Non-secretory multiple myeloma: from biology to clinical management

Abstract

Multiple myeloma (MM) is the second most common hematologic malignancy in the US. It is typically characterized by production of large amounts of defective immunoglobulin (Ig). Diagnosing MM and monitoring treatment response, including eventual relapse, are largely based on sequential measurements of Ig. However, a small subset of MM called non-secretory multiple myeloma (NSMM) produces no detectable Ig. This subset of true NSMM has become even smaller over time, as the advent of the serum free light chain assay has resulted in the majority of NSMM patients being recategorized as light-chain MM - that is, MM cells that produce only the light-chain component of Ig. True forms of NSMM, meaning MM that secretes no monoclonal proteins whatsoever, constitute a distinct entity that is reviewed; definition of NSMM using current detection methods, discuss the biology underpinning NSMM development, and share recommendations for how NSMM should be managed clinically with respect to detection, treatment, and monitoring.

Keywords: immunoglobulin; multiple myeloma; non-secretory.

Figure 1

Mechanism of synthesis and secretion of Ig by PC and sources of error. Notes: (1) Transcription-aberrant VDJ arrangements, splice site mutations, and stop codons can produce truncated (or no) heavy chain and less often light chain. (2) Folding, if appropriate, can lead to further processing. (3) If not, it leads to protein degradation, often via the proteasome (2a). (3) Multimeric proteins are assembled, and post-translational modifications are made to assist in transport to the cell membrane. (4) Igs are transported to the surface in vesicles. (5) If folded and modified appropriately, Igs will be secreted from the cells (top). If there are errors, Igs will be secreted in vesicles (bottom) and may not be detectable by SPEP, IFE, or SFLC analysis. Abbreviations: Ig, immunoglobulin; PC, plasma cell; SPEP, serum protein electrophoresis; IFE, immunofixation electrophoresis; VDJ, variable-diversity-joining.

Figure 2

Defining the terms of NSMM. Abbreviations: NSMM, non-secretory multiple myeloma; PC, plasma cell; MM, multiple myeloma; SFLC, serum free light chain; Ig, immunoglobulin.