Reactive Polyclonal Gammopathy Associated with Polyclonal Plasmacytosis Is Common in Patients with Multiple Myeloma Receiving Prolonged Lenalidomide Therapy: A Retrospective Study of 104 Patients

Prolonged lenalidomide treatment is frequently used in patients with multiple myeloma (MM), both in the upfront and relapsed settings. We have previously reported a small series of 6 patients receiving prolonged lenalidomide treatment who presented with a polyclonal IgA gammopathy characterized by a marked elevation in the serum IgA level, polyclonal plasmacytosis in the bone marrow, and without any evidence of clinical disease progression. Although the immunologic mechanism underlying this observation is currently under investigation, it is important to recognize and characterize its incidence, clinical features, and prognostic significance. For these purposes, we have undertaken a retrospective analysis of all patients treated at MSKCC with prolonged course of lenalidomide.

We retrospectively identified 104 patients with MM who received a prolonged course of lenalidomide (>6 months). Among these patients, 21 (20%) were noted to have polyclonal immunoglobulin (Ig) elevation above the upper limit of normal during lenalidomide therapy, affecting IgA in 13, IgG in 6, and both IgA and IgG in 2 patients. All 21 patients were without evidence of relapse or progression (R/POD) by serologic or clinical criteria at the time of polyclonal Ig elevation. In 15 patients the polyclonal Ig did not involve the initial monoclonal isotype. The median time from lenalidomide initiation to polyclonal elevation of Ig level was 10.9 months (range 2 to 38.6 months), with the median peak IgA level of 587 mg/dl (range 374 to 1190 mg/dl), and the median peak IgG level of 1800 mg/dl (range 1575 to 2650 mg/dl). Bone marrow aspirates and biopsies were available in 12 patients during the period of Ig elevation and the median plasmacytosis was 12% (range 5 to 20%) on the aspirate. Immunohistochemical (IHC) studies of the bone marrow biopsy showed moderate increase in CD138+ cells without light chain restriction. IHC using IgA and IgG antibody staining in the patients with IgA elevation confirmed that most plasma cells were IgA-producing and were not consistent with the original myeloma clone. To evaluate for the association of polyclonal gammopathy with progression free survival, we performed a landmark analysis on all 104 patients based on the magnitude of the absolute Ig elevation measured at 6 months after initiation of lenalidomide. The patients were divided into 2 groups on the basis of the median absolute elevation in the levels of IgA (40 mg/dl) or IgG (150 mg/dl) from the baseline prior to therapy initiation to 6 months after starting the treatment. Statistical comparison was limited by the small number of patients who had R/POD in the sample (n=16), but there was a trend toward improved PFS in the patients who achieved absolute IgA elevation >40mg/dl, though any difference was attenuated by 36 months following the 6-month landmark (logrank p-value: 0.54). Interestingly, when focusing exclusively on the 16 patients with R/POD during the followup, the median time to progression was 27.5 months and 13.1 months in patients with absolute IgA elevation >40mg/dl (n=10), and those with absolute IgA elevation <40mg/dl (n=6) at the 6 month landmark, respectively.

Polyclonal gammopathy with Ig levels exceeding the normal range associated with polyclonal plasmacytosis occurs with a relatively high frequency (20%) in patients treated with prolonged courses of lenalidomide. Awareness of this effect is important especially in view of the associated significant bone marrow plasmacytosis, which may mistakenly be construed as R/POD in patients who are actually responding to treatment. In addition, the absolute elevation in the IgA level measured at 6 months post initiation of treatment may be a prognostic indicator of progression, with high elevations potentially indicating an extended benefit from lenalidomide treatment. Further studies are needed to validate these observations and to elucidate their mechanism.

Giralt:Celgene: Honoraria, Research Funding. Landau:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding. Hassoun:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding.