Myelomas that “lack” a monoclonal protein can be divided further into those that produce some protein and yet do not secrete it or whose serum concentration is so low that it cannot be measured, and those that truly produce no monoclonal protein at all.
Drs. Lonial and Kaufman provide a concise review of the biology and clinical implications of a myeloma variant that cannot be monitored using the standard biomarkers, the monoclonal proteins. The clinical availability of measurements of these monoclonal proteins in myeloma positions the disease uniquely among human malignancies in that it is the disease with the best available biomarker. Monoclonal proteins arise from pathologic expansions of B cells undergoing maturation, up to the point of a neoplastic transformation. For decades now, these monoclonal proteins have been measured in the clinic to diagnose and monitor patients with plasma cell neoplasms. The techniques for measuring proteins have improved, including the recent advent of the ability to measure serum free light chains and to peform combined measurement of clonal heavy and light chains (Hevylite®). Because B cells produce a protein that has undergone genetic rearrangements and mutations, these protein markers can be considered “genetic fingerprint” surrogates for the neoplastic plasma cells that give rise to them. Monoclonal proteins are ideal biomarkers, unsurpassed by biomarkers in any other neoplasm, because they are disease-specific and diagnostic (eg, monoclonal vs polyclonal), they are patient-specific (eg, they can demonstrate that a patient’s myeloma is immunoglobulin A kappa), and they are even clone-specific. Subsets of myeloma patients may have two (or more) clones that produce different immunoglobulins, the biclonal gammopathies, and in these cases the two monoclonal proteins can be measured individually and monitored. Hence the apprehension of physicians who care for myeloma patients who lack such markers to monitor the disease.
Myelomas that “lack” a monoclonal protein can be divided further into those that produce some protein and yet do not secrete it or whose serum concentration is so low that it cannot be measured, and those that truly produce no monoclonal protein at all. With more sensitive methods of detection, such as the serum free light chain assay, the proportion of patients with no measurable disease has been reduced substantially, arguably even to less than the 3% reported by Lonial and Kaufman. How to monitor this patient population is a major challenge, since currently available imaging studies can only provide an approximation of disease burden (eg, that provided by positron emission tomography [PET]/CT) or past damage (eg, the assessment provided by bone surveys). (Molecular imaging techniques that target plasma cells should be developed; these might be able to be used to monitor myeloma patients, even those who have measurable disease in the serum.) Repeated examinations of the bone marrow are cumbersome, associated with patient discomfort, and not precise enough to accurately monitor progress of treatment. Thus, clinicians caring for these patients are left with subjective and semi-quantitative tools for assessing disease burden. Perhaps an indirect approach might be better-for example, more sensitive methods of measuring end-organ damage, such as bone disease. While they would require the development of special tools, real-time ongoing measurements of bone destruction could hypothetically serve as surrogate markers of disease activity, especially in those cases where there is no measurable monoclonal protein.
An important issue addressed by Lonial and Kaufman is the fact that very limited information is available regarding the clinical behavior and prognosis of patients with non-secretory myeloma. The data that are available, which come from very small series, suggest that these patients do not have a more aggressive disease. The results of such studies are counterintuitive, since one would predict that non-secretory myeloma is a more advanced clonal state of plasma cell tumors, and hence would display more aggressive clinical features. Recent work by our group and others has shown the Darwinian process of clonal evolution constantly occurring in myeloma, a process that can lead to conversion to “non-secretion.” The transformation of myeloma from a disease that produces both a heavy and a light chain to one that produces a light chain only, the so-called Bence-Jones transformation, has been traditionally identified with disease progression (and regarded as a signal of clonal evolution). Likewise, and despite the clinical studies presented by Lonial and Kaufman and as noted by them, non-secretory myeloma that results from disease progression is likely to be associated with increased disease aggressiveness. The molecular mechanisms of transformation from secretory to non-secretory disease have been explored in detail elsewhere and support the notion of a stochastic process that reflects this clonal evolution. Thus, it is critically important to make a clinical distinction between patients who present with non-secretory myeloma and those who evolve into it.
Although it lacks the nomenclature of proteomics or biomarker discovery, myeloma has nonetheless been at the forefront of our understanding of the clinical implications of serum biomarkers for disease diagnosis and monitoring. The disease can serve as a model for all other tumors, showing how the incorporation of biomarkers into daily clinical practice allows information feedback (on changing concentrations of these markers) to guide the tailoring, adjustment, or change of therapy.
Therapy of myeloma has greatly improved over the last 15 years, with many new drugs now available to patients, including proteasome inhibitors and immunomodulatory drugs. It would be interesting to understand better what the implications are for protein production and detection in the setting of proteasomal inhibition. Since these drugs will have an effect on protein metabolism, their use might result in small amounts of monoclonal proteins being detected in some patients with non-secretory myeloma. New avenues for treatment include the ongoing clinical development of monoclonal antibodies such as elotuzumab and daratumumab. As has been noted by Lonial and Kaufman, myeloma is the only human disease that produces a monoclonal antibody and for which there is no therapeutic monoclonal antibody! Unfortunately, myeloma does not always produce a monoclonal protein.
Financial Disclosure: Dr. Fonseca has received a patent for the prognostication of multiple myeloma based on genetic categorization of the disease. He has received consulting fees from Medtronic, Otsuka, Celgene, Genzyme, Bristol-Myers Squibb, Lilly, Onyx, Binding Site, Millennium, and Amgen.
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2. Szczepanski T, van ‘t Veer MB, Wolvers-Tettero IL, et al. Molecular features responsible for the absence of immunoglobulin heavy chain protein synthesis in an IgH(-) subgroup of multiple myeloma. Blood. 2000;96:1087-93.
3. Keats JJ, Chesi M, Egan JB, et al. Clonal competition with alternating dominance in multiple myeloma. Blood. 2012;120:1067-76.