An asymptomatic 61-year-old man with BCR-ABL-positive bone marrow following autologous transplantation for multiple myeloma.

A 60-year-old male was referred with a recent diagnosis of multiple myeloma. He presented at an outside institution with severe low back pain due to pathologic compression fractures of the thoracic spine treated with T12 vertebroplasty and T11 kyphoplasty. Workup at our institution demonstrated an IgA kappa monoclonal protein (M-spike) of 1.83 grams/dL. Bone marrow examination showed that 25% of the marrow cellularity consisted of plasma cells. Cytogenetic analysis was not performed. Blood studies showed: total calcium, 10.7 mg/dL; hemoglobin, 12.4 gm/dL; hematocrit, 33.7%; albumin, 3.6 gm/dL; and β2 microglobulin, 5.3 μg/mL. His 24-hour urine electrophoresis showed a total protein of 23.2 mg in 24 hours. The kappa free light chain was 69.7 mg/L, the lambda free light chain was 2.25 mg/L, and the kappa/lambda ratio was 31 (normal 0.26–1.65). Radiologic studies revealed diffuse osteopenia and lytic lesions in the humeri and the pelvic bones. This patient with newly diagnosed IgA K light chain multiple myeloma (ISS II, Durie-Salmon Staging III disease) was started on thalidomide and dexamethasone, to which bortezomib was subsequently added. The bone disease was treated with zoledronate and a repeat vertebroplasty, which ameliorated the patient’s back pain. He developed a mild peripheral neuropathy, but otherwise tolerated treatment well. After four cycles of therapy, serum protein electrophoresis and immunofixation failed to detect a paraprotein, and bone marrow examination failed to identify a clonal CD138-positive plasma cell population by either immunohistochemistry or flow cytometry. Cytogenetic analysis was normal. Six months following presentation the patient underwent autologous transplantation after conditioning with melphalan (200mg/m2) using stem cells obtained by mobilization with cyclophosphamide. The immediate post-transplantation course was uneventful. His only complaints were related to frequent upper respiratory and sinus infections, which responded well to levofloxacin. Monthly treatment with zoledronate was continued. Immunofixation studies performed 4, 8, and 10 months post-transplantation failed to detect a paraprotein, but did reveal low IgA levels ranging from 29 to 62 mg/dL. CBCs performed 4, 8, and 10 months post-transplantation showed stable peripheral blood counts. During this time interval, the WBC ranged from 4.1 to 6.0 x 103/μl, the hemoglobin level from 11.4 to 13.1 gm/dl, the hematocrit from 31.9% to 37.7%, and the platelet count from 126 to 139 x 103/μl. Other laboratory studies were within normal limits. The patient returned for a routine follow-up clinic visit 12 months post-transplantation. He felt well and had no complaints. There was no palpable organomegaly or lymphadenopathy. A CBC revealed a WBC of 7.3 x 103/μl, a hemoglobin level of 13.1 gm/dL, and hematocrit of 38.1%, and a platelet count of 138 x 103/μl. A routine surveillance bone marrow biopsy and aspirate revealed a slightly hypocellular marrow with a mild relative predominance of erythroid precursors, trilineage maturation, and scattered normal-appearing plasma cells; there was no eosinophilia or basophilia (Fig. 1). Cytogenetic analysis of aspirated marrow, sent to screen for abnormalities associated with multiple myeloma, showed the presence of a balanced translocation involving chromosomes 9 and 22 (the so-called Philadelphia chromosome) in 15 of 20 metaphases (Fig. 2A). Fluorescence in situ hybridization (FISH) with probes specific for BCR and ABL demonstrated the presence of a BCR-ABL fusion gene in 20 of 100 interphase nuclei scored (Fig. 2B). Figure 1 Bone marrow biopsy (40X, Wright Giemsa stain, 12 months after auto-transplantation for multiple myeloma). The marrow is slightly hypocellular and exhibits trilineage maturation and erythroid predominance; plasma cells are not increased in number. Figure 2 Detection of the t(9;22) and a BCR-ABL fusion gene. Cytogenetic and FISH analyses performed on a bone marrow aspirate obtained at the time of the biopsy shown in Figure 1 revealed the t(9;22) in metaphase chromosome spreads (A) and the presence of a ... Two weeks later, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis of peripheral blood revealed the presence of a chimeric BCR-ABL fusion mRNA transcript created by splicing of BCR exon 2 to ABL exon 2 (a b2/a2 fusion transcript). The level of the BCR-ABL fusion mRNA, relative to that of β-glucoronidase (GUS) mRNA, an internal housekeeping gene control, was 8.6%; by point of comparison, in this assay most patients presenting with chronic myelogenous leukemia (CML) have levels of 10% or greater. Because the significance of a BCR-ABL fusion gene in the absence of any clinical or pathologic evidence of hematologic malignancy was uncertain, an initial decision was made to follow the patient closely with serial CBCs and qRT-PCR analysis of BCR-ABL transcript levels. Four weeks later, the patient returned to the clinic feeling well, without weight loss, fever or other constitutional signs. The WBC was 5.7 x 103/μl, the hemoglobin level was 13 gm/dL, the hematocrit was 37.8%, and the platelet count was 136 x103/μl. However, the BCR-ABL B2/A2 fusion mRNA level in peripheral blood cells was increased to 52.2%, relative to the GUS internal mRNA control. DNA sequencing revealed that the ABL kinase coding domain of the fusion transcript matched the wild type sequence (not shown), and was therefore likely to encode a functional BCR-ABL kinase. Based on the rising BCR-ABL fusion mRNA levels, the patient was started on imatinib (Gleevec), 400 mg per day, 8 weeks after initial detection of BCR-ABL-positive cells. At the time of initiation of imatinib, the WBC was 6.7 x 103/μl, the hemoglobin was 13.3 gm/dL, the hematocrit was 37.5%, and the platelet count was 121 x 103/μl. Imatinib therapy was associated with mild periorbital edema, slightly loose bowel movements, occasional cramping of the hands and feet, and mild sustained decreases in the WBC and hemoglobin level, but was otherwise well tolerated. By six months of therapy, cytogenetic analysis revealed a normal 46, XY karyotype, and by 18 months of therapy a complete molecular response was achieved, as judged by a greater than 3-log drop in the level of the BCR-ABL fusion transcript (Fig. 3). As of this writing almost 3 years after the initial detection of the t(9;22), his “CML” and multiple myeloma remain in remission on Gleevec and zoledronate. Figure 3 BCR-ABL fusion transcript levels. Reverse-transcriptase polymerase chain reaction (RT-PCR) was used to detect and quantify the levels of BCR-ABL fusion transcripts, relative to an internal housekeeping control gene (GUS), at various points in the patient’s ...