Non-Secretory Myeloma: A Clinician’s GuidePublished on Neurology Times (http://www.neurologytimes.com)

Non-Secretory Myeloma: A Clinician’s GuideReview Article [1] | September 15, 2013By Sagar Lonial, MD [2] and Jonathan L. Kaufman, MD [3]

Numerous small series of patients suggest that the prognosis for non-secretory myeloma patients islikely no worse than the prognosis for patients with traditional secretory myeloma, and in somesettings may be superior.

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 butthere is no evidence of end-organ damage (this is known as “monoclonal gammopathy of unknownsignificance” [MGUS] or “smoldering myeloma”).[2] However, a hallmark of most cases of multiplemyeloma 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 monoclonalantibodies (heavy chain or light chain). It is often this protein production that calls the disease toattention in the smoldering or MGUS stage, since patients frequently have no other signs ofdisease.[3]

A unique feature of malignant plasma cells is continued protein production, a function that istypically lost when cells are transformed from a normal to a malignant phenotype. In addition, theprotein produced can often serve as a reliable biomarker for disease presence. The availability of thisprotein 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 responseassessment in most cases of myeloma, since the assessment can be done with routine blood andurine testing rather than requiring imaging or bone marrow assessment, as in other hematologicmalignancies.[4] While the concept of biomarker assessment as a surrogate for response is useful inmost cases of myeloma, in patients with high-risk disease, light chain or non-secretory escape mayoccur, likely as a consequence of clonal evolution: although a protein was initially produced, it is lostwith relapse. This possibility, in conjunction with the fact that relapse remains inevitable even inpatients who achieve a complete remission, as determined via serum and urine studies, has led anumber of groups to evaluate more stringent methods for assessing disease status,[5-9] and it islikely that these methods will prove useful as we seek to define the optimal methods for assessingresponse 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 typicallyproduce a serum or urine paraprotein. The serum protein is often characterized by an intactimmunoglobulin (heavy and light chain), or it may be characterized by the light chain alone. In theurine, an intact immunoglobulin is also often present, although some patients have predominantlylight 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 ofimmunoglobulin molecules, while in others there was no evidence of immunoglobulin production bythe plasma cells.[10-12] This observation allows us to divide non-secretory myeloma patients intoseveral groups. The first group consists of patients who are “non-producers.” These are patientswhose tumors may have defects in immunoglobulin synthesis. While these tumors may have all thefeatures of a plasma cell disorder, they are not able to synthesize or secrete a protein.[13] Patientswho have no measurable protein in the blood or urine, yet who still have a significant plasma cellburden 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, sincethey do not make a protein.

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Non-Secretory Myeloma: A Clinician’s GuidePublished on Neurology Times (http://www.neurologytimes.com)

The next category of non-secretory myeloma patients consists of those whose tumors produce aprotein but have defects in secretion. It has been demonstrated in vitro that a single amino acidsubstitution in a light chain can potentially block secretion outside of the cell, and in a patientsample, it has been demonstrated that a mutation in the immunoglobulin gene can account for alack of secretion in a patient with non-secretory myeloma.[14] However, among those patientswhose tumors have defects in Ig secretion, there is a subset of patients who have impaired secretionbut are able to secrete some low levels of light chains. These are patients who have oligosecretorymyeloma, and while their protein secretion may not be as high as that seen in typical myeloma, theyare 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 bedetected by either SPEP or UPEP (both with immunofixation), often fall into a more recently identifiedgroup who have “free light–only” myeloma. These are patients in whom disease can be revealedonly with the free light assay, which is known to more accurately detect kappa and lambda lightchains in the blood.[15,16] Drayson et al noted that in a series of 28 patients, 19 had elevations inthe serum kappa or lambda light chains, as measured by the free light assay.[17] It is important tonote that while serum measurement of free light chains has now become a standard diagnostic testfor plasma cell disorders,[18] disease assessment with the urinary free light chain assay isnotoriously unreliable, and this approach should not be routinely used in clinical practice. The urinaryfree light chain assay is different from the UPEP with immunofixation, which remains the optimalstudy to use when assessing urinary protein production.TABLE 1

