• © 2009 by American Society of Clinical Oncology

Spontaneous Remission in a Patient With t(4;14) Translocation Multiple Myeloma

A 60-year-old woman was found to have a high erythrocyte sedimentation rate (121 mm/h) and low hemoglobin (113 g/L) in December 2005. Further work-up led to the diagnosis of Durie-Salmon stage 1A/International Staging System stage I multiple myeloma (MM) based on the following: (1) a protein electrophoresis showed immunoglobulin (Ig) G, 14.0 g/L; IgA, 30.3 g/L; and IgM, 0.37 g/L; with a major spike in the beta region identified as an IgA-kappa paraprotein (Fig 1); (2) a bone marrow biopsy revealed 20% to 30% infiltration with atypical plasma cells, kappa restricted (Fig 2). A metastatic x-rays survey showed osteopenia throughout the axial skeleton with multiple subtle lucencies in the proximal humeral diaphyses bilaterally. A 24-hour urine collection showed 0.05 g/L of proteinuria with no Bence-Jones protein excretion. Peripheral blood counts revealed a hemoglobin level of 113 g/L (mean corpuscular volume, 90 fL), platelets at 281 × 10⁹/L, and WBC of 6.8 × 10⁹/L with 4.2 absolute neutrophil count. Electrolytes and calcium were within normal limits, but creatinine was slightly elevated at 107 μmol/L (normal, < 99 μmol/L). β₂-microglobulin, C-reactive protein, and albumin were 219 nmol/L (normal, ≤ 219 nmol/L), 4 mg/L (normal, ≤ 12 mg/L), and 36 g/L (range, 36 to 50 g/L), respectively. Further analysis of the malignant plasma cells by fluorescent in situ hybridization coupled to cytoplasmic staining of specific Ig revealed them to be positive for t(4;14) (Fig 3, white arrows). IgH-MMSET fusion transcripts were also detected by reverse transcriptase polymerase chain reaction, confirming the presence of t(4;14) cells in the specimen (data not shown). The plasma cells expressed FGFR3 by flow cytometry (data not shown). In addition, in vitro exposure of bone marrow mononuclear cells from this patient to XL999, a selective inhibitor of FGFR3 preferentially induced apoptosis of the CD138+ cell fraction. Array comparative genomic hybridization revealed an amplification of the der⁴t(4;14) chromosome, thus explaining the three fusion signals seen by fluorescent in situ hybridization. Array comparative genomic hybridization also defined a hyperdiploid karyotype with trisomies of chromosomes 3, 4, 9, 18, and 19, and monosomy 13, as well as a focal deletion on chromosome X containing CYLC1, RPS6KA6, and SATL1—three genes that have been implicated in the pathogenesis of cancer (Fig 4).¹ No active therapy was recommended apart from monthly intravenous pamidronate. A progressive decline of her M-protein was documented as of June 2006 with a protein electrophoresis revealing IgG, 7.7 g/L; IgA, 2.23 g/L; and IgM, 0.63 g/L; and no paraprotein detected by immunofixation. A recent bone marrow biopsy showed less than 5% plasma cells. Peripheral blood counts and serum biochemistry remains within normal limits, and her skeletal survey remains unchanged. No significant proteinuria was detected after a 24-hour collection (0.07 g/L). Recent serum free light chains assay has revealed kappa of 13.8 mg/L and lambda of 11.0 mg/L with normal kappa:lambda ratio. Past medical history was significant for type I cryoglobulinemia IgA-kappa diagnosed in 1985 when she presented with arthritis, purpura, and Raynaud's phenomenon. Cryocrit had ranged from 0% to 25% over the years and most recently was 5%. She did not require treatment until 1989, when she was placed on low-dose prednisone 5 to 7.5 mg/d. Flares consisted of lower limb arthralgias and purpura. She also had recurrent episodes of transient global amnesia, delayed gastric emptying, and inflammatory bowel syndrome.

