Conversion of Non-Secretory to Hyper-Secretory Myeloma: The Antithesis of the Common Pathway of Dedifferentiation with Myeloma Progression: A Case Study

Non-secretory myeloma is characterized by the absence of M protein in both the serum and urine along with normal immunofixation. It occurs in approximately 2% of all patients with multiple myeloma (MM). Here we present the case of a non-secretory myeloma, which converted to secretory disease after treatment with high intensity chemotherapy.

A 50-year-old male without any significant past medical history presented in April of 2007 with diplopia and left-sided headaches. Imaging studies with CT and MRI of the brain revealed an enhancing lesion in the clivus extending into the sella turcica invovlving the cavernous sinus as well as a calvarial mass. A subsequent trans-sphenoidal biopsy of the mass was consistent with plasmacytoma and the patient underwent resection of both masses. Further bone marrow, imaging and serum studies showed no evidence of MM. Patient was subsequently treated with local radiation, which resulted in a great improvement of the patient's vision, followed by Thalidomide 200 mg for 7 months. In May 2008 the patient presented to our institute for re-staging and follow up. MRI studies showed a recurrence of the plasmacytoma in the sphenoid sinus as a 4. 5 cm focal lesion and new 1. 5 cm focal lesion in the manubrium sterni. A CT scan revealed more than 30 osteolytic lesions; however, a PET scan remained negative. Serum IgG and kappa free light chain were within normal limits and a bone marrow aspirate revealed 14% plasma cells (PC) with a normal karyotype. Flow cytometric analysis (DNA/cIg) showed a near diploid clone with kappa light chain excess in 1% with cIg index of 3. 2. The patient was treated with Bortezomib, Dexamethasone, Thalidomide, Cisplatin, Adriamycin, Cyclophosphamide, Etoposide (VDT-PACE) followed by Melphalan 200 mg/m² based autologous transplantation, achieving a very good partial response by IMWG criteria. The one-year follow-up in October 2009, in the absence of maintenance therapy, revealed that all focal lesions had resolved on MRI. However a slight increase in kappa free light chains (up to 10 mg/dl) was noted, prompting the start of Lenalidomide as maintenance therapy. In May 2010 the patient had a bone marrow with 30% PC's on aspirate and 20% on biopsy with a cellularity of 30%. Gene expression profiling revealed low risk disease. MRI showed small focal lesions in the spine, shoulders, and left ilium, that were not seen on PET. For the first time, serum (free kappa 60 mg/dl) and urine markers (urine M 889 mg/l) were significantly increased. Treatment was changed to VDT with normalization of all markers within a month. The current evaluation as of May 2012 shows increased free kappa light chain levels of 1080 mg/dl, urine M protein of 6704 mg/l, with undetectable serum M protein at any point in time. Bone marrow aspirate and biopsy have 16% and < 5% PC respectively with a cellularity 40%. DNA/cIg flow cytometry remains normal and MRI and PET show no evidence for focal lesions, whereas cytogenetic analysis reveals a complex karyotype in 3/20 cells with a t[11:14] consistent with MM(43, X, -Y, add(1)(p36. 3), dup(1)(q12q44), add(11)(q25), t(11;14)(q12∼13. 1;q32), −14, +15, −16, −22, inc[3]/46, XY[17]) and transformation to high risk disease on GEP. Comparison of the first available GEP from 5/2010 with the last from 4/2012 reveals a 2. 5 –fold increase of the immunoglobulin kappa constant gene (IGKC).

Since the implementation of the free light chain assays, the diagnosis of non-secretory myeloma has become increasingly rare. Here we report an unusual case, which initially presented as a non-secretory solitary intracranial plasmacytoma. After initial response to local treatment this disease recurred systemically. Treatment with high dose chemotherapy resulted in the resolution of all active focal lesion and decreasing bone marrow plasmacytosis. However, the disease recurred within one year with the slight increase of kappa free light chains in the serum. That followed 2 years later by the detection of a clone with a t[11:14] with free light chains in the serum as well as M protein in the urine, indicating the emergence of a secretory clone, reaching hyper-secretory features on further progression. Contrary to the well-known dedifferentiation of secretory MM to “Bence Jones” escape and on to non-secretory status, the opposite development has to our knowledge not been reported.

No relevant conflicts of interest to declare.