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Blood, 1 November 2001, Vol. 98, No. 9, pp. 2791-2799
NEOPLASIA
Persistent preswitch clonotypic myeloma cells correlate with
decreased survival: evidence for isotype switching within the
myeloma clone
Tony Reiman,
Karen Seeberger,
Brian J. Taylor,
Agnieszka J. Szczepek,
John Hanson,
Michael J. Mant,
Robert W. Coupland,
Andrew R. Belch, and
Linda M. Pilarski
From the Departments of Oncology and Medicine,
University of Alberta and Cross Cancer Institute, Edmonton, Alberta,
Canada.
Multiple myeloma (MM) is identified by unique immunoglobulin heavy
chain (IgH) variable diversity joining region gene rearrangements, termed clonotypic, and an M protein termed the "clinical" isotype. Transcripts encoding clonotypic pre and postswitch IgH isotypes were
identified in MM peripheral blood mononuclear cells (PBMCs), bone
marrow (BM), and mobilized blood. For 29 patients, 38 BM, 17 mobilized
blood, and 334 sequential PBMC samples were analyzed at diagnosis,
before and after transplantation for 2 to 107 months. The clinical
clonotypic isotype was readily detectable and persisted throughout
treatment. Eighty-two percent of BM and 38% of PBMC samples also
expressed 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 IgM was detected in only 12%. Patients
with persistent clonotypic IgM expression had adverse prognostic
features at diagnosis (lower hemoglobin, higher
 2-microglobulin) and higher numbers of BM plasma cells compared with patients with infrequent/absent clonotypic IgM. Patients
with persistent clonotypic IgM expression had significantly poorer
survival than patients with infrequent IgM expression
(P < .0001). In a multivariate analysis, persistent
clonotypic IgM expression in the blood correlated independently with
poor survival (P = .01). In nonobese diabetic severe
combined immunodeficiency mice, xenografted MM cells expressed clinical
and nonclinical postswitch clonotypic isotypes. MM expressing
clonotypic IgM engrafted both primary and secondary mice, indicating
their persistence within the murine BM. This study demonstrates that MM
clonotypic cells expressing preswitch transcripts are tied to disease
burden and outcomes. Because MM pathology involves postswitch plasma cells, this raises the possibility that IgH isotype switching in MM may
accompany worsening disease.
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