Criteria for Non-Secretory Myeloma

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 quantificationis, in fact, even more challenging as we enter an era of different methods of response assessment. Inthe era before the routine use of the free light assay, Kyle et al estimated the frequency ofnon-secretory myeloma to be around 3% in a cohort of 1,027 patients with newly diagnosedmyeloma.[19] When these non-secretory patients were followed over time, 22 of the 29 patientsinitially deemed non-secretory remained non-secretory over the course of their disease. When moremodern immunoglobulin testing methods are used, the patients in the non-secretory category stillrepresent around 3% of all myeloma patients at the time of diagnosis; however, as patients livelonger, it has been noted that, through clonal evolution, others may develop non-secretory myelomaas a consequence of long-term treatment (“light chain escape phenomenon”). The loss of proteinproduction with subsequent disease progression that these increasing numbers reflect is typicallyseen 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 oligosecretorymyeloma, in which proteins are produced but at very low levels that make reliable measurementmore challenging. Oligosecretory multiple myeloma is often characterized by serum protein of < 1.0g/dL, urine protein of < 200 mg/24 hrs, and free light chain values of < 100 mg/L (or 10 mg/dL).[15]Clinically, patients who present with true non-secretory disease at diagnosis behave differently frompatients who present with oligosecretory disease at the outset, as well as from those who progressfrom having secretory disease at diagnosis to oligosecretory or non-secretory disease at the time ofrelapse. These latter patients typically have high-risk myeloma, genomic instability, and rapid clonalevolution.

Diagnosis and Workup of Non-Secretory Patients

TABLE 2

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Recommended Workup of Suspected Non-Secretory Myeloma

Given the paucity of information on these patients, how should the clinician approach the workupand treatment of patients with known or suspected non-secretory myeloma? The standard workupfor newly diagnosed myeloma as recommended by the consensus statement from the InternationalMyeloma Workshop[2] is a good place to start. According to this statement, the workup for all newlydiagnosed myeloma patients includes SPEP, UPEP, and serum free light chain assay, in addition tobasic imaging using a skeletal survey (Table 2). Patients with light chain myeloma may have only aserum free light chain abnormality; in modern parlance, these patients are not considered to havetrue non-secretory myeloma. Although in older series these patients were reported to havenon-secretory disease, the free light chain assay now provides us with a biomarker that can be usedto assess response. However, there remains a group who comprise around 2% to 4% of patients andfor whom there is no measurable biomarker and thus no serum, urine, or free light chain–basedmethod of response assessment. These patients represent the subset with true non-secretorymyeloma. In these patients, positron emission tomography (PET)/CT imaging can serve as arelatively objective assay that can be used, along with marrow plasmacytosis, to assess the level ofdisease response; PET/CT imaging can help identify sites of bone disease, and after therapy, it canbe used to evaluate active vs quiescent bone lesions in the context of therapy.

