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.
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. 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”). 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.
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. 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. 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. 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. It is important to note that while serum measurement of free light chains has now become a standard diagnostic test for plasma cell disorders, 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.
Those patients in whom more modern immunoglobulin testing methods can detect no serum, urine, or free light–based disease are the patients with truly non-secretory myeloma (Table 1).
The absolute frequency of non-secretory myeloma can be difficult to analyze, and such quantification is, in fact, even more challenging as we enter an era of different methods of response assessment. In the era before the routine use of the free light assay, Kyle et al estimated the frequency of non-secretory myeloma to be around 3% in a cohort of 1,027 patients with newly diagnosed myeloma. When these non-secretory patients were followed over time, 22 of the 29 patients initially deemed non-secretory remained non-secretory over the course of their disease. When more modern immunoglobulin testing methods are used, the patients in the non-secretory category still represent around 3% of all myeloma patients at the time of diagnosis; however, as patients live longer, it has been noted that, through clonal evolution, others may develop non-secretory myeloma as a consequence of long-term treatment (“light chain escape phenomenon”). The loss of protein production with subsequent disease progression that these increasing numbers reflect is typically seen in patients with high-risk myeloma and is often associated with a “de-differentiated” pathological specimen that may or may not express CD138 or CD38, and that often expresses CD20.
As mentioned earlier, non-secretory myeloma must also be distinguished from oligosecretory myeloma, in which proteins are produced but at very low levels that make reliable measurement more challenging. Oligosecretory multiple myeloma is often characterized by serum protein of < 1.0 g/dL, urine protein of < 200 mg/24 hrs, and free light chain values of < 100 mg/L (or 10 mg/dL).
Clinically, patients who present with true non-secretory disease at diagnosis behave differently from patients who present with oligosecretory disease at the outset, as well as from those who progress from having secretory disease at diagnosis to oligosecretory or non-secretory disease at the time of relapse. These latter patients typically have high-risk myeloma, genomic instability, and rapid clonal evolution.
1. Lonial S, Miguel JF. Induction therapy for newly diagnosed multiple myeloma. J Natl Compr Canc Netw. 2013;11:19-28.
2. Dimopoulos M, Kyle R, Fermand JP, et al. Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. Blood. 2011;117:4701-5.
3. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med. 2004;351:1860-73.
4. Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117:4691-5.
5. Paiva B, Gutierrez NC, Rosinol L, et al. High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma. Blood. 2012;119:687-91.
6. Paiva B, Martinez-Lopez J, Vidriales MB, et al. Comparison of immunofixation, serum free light chain, and immunophenotyping for response evaluation and prognostication in multiple myeloma. J Clin Oncol. 2011;29:1627-33.
7. Paiva B, Vidriales MB, Cervero J, et al. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood. 2008;112:4017-23.
8. Zamagni E, Cavo M. The role of imaging techniques in the management of multiple myeloma. Br J Haematol. 2012;159:499-513.
9. Zamagni E, Patriarca F, Nanni C, et al. Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation. Blood. 2011;118:5989-95.
10. Blade J, Kyle RA. Nonsecretory myeloma, immunoglobulin D myeloma, and plasma cell leukemia. Hematol Oncol Clin North Am. 1999;13:1259-72.
11. Smith DB, Harris M, Gowland E, et al. Non-secretory multiple myeloma: a report of 13 cases with a review of the literature. Hematol Oncol. 1986;4:307-13.
12. Ma ES, Shek TW, Ma SY. Non-secretory plasma cell myeloma of the true non-producer type. Br J Haematol. 2007;138:561.
13. Decourt C, Galea HR, Sirac C, Cogne M. Immunologic basis for the rare occurrence of true nonsecretory plasma cell dyscrasias. J Leukoc Biol. 2004;76:528-36.
14. Coriu D, Weaver K, Schell M, et al. A molecular basis for nonsecretory myeloma. Blood. 2004;104:829-31.
15. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:2220.
16. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121:749-57.
17. Drayson M, Tang LX, Drew R, et al. Serum free light-chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma. Blood. 2001;97:2900-2.
18. Dispenzieri A, Kyle R, Merlini G, et al. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia. 2009;23:215-24.
19. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78:21-33.
20. Terpos E, Apperley JF, Samson D, et al. Autologous stem cell transplantation in multiple myeloma: improved survival in nonsecretory multiple myeloma but lack of influence of age, status at transplant, previous treatment and conditioning regimen. A single-centre experience in 127 patients. Bone Marrow Transplant. 2003;31:163-70.
21. Avet-Loiseau H, Garand R, Lode L, et al. Translocation t(11;14)(q13;q32) is the hallmark of IgM, IgE, and nonsecretory multiple myeloma variants. Blood. 2003;101:1570-1.
22. Kumar S, Perez WS, Zhang MJ, et al. Comparable outcomes in nonsecretory and secretory multiple myeloma after autologous stem cell transplantation. Biol Blood Marrow Transplant. 2008;14:1134-40.
23. Cavo M, Rajkumar SV, Palumbo A, et al. International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood. 2011;117:6063-73.
24. Nooka A, Langston A, Waller EK, et al. Early versus delayed autologous stem cell transplant (ASCT)in patients receiving induction therapy with lenalidomide, bortezomib, and dexamethasone (RVD) for newly diagnosed multiple myeloma (MM). Presented at ASCO 2013 Annual Meeting; May 31 – Jun 4, 2013; Chicago, IL; Abstract 8540.
25. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679-86.26. Kaufman JL, Nooka A, Vrana M, et al. Bortezomib, thalidomide, and dexamethasone as induction therapy for patients with symptomatic multiple myeloma: a retrospective study. Cancer. 2010;116:3143-51.
27. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-85.
28. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29-37.
29. Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010;28:4621-9.
30. Corradini P, Cavo M, Lokhorst H, et al. Molecular remission after myeloablative allogeneic stem cell transplantation predicts a better relapse-free survival in patients with multiple myeloma. Blood. 2003;102:1927-9.
31. Ladetto M, Pagliano G, Avonto I, et al. Consolidation with bortezomib, thalidomide and dexamethasone induces molecular remissions in autografted multiple myeloma patients. ASH Annual Meeting Abstracts. 2007;110:530.
32. Paiva B, Almeida J, Perez-Andres M, et al. Utility of flow cytometry immunophenotyping in multiple myeloma and other clonal plasma cell-related disorders. Cytometry B Clin Cytom. 2010;78:239-52.