Non-Secretory Myeloma: One, Two, or More Entities?

Drs. Lonial and Kaufman present a comprehensive review of non-secretory multiple myeloma,[1] summarizing the data in the literature on the incidence, laboratory features, response to treatment, and prognosis of this entity. Non-secretory myeloma is a myeloma subtype with evolving diagnostic criteria.[2] Until a few years ago, the diagnosis of non-secretory myeloma, according to current World Health Organization criteria, was established by demonstration of monoclonal plasma cells in the bone marrow and by negative results on serum and urine electrophoresis and immunofixation studies.[3] In some patients, immunohistochemical staining of the bone marrow plasma cells demonstrates the presence of immunoglobulin molecules, indicating that a monoclonal immunoglobulin is produced but that there is a defect in its secretion.[4] The molecular basis of non-secretory myeloma is incompletely understood. Alterations in messenger RNA splicing, as well as frameshift mutations in the genes encoding the variable region of light chains, have been described; these induce misfolding light chain proteins that are then targeted for proteasome-mediated degradation.[5,6]

If one uses the traditional diagnosis of non-secretory myeloma, several comments can be made. First, non-secretory myeloma is probably over-diagnosed; this is due to the fact that in everyday practice not all patients with a new diagnosis of myeloma undergo a thorough evaluation, with electrophoresis and immunofixation of a sample from a 24-hour urine collection, as the International Myeloma Working Group has suggested be done.[7] It is likely that some patients with “non-secretory myeloma” actually have light chain–only myeloma with small amounts of Bence-Jones proteinuria.

Second, most patients with non-secretory myeloma present with symptomatic bone lesions; anemia is less frequent than in patients with secretory myeloma, and myeloma-related renal impairment is extremely rare.[8] As a consequence, these patients’ International Staging System stage tends to be lower than that of patients with secretory disease.

TABLE

Proposed Nomenclature for Myeloma Patients Who Do Not Have ‘Measurable Disease’

Third, sometimes a case may pose a diagnostic dilemma, in which non-secretory myeloma may be confused with an unknown primary cancer presenting with bone metastases only. The process of discerning the correct diagnosis can be even more complex in cases of the unusual macrofocal variant of myeloma, which is characterized by multiple lytic lesions without intervening bone marrow plasmacytosis.[9]

Fourth, the evaluation of response in patients with non-secretory myeloma can be challenging, since it depends on changes in bone marrow plasmacytosis.[10] Because of the patchiness of bone marrow infiltration in myeloma, the precision of this method of assessing response is far from accurate. As Drs. Lonial and Kaufman point out in their review, multi-parameter flow cytometry plays an important role in the measurement of minimal residual disease in the bone marrow of patients with non-secretory myeloma. Furthermore, post-treatment MRI and positron emission tomography (PET)/CT scans may be valuable in assessing bone response.

Fifth, all information on disease features, prognostic factors, and outcomes in patients with non-secretory myeloma comes from retrospective studies, since these patients are typically excluded from clinical trials.

With the development of a reliable assay by which we can measure the free light chain (FLC) in the serum, the definition of non-secretory myeloma is changing. In at least half of patients with a diagnosis of traditional non-secretory myeloma, an abnormal FLC ratio is seen, indicating that these patients actually secrete very small amounts of monoclonal protein.[11,12] This test may separate patients with non-secretory myeloma into those with “true non-secretory myeloma” and those with “serum free light chain–only myeloma.”

The emerging concept of oligosecretory myeloma is making the field even more complex. This diagnosis applies to patients with small amounts of serum and/or urine monoclonal protein that are below thresholds considered to be measurable. Measurable disease is defined as a serum monoclonal protein of at least 1 g/dL, a urine monoclonal protein of at least 200 mg/d, or both.[13] These thresholds were chosen because at lower levels electrophoretic studies are not precise enough to adequately detect a decrease of > 50%, which is the requirement for determining response. However, recent data suggest that approximately 60% of patients with oligosecretory myeloma have an abnormal FLC ratio and an involved (monoclonal component) FLC level of at least 10 mg/dL, which could be used to measure disease response.[14] One could use the foregoing serum FLC level to separate patients with serum free light chain–only myeloma into those with and without measurable disease.

As shown in the Table, five subtypes of myeloma patients who do not have measurable disease can be defined on the basis of readily available parameters. To define the differences between these subtypes, not only prospective collection of clinical and laboratory data are needed, but also cytogenetics and molecular profiling. As already pointed out by Drs. Lonial and Kaufman, there is preliminary evidence that true non-secretory myeloma may have a better outcome than oligosecretory disease, but collaborative efforts are clearly needed to elucidate these issues.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

REFERENCES

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4. Lorsbach RB, Hsi ED, Dogan A, Fend F. Plasma cell myeloma and related neoplasms. Am J Clin Pathol. 2011;136:168-82.

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6. Dul JL, Argon Y. A single amino acid substitution in the variable region of the light chain specifically blocks immunoglobulin secretion. Proc Natl Acad Sci USA.1990;87:8135-9.

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8. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78:21-33.

9. Dimopoulos MA, Pouli A, Anagnostopoulos A, et al. Macrofocal multiple myeloma in young patients: a distinct entity with favorable prognosis. Leuk Lymphoma. 2006;47:1553-6.

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11. Tosi P, Tomassetti S, Merli A, Polli V. Serum free light-chain assay for the detection and monitoring of multiple myeloma and related conditions. Ther Adv Hematol. 2013;4:37-41.

12. Drayson M, Tang LX, Drew R, et al. Serum free light-chain measurements for identifying and monitoring patients with non-secretory multiple myeloma. Blood. 2001;97:2900-2.

13. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467-73.

14. Larson D, Kyle RA, Rajkumar SV. Prevalence and monitoring of oligosecretory myeloma. N Engl J Med. 2012;367:580-1.