Prognosis

The characteristics of patients with non-secretory myeloma have been reported in a number of smallseries. In a series from France, it was reported that there was a higher proportion of patients withthe t(11;14) translocation among patients with non-secretory myeloma, as well as among those withIgM and IgE myelomas. There was no clear biologic reason for this unique feature; nonetheless, thefrequency of this translocation in non-secretory myeloma patients was 83% in a cohort of 24patients. This may in part account for differences in outcomes for non-secretory myeloma patients.A few series have been reported that compared the outcomes of non-secretory patients with those ofmore traditional secretory myeloma patients. In a group of 127 myeloma patients from the UK whohad undergone transplantation, 6 were found to be patients with non-secretory disease; the overallsurvival (OS) and progression-free survival (PFS) in that small group of patients were found to besuperior to those of the patients with a more traditional secretory myeloma phenotype.[20] The PFSfor this group was 36 months following high-dose therapy (HDT), while the PFS for all the othersecretory groups in aggregate was 23 months. The authors of this paper suggest that enhancedsensitivity to HDT may be a feature of a less mature plasma cell phenotype that is not secretingimmunoglobulin; however, an alternative hypothesis could be that there is a lower frequency ofhigh-risk genetic alterations in the non-secretory patients, which allows for their improved outcomescompared with the outcomes of patients with IgG, IgA, or light chain myelomas.[21] It has beensuggested by others that patients with light chain or IgA myeloma may harbor a higher frequency ofthe t(4;14) translocation or other high-risk features that account for their shorter PFS and OS.In the series from Kyle et al, the outcomes for patients with non-secretory myeloma were similar tothose of patients with secretory myeloma, with a median OS of 38 months for the non-secretorypatients vs 33.4 months for the remaining patients in the 1,027-patient cohort.[19]Finally, in a series from the Center for International Blood & Marrow Transplant Research (CIBMTR),which assembled the largest set of non-secretory patients to date, 110 patients with non-secretorymyeloma were compared with matched controls in a 4:1 fashion. This study showed no difference inPFS or OS between the non-secretory patients and the matched controls.[22] All patients in thisseries underwent HDT and autologous transplant, but the data on how many of these patients hadfree light–measurable disease (true non-secretors vs those with oligosecretory disease) was notavailable. There also was insufficient information on genetics and fluorescence in situ hybridization(FISH) results to determine whether the molecular basis for either similar or improved outcomes fornon-secretory patients lies in the underlying biology of the disease—although the authors do

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speculate that this is likely the cause.

Treatment of Non-Secretory Myeloma

The management of newly diagnosed myeloma has changed dramatically now that we have newagents to use in all phases of treatment. Nowhere is the explosion in new regimens more apparentthan in the setting of induction therapy. Three-drug combinations, in which proteasome inhibitors arecombined with immunomodulatory agents or alkylating agents, are commonly used inductionregimens for patients being considered for HDT and autologous transplant.[1] With improvedinductions, a greater proportion of patients are achieving a complete response, and through novelconsolidation and maintenance therapy, patients are now achieving molecular or flow cytometriccomplete remission as well.[23]While there are no studies of large numbers of non-secretory myeloma patients, an analysis byNooka et al at our center evaluated the PFS and OS for patients receiving lenalidomide, bortezomib,and dexamethasone (RVD) induction followed by either early or late transplant.[24] Among allpatients, the 3-year OS was > 85%, and this appeared to be similar in all analyzed patients, and inthe small subset of patients in the same cohort who were defined as non-secretory. These results—inconjunction with those from the larger series of patients reported earlier in this paper,[19] whichprovide evidence that as the OS for patients with myeloma has improved, the OS for non-secretorypatients has improved by a similar magnitude—suggest that the gains in outcomes associated withthe use of new agents are similar for secretory and non-secretory myeloma. Thus, optimal inductionlikely includes the use of a three-drug combination that involves either proteasome inhibitorstogether with immunomodulatory agents (RVD[25] or bortezomib, thalidomide, and dexamethasone[VTD][26,27]), or proteasome inhibitors in combination with alkylating agents (bortezomib,cyclophosphamide, and dexamethasone [VCD]). Patients not considered to be suitable for triplecombinations may be treated with doublets, such as lenalidomide/dexamethasone (RD)[28] orbortezomib/dexamethasone (VD).[29]

