfront and relapsed settings and appears to also yield promising results as maintenance therapy after autologous stem cell transplantation. The immunomodulatory mechanisms of action of lenalidomide are complex and the side effects of long-term therapy are still not fully known. Here we report a series of patients on lenalidomide maintenance therapy who demonstrated significant elevation of serum polyclonal immunoglobulin A (IgA) levels with associated polyclonal plasmacytosis in the absence of disease progression.

We identified 6 patients who, in the course of lenalidomide maintenance therapy, were noted to have asymptomatic elevation of serum IgA levels above normal limits without evidence of monoclonality by immunofixation of serum protein electrophoresis. The original myeloma-associated monoclonal protein was IgG kappa in 5 patients and IgG lambda in 1 patient. Two patients received lenalidomide as part of their induction regimen prior to autologous stem cell transplantation, and transient elevation of IgA level was noted at that time. None of the patients had evidence of IgA gammopathy prior to initiation of lenalidomide. Mean time from initiation of lenalidomide maintenance therapy to elevation of IgA level was 9.8 months (range 2 to 22 months). The mean highest IgA level reached for the 6 patients was 534 mg/dl (range 520 to 1190 mg/dl). Bone marrow aspirate and biopsy were available in 3 patients during the period of IgA elevation. The plasma cell population accounted for 9%, 12% and 20% of the bone marrow nucleated cells on the aspirate. Immunohistochemical staining (HIS) of the bone marrow biopsy showed a moderate increase in the number of CD138 positive plasma cells without light chain restriction. HIS using IgA antibody revealed that the plasma cells were mostly IgA producing. None of the 6 patients had any evidence of progression of their original myeloma-associated paraprotein in the setting of polyclonal IgA elevation. Five patients continue to receive lenalidomide maintenance to date (treatment time length ranging between 17.3 and 43.4 months) with no evidence of serologic or clinical disease progression and with persistently elevated IgA levels. One patient discontinued lenalidomide therapy secondary to development of neuropathy with subsequent normalization of IgA level 21 months later.

Polyclonal IgA gammopathy associated with polyclonal IgA-producing plasmacytosis can occur with lenalidomide maintenance and perhaps lenalidomide treatment. The immunologic basis and implication of this observation is unknown. Awareness of this effect is important especially in view of the associated significant bone marrow plasmacytosis, which may mistakenly be construed as disease relapse or progression in patients who are actually responding to treatment.

No relevant conflicts of interest to declare.