Multiple myeloma patients are deficient in normal polyclonal serum immunoglobulins. To determine the reasons for this decrease, we quantitated and compared the number of surface IgM+ B lymphocytes, and the number of B cells susceptible to transformation by Epstein-Barr virus (EBV) with the concentration of IgM in serum. Serum IgM levels varied considerably in individual patients, temporally shifting from undetectable to normal amounts and then dropping again to undetectable levels. A transient rise to normal serum IgM concentrations was seen in 42% of patients assessed at two or more time points. Of 44 patients, 52% showed a lack of correlation between the number of surface IgM+ (sIgM+) B cells and serum IgM concentration. One subset of patients (25%) had detectable to normal numbers of sIgM+ B cells in blood but undetectable levels of serum IgM. Transformation of B cells from these patients indicated a block in IgM secretion that was extrinsic to the B cells that were fully able to transcribe, translate, and secrete IgM after EBV transformation. A second subset of patients (27%) had undetectable numbers of sIgM+ B cells but near normal levels of serum IgM, suggesting abundant secretion by few clones of B cells. Of 18 patients with monoclonal gammopathy of undetermined significance (MGUS), 26% showed a lack of correlation between the numbers of sIgM+ B cells and serum IgM concentration. We suggest that in patients with multiple myeloma, and in some with MGUS, there exists a mechanism(s) extrinsic to the B cell that mediates an arrest in terminal B lymphocyte maturation.