Persistent preswitch clonotypic myeloma cells correlate with decreased survival: evidence for isotype switching within the myeloma clone

Multiple myeloma (MM) is identified by unique immunoglobulin heavy chain (I gH) variable diversity joining region gene rearrangements, termed clonotypi c, and an M protein termed the "clinical" isotype. Transcripts encoding clo notypic pre and postswitch IgH isotypes were identified in MM peripheral bl ood mononuclear cells (PBMCs), bone marrow (BM), and mobilized blood. For 2 9 patients, 38 BM, 17 mobilized blood, and 334 sequential PBMC samples were analyzed at diagnosis, before and after transplantation for 2 to 107 month s. The clinical clonotypic isotype was readily detectable and persisted thr oughout treatment. Eighty-two percent of BM and 38% of PBMC samples also ex pressed nonclinical clonotypic isotypes. Clonotypic immunoglobulin M (IgM) was detectable in 68% of BM and 25% of PBMC samples. Nonclinical clonotypic isotypes were detected in 41% of mobilized blood samples, but clonotypic I gM was detected in only 12%. Patients with persistent clonotypic IgM expres sion had adverse prognostic features at diagnosis (lower hemoglobin, higher beta (2)-microglobulin) and higher numbers of BM plasma cells compared wit h patients with infrequent/absent clonotypic IgM. Patients with persistent clonotypic IgM expression had significantly poorer survival than patients w ith infrequent IgM expression (P < .0001). In a multivariate analysis, pers istent clonotypic IgM expression in the blood correlated independently with poor survival (P = .01). In nonobese diabetic severe combined immunodefici ency mice, xenografted MM cells expressed clinical and nonclinical postswit ch clonotypic isotypes. MM expressing clonotypic IgM engrafted both primary and secondary mice, indicating their persistence within the murine BM. Thi s study demonstrates that MM clonotypic cells expressing preswitch transcri pts are tied to disease burden and outcomes. Because MM pathology involves postswitch plasma cells, this raises the possibility that IgH isotype switc hing in MM may accompany worsening disease. (C) 2001 by The American Societ y of Hematology.