The case hereby presented fulfills the diagnostic criteria for asymptomatic (smoldering) myeloma established by the International Myeloma Working Group in 2003.² The subtle findings in the patient's skeletal survey were felt not significant enough to justify the diagnosis of symptomatic MM, and therefore no active treatment apart from monthly pamidronate was recommended. To date, paraprotein has not been detected and a recent bone marrow biopsy identified less than 5% plasma cells. Therefore, we have documented spontaneous remission (SR) in a patient with IgA-kappa MM only receiving pamidronate and intermittent low-dose prednisone. SR of cancer is defined as a complete or partial, temporary or permanent disappearance of all or at least some parameters of a soundly diagnosed malignant disease without any medical treatment or with treatment that is considered inadequate to produce the resulting regression.³ This is an extremely rare event with a reported incidence of less than one in 60,000 to 100,000 people with cancer.⁴ Although SR is seen sporadically, it has been reported especially in cases of malignant melanoma, renal cell cancer, low-grade non-Hodgkin's lymphoma, and childhood neuroblastoma, where the host immune system is known to play an important role. To our knowledge, only one case of SR of MM has previously been described in the literature.⁵ García-Rayo et al referred to a 68-year-old man diagnosed with nonsecretory MM after presenting with multiple lytic lesions. The patient developed a spinal cord compression requiring surgery and had a Staphylococcus aureus infection as a postoperative complication. After 10 cycles of chemotherapy with vincristine, cyclophosphamide, melphalan, and prednisone/vincristine, carmustine, doxorubicin, and prednisone, García-Rayo et al documented complete radiological resolution of the bone lesions precipitating the diagnosis and absence of plasma cells in a repeat bone marrow biopsy. This was interpreted as a case of SR in the context of infection. Our patient was also diagnosed with type I cryoglobulinemia IgA-kappa. Cryoglobulinemia refers to the presence of immunoglobulins in serum that precipitate at cold temperatures. Type I cryoglobulins are composed of isolated monoclonal immunoglobulins; types II and III are mixed cryoglobulins composed of monoclonal or polyclonal IgM, respectively, having rheumatoid factor activity. Type I cryoglobulins account for 10% to 15% and are usually IgM, with rare cases belonging to the IgA isotype.⁶ Clinically, type I cryoglobulinemia presents with signs of vasculitis and peripheral vessel occlusion, as well as hyperviscosity syndrome as purpura, acrocyanosis, and Raynaud phenomena.⁶ This presentation is consistent with our patient's presentation. Many series have reported the association of cryoglobulinemia with specific clinical conditions, including hematological diseases.⁶ Specifically, type I is usually associated with lymphoproliferative disorders including MM, which is corroborated with our case. MM is an incurable condition with a median overall survival of 3 to 5 years with conventional treatment. Genetic abnormalities are powerful prognostic factors in MM. In this regard, it is now well established that patients with the IgH translocation t(4;14) detected in our case have a poor outcome following conventional chemotherapy or high-dose therapy with stem-cell transplantation.⁷The t(4;14) translocation results in ectopic expression of the receptor tyrosine kinase FGFR3 and enhanced expression of the histone methyltransferase MMSET, two putative oncogenes. Although MMSET is dysregulated in all cases only two thirds of t(4;14) tumors express FGFR3.⁸ In our case, FGFR3 was detected by flow cytometry and furthermore, the malignant cells responded to an FGFR3 inhibitor, suggesting a potential role for FGFR3 in the tumor pathogenesis. Rare tumors with t(4;14) can acquire kinase-activating mutations resulting in constitutive FGFR3 signaling and there is evidence that the survival of these tumors is dependent on mutated FGFR3.⁹ The significantly increased prevalence of t(4;14) in MM compared with monoclonal gammopathy of undetermined significance (15% versus 3%) suggests that the translocation promotes a myeloma-like phenotype.¹⁰ However, it is also known that the translocation is neither necessary for transformation nor is it a sign of inevitable or rapid transformation.¹⁰ The latter has also been observed in our case. Our patient was only treated with monthly pamidronate. Bisphosphonates are a class of antiresorptive drugs effective in the treatment of osteoclast-mediated bone disease. It has been demonstrated that nitrogen-containing bisphosphonates can have antitumor effect in human myeloma cells in vitro as a result of inhibition of enzymes of the mevalonate pathway.¹¹ Studies in vivo using murine models of MM have reported contradictory results. Two bisphosphonates, pamidronate and zoledronic acid, have been studied in the 5T2MM murine model of MM.¹² Pamidronate reduced radiological and histological indices of bone destruction but had no effect on tumor burden. Zoledronic acid prevented the formation of osteolytic lesions and decreased tumor burden as well as the microvessel density in areas of tumor cell growth. Importantly, these changes in tumor activity, angiogenesis and bone resorption were associated with significant increase in survival.¹² In contrast, other authors using the same murine model found that treatment with a high-dose of the potent bisphosphonate ibandronate had no effect on either myeloma cell number or the proportion of myeloma cells undergoing apoptosis within the bone marrow.¹³ To our knowledge, only four cases suggesting antimyeloma effects of bisphosphonates, specifically pamidronate, have been reported in humans in the literature.^14–16 The authors documented improvement in some parameters of the disease (marrow plasmacytosis, immunoglobulin levels, bone mineral density, and degree of anemia), but a complete remission was not achieved in any of the cases. Recently, it has been discovered that nitrogen-containing bisphosphonates such as pamidronate can stimulate human γδT-cells, both in vivo and in vitro.¹⁷ We speculate that the cytolytic activity against MM cells exerted by γδT-cells stimulated by pamidronate could be one of the mechanisms responsible for the SR of our patient, as we were not able to demonstrate direct antitumor activity of pamidronate against cells lines or primary patient samples in vitro (results not shown).