Extramedullary relapse of multiple myeloma associated with a shift in secretion from intact immunoglobulin to light chains

Biological therapies in multiple myeloma have heralded a newand exciting era for treatment to combat this disease. Howeverthe evolutionary pressures that these drugs place on the microenvironmenthas resulted in a change in the biological behaviour of thismalignancy and novel manifestations of relapsed disease. Thisis illustrated in our series of three patients showing fulminantrelapse of disease with plasmablastic features, an extramedullarypredilection and a shift in secretion from intact immunoglobulinto free light chains only.

Multiple myeloma is a clonal malignancy of plasma cells characterizedin part by the development of a serum monoclonal protein. Theimmunoglobulin produced by the neoplastic plasma cells can beof any immunoglobulin class and in more than 80% of patientsis present as an intact immunoglobulin (IIG) composed of heavyand light chains.¹ Of those patients with intact immunoglobulinmultiple myeloma (IIGMM), 95% also have abnormal serum freelight chain (SFLC) concentrations.² As the vast majority ofpatients with IIGMM show parallel fluctuations of their IIGand SFLC, the utility of SFLC assays in these patients has beenquestioned.³ The era of stem cell transplantation and biologicaltherapies including thalidomide and its analogs has changedthe natural history of myeloma. This selective pressure hasculminated in novel manifestations of relapsed disease. Thisis evidenced by our presentation of three patients with floridextramedullary relapse with a marked increase in SFLC in theabsence of a parallel rise in IIG – light chain escapefrom plateau phase (LEPP)

All three patients were diagnosed with IIGMM in which therewas initially a parallel correlation of the IIG level with diseaseactivity. Serial measurements of SFLC were not performed throughouttheir disease however, urinary Bence-Jones protein (UBJP) levelswere assayed with each measurement of IIG and failed to showany discrepancy until the onset of LEPP. The onset of LEPP inthese patients was heralded by a fulminant relapse of theirdisease associated with a marked rise in their SFLC but no alterationin their IIG levels (Figure 1). Common features accompanyingthe presentation of LEPP included multiple extramedullary sitesof relapse, plasmablastic morphology, acute renal failure, araised lactate dehydrogenase and ß₂-microglobulin.An important feature preceding the onset of LEPP was the useof biological therapies, in particular thalidomide and lenalinomide.LEPP followed an aggressive clinical course, with the subsequenttherapies employed offering only marginal benefits.

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Figure 1. 1A. A temporal sequence illustrating the dramatic development of LEPP. 1B. A more detailed view of the changes in immunoglobulin levels following the onset of LEPP. 1) Induction with 4 cycles of cyclophosphamide, idarubicin and dexamethasone, 2) thalidomide commenced as a result of progressive disease, 3) thalidomide ceased due to side-effects, 4) fulminant relapse of disease with onset of LEPP, 5) intermediate dose melphalan (25mg/m2) given as salvage therapy, 5) melphalan and prednisolone given as further salvage with little effect. It should be noted that light chains were not detected by protein electrophoresis and immunofixation electrophoresis on urine at diagnosis or throughout the course of the illness until the development of LEPP. Serum free light chains were detected using previously described methods.¹²

Case 1

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Case 1

A 63-year old man diagnosed with IgA- ${kappa}$ IIGMM with no detectableUBJP achieved a good partial response to induction therapy.He refused autologous stem-cell transplantation and was commencedon thalidomide when his disease progressed. He achieved a completeresponse (CR) on thalidomide and was maintained on this for11 months. He ceased thalidomide due to intolerable somnolenceand constipation. Five months later he had a florid relapseof his disease with features of LEPP (Figure 1).

Case 2

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Case 2

A 68-year old woman diagnosed with IgG- ${lambda}$ IIGMM with no detectableUBJP had a protracted course with multiple therapies employedto control her disease. As a consequence of progressive diseaseshe commenced thalidomide and achieved a near CR. She was maintainedon this therapy until a dramatic extramedullary relapse withthe features of LEPP.

Case 3

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Case 3

A 69-year old woman initially diagnosed with IgA- ${kappa}$ IIGMM hada CR to a course of dexamethasone and commenced lenalinomideas part of a clinical trial. Two months following this she hadrelapsed in multiple extramedullary sites and demonstrated featuresof LEPP.

More detailed clinical information about the patients is summarizedin Table 1.

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Table 1. Patient demographics.

The ability of plasma cells to produce IgG or IgA instead ofIgM requires a complex rearrangement of the IgH gene. This switchingprocess usually occurs on one allele whilst in a large proportionof MM the other allele is involved in translocations with putativeoncogenic partners;^4,5 however, both alleles of the IgH genemay be involved in such translocation events.^4–6 In IIGMMone allele is involved in a productive rearrangement of theV-D-J genes allowing the production of a functional heavy chainwhereas in light-chain MM the IgH gene is either in germlineconfiguration or has acquired illegitimate translocations ofone or both alleles neither of which has the capacity to producefunctional heavy chains.^5,6 The most plausible explanation forthe lack of heavy chain secretion seen in LEPP is the accumulationof genetic mutations during clonal evolution that compromisethe production of intact heavy chains. Mechanisms includinglack of IgH mRNA transcription, instability or degradation ofIgH mRNA or translation errors could underlie this loss of capacity.

Several investigators have demonstrated highly clonogenic cellsin both peripheral blood and bone marrow that share immunoglobingene sequences and idiotype specificity with the malignant plasmacells in patients with multiple myeloma.^7,8 These clonally relatedB cells might represent the proliferating fraction of MM andhave increased resistance to chemotherapy.⁸ Novel biologicaltherapies such as thalidomide and lenalinomide are immunomodulatorsaimed at altering the stromal dependence of myeloma cells.⁹There have been numerous reports documenting increased extramedullaryrelapse and altered biological behavior following these therapies.^10,11It is this environment of evolutionary pressure that is likelyto engender the LEPP variant. In the context of targeted therapies,it is conceivable that LEPP represents a clonal expansion ofthose proliferative precursors that have not only acquired stromalindependence but also lost the capacity to secrete IIG. ConsequentlyLEPP manifests as plasmablastic cells with an extramedullarypredilection that secrete only free light chains. Our casesrepresent the first documented series of this rare but clinicallyimportant mode of relapse. Whilst it is premature to suggestthat all patients with IIGMM should be followed with serialSFLC measurements our cases emphasize the changing natural historyof multiple myeloma in the era of biological therapies and furtherserve to highlight the role of SFLC assays in monitoring patientswith IIGMM especially following these therapies.

References

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