Disease Assessment and Response

Response assessment in myeloma is typically based on clearance of measurable protein, with thelatest definition of complete response requiring no detectable protein in the blood or urine and anormal free light ratio. Even with a response that meets these criteria, more in-depth assessmentusing molecular techniques, such as polymerase chain reaction (PCR) testing,[30,31] DNAsequencing, and multi-parameter flow cytometry (MPF),[6,7,32] is able to identify remaining diseaseburden that likely will contribute to relapse.Non-secretory myeloma typically presents with cytopenias or bone disease; thus, objective measuresof disease response include marrow assessment and imaging studies.[16] While marrow involvementin the context of most myelomas can be patchy and inconsistent, in the setting of non-secretorydisease, marrow involvement may be the only true objective measure of disease burden.It should be noted that while marrows have historically been used as the sole measure of diseaseresponse and activity in the setting of non-secretory myeloma, assessment of disease burden usingroutine marrow histology and routine flow cytometry is notoriously inaccurate, due in large part tothe patchy nature of marrow involvement and issues with sampling.[6] However, the use ofspecialized flow cytometry, as championed by the Spanish Myeloma Group, has allowed us to moreintensely evaluate the marrow, thus making marrow evaluation a more reliable means of diseaseassessment. Rather than using flow cytometry as a method for assessing crude disease involvement,MPF is now being used as a measure of minimal residual disease (MRD), and MPF results have notonly predictive but also prognostic implications in the setting of disease assessmentpost-transplant.[7]TABLE 3

Recommended Tests to Assess Response and Disease Status in a Patient With Non-SecretoryMyeloma

However, while assessment of disease using MPF is a significant improvement over conventional flow

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cytometry or histologic assessment of plasma cell number, MPF alone is probably not sufficient toassess total body myeloma burden. For this reason, the pairing of imaging and more sensitivemarrow assessment represents an optimal method by which to assess response to therapy and MRD,and will likely be applied to all myeloma patients, not just non-secretory patients in whom theinability to use SPEP or UPEP limits methods of response assessment (Table 3).For serial assessment of bone disease, a skeletal survey is inadequate for identifying active vsquiescent bone lesions; however, PET imaging is potentially able to help bridge the gap in thisinstance.[8,9] Patients with non-secretory or oligosecretory myeloma often not only havebone-based lytic disease, but may also have extra-medullary manifestations of disease, which arebest evaluated using serial PET/CT scans. Quiescent bone disease may show up as lytic bone diseaseon a CT scan but is typically not fluorodeoxyglucose (FDG)-avid (a feature that would allow theclinician to more fully assess the efficacy of therapy). It should be noted that marrow and imagingassessment together is the best method for assessing response in non-secretory disease, since thetwo technologies often complement one another. It is likely that, in the near future, MRD assessmentand imaging with more modern methods, such as PET/CT, will become more routine in secretorymyeloma as well.

Conclusion

The diagnosis of non-secretory myeloma has evolved as our methods for assessing protein and nowplasma cell numbers in the marrow have increased in sensitivity. While this development hasreduced the number of patients defined as having non-secretory myeloma, it has not changed thechallenge we clinicians have in determining response, and depth or duration of response.Fortunately, numerous small series of patients suggest that the prognosis for these patients is likelyno worse than the prognosis for patients with traditional secretory myeloma, and in some settingsmay be superior. The use of MPF in conjunction with PET/CT scanning provides the opportunity tomore formally assess low levels of disease regardless of the secretory potential of the malignantplasma cell, and this combination approach will likely be used to determine response and possiblycure in all patients in the near future. A careful and thorough initial evaluation is key to arriving atthe correct data, which are necessary in order to best define a long-term strategy for disease controland assessment.Financial Disclosure: Dr. Lonial serves as a consultant for Bristol-Myers Squibb, Celgene, Janssen,Millennium, Novartis, and Onyx. Dr. Kaufman serves as a consultant for Celgene, Janssen,Millennium, Novartis, and Onyx; he receives research support from Celgene, Merck, and Novartis. References:

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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.

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(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.

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27. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasonecompared with thalidomide plus dexamethasone as induction therapy before, and consolidationtherapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: arandomised phase 3 study. Lancet. 2010;376:2075-85.

28. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versuslenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma:an open-label randomised controlled trial. Lancet Oncol. 2010;11:29-37.

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32. Paiva B, Almeida J, Perez-Andres M, et al. Utility of flow cytometry immunophenotyping inmultiple myeloma and other clonal plasma cell-related disorders. Cytometry B Clin Cytom.2010;78:239-52. Source URL: http://www.neurologytimes.com/non-secretory-myeloma-clinician%E2%80%99s-guide

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