Frequent Gains of Chromosome Arm 1q21 in Plasma Cell Dyscrasia Detected by Fluorescence In Situ Hybridization: Incidence Increases from MGUS to Relapsed Myeloma and Is Related to Disease Progression and Prognosis.

Background: High-dose therapy with autologous stem cell transplantation (HDT-ASCT), effecting complete remissions in > 40% with median overall survival exceeding 6 years, has become the standard of care for patients with multiple myeloma (MM). Poor outcome following HDT-ASCT has been linked most strongly to metaphase cytogenetic abnormalities (CA). Tandem duplications and jumping translocations of the chromosome 1q21 region is a recurrent event in advanced MM and 1q21 amplification (amp1q21) and high expression of the CKS1B gene (mapping to 1q21), both signify poor survival in MM treated with HDT-ASCT. Smoldering multiple myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS) have many of the genetic hallmarks of overt MM, but especially MGUS rarely proceeds to MM requiring treatment. The aim of this study was determine if amp1q21 relates to disease progression and prognosis.

Patients and Methods: 467 untreated patients with MGUS (n = 14), SMM (n = 32) and MM (n = 421) as well as 42 with relapsed MM were examined by means of triple color interphase fluorescence in situ hybridization (TRI-FISH) of the CKS1B locus.

Results: The frequency of ampq21 was 0% in 14 patients with MGUS, 43% in 32 with SMM, 43% in 421 with newly diagnosed MM and 78% in 42 with relapsed MM (p<0.001; untreated vs relapsed MM). Among SMM patients, 11 of 14 (78%) with amp1q21 but only 2 of 18 (11%) without amp1q21 progressed to active MM (p<0.001) (median follow-up, 44 mo; range, 0–120 mo). In 421 MM patients treated on Total Therapy 2 (high-dose melphalan-based tandem autotransplants +/− thalidomide), 5-yr overall survival/event-free survival were 75%/61% in without amp1q21 compared to 48%/34% with amp1q21 (both p<0.001). Among 42 relapses, amp1q21 was present in 20/21 occurring on thalidomide vs 13/21 on no thalidomide (p=0.020); the median post-relapse survival in those with amp1q21 was only 11 mo vs 25 mo in patients without amp1q21 (p=0.02).

Conclusion: (1) Amp1q21 was absent in MGUS and present in >40% of symptomatic MM and SMM. (2) in SMM, amp1q21 was associated with a higher risk of conversion to MM. (3) In overt MM, amp1q21 conferred inferior event-free and overall survival.