Case Presentation: A 68-year-old Caucasian male with intact immunoglobulin multiple myeloma (IIMM), presents with a 1-day history of fevers, confusion, and weakness. This patient’s IIMM was characterized by elevated serum IgA levels (5,186 mg/dL on diagnosis. Normal 82-453 mg/dL) and an elevated monoclonal IgA lambda (m-spike) on serum electrophoresis (6.13 g/dL on initial diagnosis), but he was currently in clinical remission. On day of presentation, the patient was confused with unintelligible speech, febrile, unable to follow commands, and had diffuse weakness. MRI of the brain showed an increase in size of a previously seen frontal diploic mass with a subacute left frontoparietal infarct. Venogram showed occlusion of the anterior third of the superior sagittal sinus due to external compression from the mass. Serum IgA lambda m-spike on presentation was low at 0.18 g/dL, initially suggesting that his MM remained in remission and that his current presentation may be due to meningitis versus an acute stroke. However, serum lambda free light chains (FLC) later returned elevated at 11,350 mg/L (normal 5.71-26.3 mg/L), consistent with persistent systemic MM, specifically a MM that had now evolved to one that produces lambda FLC compared to intact immunoglobulins (IgA lambda). Bone marrow confirmed the diagnosis, revealing >50% plasma cells. It was now thought that the frontal mass was either a progressing plasmacytoma versus a new clonal evolution of the MM, which was now causing outflow obstruction of the superior sagittal sinus, leading to a venous stroke and subsequent seizures. The plasmacytoma was initially treated with radiation therapy and steroids, however the patient unfortunately passed from septic shock. 

Discussion: The evolution of multiple myeloma (MM) is complex, following several paths over the lifetime of a patient, including 1) stable disease 2) linear evolution due to the acquisition of genetic mutations by the tumor cells or 3) the mixture of several clones with different clones being dominant at different times. Due to the heterogeneity of MM clones, therapy will be deferentially more active against certain clonal cells (in this case, clonal cells producing intact immunoglobulins), leading to the evolution and escape of free light chain (FLC)-only secreting cells, a phenomenon called the “free light chain escape.” Our patient initially had IIMM, characterized by the secretion of IgA and IgA lambda paraprotein, whose levels were monitored to determine clinical response. However, after 3 years of varying therapies, fulminant relapse occurred characterized by an increase in serum FLC without the parallel rise in paraprotein level. In 2007, Dawson et al described this similar situation in three patients and found that a common feature seen that preceded the onset of relapse was the use of biological therapies, in particular thalidomide and lenalidomide. Interestingly, our patient was also treated with lenalidomide. 

Conclusions: The free light chain (FLC) escape phenomenon has been found to be more difficult to treat and more resistant to therapy. The different clonal composition at relapse will ultimately have impact on sensitivity to treatment and therefore on survival. The serum FLC assay can be a tool to measure the growth of resistant FLC-producing clones when there is a suspicion for clinical relapse of MM. Further studies are being done to evaluate for additional monitoring tools to aid in recognizing relapse or residual disease, such as the heavy to light chain assay.