Non-Secretory Myeloma: A Clinician’s Guide

The treatment of patients with multiple myeloma has dramatically changed over the past 10 years due to an improved understanding of plasma cell biology and the development of new targets. The subset of these patients with non-secretory myeloma-a group of patients who do not secrete immunoglobulin or its component parts into either the blood or urine-has been challenging to treat and to assess for disease response. Newer methods of assessment for plasma cell disorders, such as the widely used serum free light chain assay, have reduced the number of patients with truly non-secretory myeloma to less than 3% of all newly diagnosed myeloma patients. With regard to prognosis, it appears from most series that patients with non-secretory myeloma have a prognosis similar to or better than that of patients with secretory myeloma. This has not been evaluated in populations from which patients with free light–only disease are excluded, but there is no reason to expect that outcomes in patients with non-secretory myeloma will be appreciably worse, since many harbor the t(11;14) translocation. Finally, imaging with positron emission tomography (PET)/CT scans, and minimal residual disease (MRD) assessment with multi-parameter flow cytometry, may provide newer methods for response assessment, something that has been severely limited in these patients due to the lack of a reliable biomarker. Future directions in response assessment include the amalgamation of imaging and MRD assessment, which may enhance our ability to assess response both in patients with non-secretory myeloma and in other patients with myeloma.

Introduction

Multiple myeloma is a disorder characterized by the presence of clonal plasma cells in the marrow, which results in end-organ damage, as manifested by hematologic, renal, or bone complications.[1] Myeloma may be preceded by a premalignant phase in which clonal plasma cells are present but there is no evidence of end-organ damage (this is known as “monoclonal gammopathy of unknown significance” [MGUS] or “smoldering myeloma”).[2] However, a hallmark of most cases of multiple myeloma and its antecedent phases is the persistent production of some form of immunoglobulin, either a complete antibody (heavy and light chain) or the individual components of monoclonal antibodies (heavy chain or light chain). It is often this protein production that calls the disease to attention in the smoldering or MGUS stage, since patients frequently have no other signs of disease.[3]

A unique feature of malignant plasma cells is continued protein production, a function that is typically lost when cells are transformed from a normal to a malignant phenotype. In addition, the protein produced can often serve as a reliable biomarker for disease presence. The availability of this protein in the blood or urine for quantitative assessment using serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), or the serum free light chain assay facilitates disease response assessment in most cases of myeloma, since the assessment can be done with routine blood and urine testing rather than requiring imaging or bone marrow assessment, as in other hematologic malignancies.[4] While the concept of biomarker assessment as a surrogate for response is useful in most cases of myeloma, in patients with high-risk disease, light chain or non-secretory escape may occur, likely as a consequence of clonal evolution: although a protein was initially produced, it is lost with relapse. This possibility, in conjunction with the fact that relapse remains inevitable even in patients who achieve a complete remission, as determined via serum and urine studies, has led a number of groups to evaluate more stringent methods for assessing disease status,[5-9] and it is likely that these methods will prove useful as we seek to define the optimal methods for assessing response and disease status in patients with non-secretory myeloma.

Biology of Non-Secretory Myeloma

Myeloma is characterized by the clonal infiltration of the marrow by plasma cells that typically produce a serum or urine paraprotein. The serum protein is often characterized by an intact immunoglobulin (heavy and light chain), or it may be characterized by the light chain alone. In the urine, an intact immunoglobulin is also often present, although some patients have predominantly light chain in the urine (typically referred to as “Bence-Jones protein”).

Years ago it was determined that in some patients with non-secretory myeloma, immunohistochemical staining of the marrow plasma cells demonstrated the presence of immunoglobulin molecules, while in others there was no evidence of immunoglobulin production by the plasma cells.[10-12] This observation allows us to divide non-secretory myeloma patients into several groups. The first group consists of patients who are “non-producers.” These are patients whose tumors may have defects in immunoglobulin synthesis. While these tumors may have all the features of a plasma cell disorder, they are not able to synthesize or secrete a protein.[13] Patients who have no measurable protein in the blood or urine, yet who still have a significant plasma cell burden in the marrow and evidence of end-organ damage, fall into this category. In these patients, even use of the free light chain assay will not reveal measurable disease as currently defined, since they do not make a protein.

The next category of non-secretory myeloma patients consists of those whose tumors produce a protein but have defects in secretion. It has been demonstrated in vitro that a single amino acid substitution in a light chain can potentially block secretion outside of the cell, and in a patient sample, it has been demonstrated that a mutation in the immunoglobulin gene can account for a lack of secretion in a patient with non-secretory myeloma.[14] However, among those patients whose tumors have defects in Ig secretion, there is a subset of patients who have impaired secretion but are able to secrete some low levels of light chains. These are patients who have oligosecretory myeloma, and while their protein secretion may not be as high as that seen in typical myeloma, they are able to secrete some proteins and these can be measured using current technology.

Patients who may initially be categorized as non-secretory, who have a protein that cannot be detected by either SPEP or UPEP (both with immunofixation), often fall into a more recently identified group who have “free light–only” myeloma. These are patients in whom disease can be revealed only with the free light assay, which is known to more accurately detect kappa and lambda light chains in the blood.[15,16] Drayson et al noted that in a series of 28 patients, 19 had elevations in the serum kappa or lambda light chains, as measured by the free light assay.[17] It is important to note that while serum measurement of free light chains has now become a standard diagnostic test for plasma cell disorders,[18] disease assessment with the urinary free light chain assay is notoriously unreliable, and this approach should not be routinely used in clinical practice. The urinary free light chain assay is different from the UPEP with immunofixation, which remains the optimal study to use when assessing urinary protein production.

TABLE 1

Criteria for Non-Secretory Myeloma

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