Clinical Features of Patients with Multiple Myeloma and C-MYC Rearrangements

The proto-oncogene c-MYC encodes a transcription factor that regulates cell proliferation, growth, and apoptosis. c-MYC is located on the long arm of chromosome 8 (8q24.1) and its rearrangement has been reported in 15% of myeloma patients independent of the disease stage (Avet-Loiseau et al. Blood 2001). However, the clinical significance of c-MYC rearrangement is not well described. Here we report the characteristics and outcome of 7 myeloma patients with c-MYC rearrangements that were treated at our institution.

Between July 2007 and May 2011, we identified 7 patients (4 males, 3 females) who had c-MYC rearrangements on fluorescence in situ hybridization (FISH) analyses at the time of diagnosis. The primary objective of this study was to describe the patient characteristics, response to therapy, time to progression (TTP), and overall survival (OS).

Median age at diagnosis was 58 years (49–72). There were 4 Caucasians, 2 African-Americans and 1 Asian. International Staging System stage was I, II, and III in 3, 2, and 2 patients, respectively. Two patients had serum creatinine of ≥2 mg/dL as well as Hgb ≤10 g/dL, two other patients had hypercalcemia at diagnosis. Six (85%) patients had myelomatous bone lesions at diagnosis. Plasma cell counts in bone marrows ranged from 20%-78%, with a mean of 51%. Abnormalities involving chromosome 8q24.1, the c-MYC locus, were detected on conventional cytogenetics in all 7 patients, including t(8;14)(q24.1) in 3 cases, a t(2;8)(p12;q24.1), a variant of the t(8;14), in 2 cases, and an abnormal chromosome 8 with unknown material attached to the 8q24.1 region confirmed by FISH in two cases. This is in contrast to an earlier report where only 25% of patients with c-MYC rearrangement on FISH had corresponding cytogenetic abnormalities. Three patients also had a del(13)(q14.1)/RB1, one of whom also had a del(17)(p13)/TP53, while two other patients had t(11;14)(q13;q32) involving CCND1-XT/IGH rearrangements. Six patients (85%) received induction with a bortezomib+ dexamethasone regimen, and one patient received thalidomide+ dexamethasone. Five patients achieved a partial (PR) or very good partial remission (VGPR) to induction, while 2 patients had <PR, with an overall response rate of 71%. Four patients went on to receive high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT). Three of these patients were in first remission, while one patient progressed prior to auto-HCT. Median follow up in all patients was 17.7 months (range 2.6–22.4). Two patients progressed at 4.4 and 4.5 months after the start of induction therapy, and 2 more patients progressed after auto-HCT, 14.4 and 16.1 months after the start of induction. Median TTP was 14.4 months, and median OS was 20.2 months. The TTP and OS appear to be shorter than what has been reported for standard-risk myeloma patients (24 and 72 months, respectively).

This is the first report describing clinical characteristics of myeloma patients with c-MYC rearrangements. All 7 patients had concurrent translocations involving chromosome 8q24 on conventional cytogenetics, and had a shorter TTP and OS than our historical data. The role of c-MYC rearrangement in myeloma needs to be explored in prospective studies.

No relevant conflicts of interest to declare.