T(4;14) Positive Multiple Myeloma Is Chemosensitive to Dexamethasone and/or Thalidomide but Not Alkylating Agents: Rapid Relapse and Not Primary Drug Resistance Explains Poor Outcomes.

Abstract

The t(4;14) simultaneously dysregulates expression of fibroblast growth factor receptor 3 (FGFR-3) and MMSET and has been detected in 15% of MM patients. Despite being an early event in the genesis of clonal gammopathy the t(4;14) is somewhat surprisingly reported as a poor prognostic factor in patients treated with both conventional chemotherapy and those undergoing autologous stem cell transplantation (ASCT). Presumably either primary drug resistance or, alternatively, rapid relapse following treatment must explain this outcome. To address this clinical issue we analyzed 128 patients who were treated with induction chemotherapy followed by melphalan 200 mg/m2 at our institution between 1998–2000. Using FISH analysis we identified 16 of these patients with a t(4;14). These patients had a predominance of the IgA isotype (56.3%) compared with t(4;14) negative patients (17.7%) (p = 0.0019). Otherwise baseline characteristics including sex, age, B-2 microglobulin, CRP, calcium, creatinine, Hb, albumin or percentage of bone marrow plasma cells were indistinguishable from the general MM poulation. Fifteen t(4;14) patients received induction chemotherapy with 4–5 cycles of vincristine, adriamycin and dexamethasone(VAD) with one receiving pulsed dexamethasone alone. Thirteen of the sixteen (81%) responded with > 50% paraprotein decrease. However 3 of these 13 patients demonstrated early progression of disease during later cycles of VAD or during stem cell collection and required further salvage prior to ASCT. Use of high dose melphalan and ASCT resulted in a further 54% of patients achieving a >50% paraprotein decrease with a mean paraprotein reduction of 49% (range 0–99%). Nevertheless the median progression free survival (PFS) post ASCT was only 9.9 months, significantly shorter than for t(4;14) negative patients (p=0.0001). Given the surprisingly short PFS following high dose alkylating agents we next examined all salvage regimens employed. Ten patients at some point received a conventional dose alkylating agent as salvage (cyclophosphamide or melphalan). Response was dismal with stable disease in 6 patients and progressive disease in 4 patients. In contrast 14 patients at some point received salvage thalidomide or high dose dexamethasone either as a single agent or in combination. Five patients demonstrated a partial response (>50–90% reduction), 4 patients a minor response and 5 patients had stable disease for an overall response rate of 64%. Two patients treated with Bortezomib demonstrated partial responses. We conclude from this preliminary analysis that t(4;14)+ve MM is poorly responsive to alkylating agents, including high dose melphalan and thus that use of these agents (including ASCT) is generally of no long term value in this patient population. Given the high response rates of 81% at induction and 64% at salvage, induction and maintenance regimens containing high dose dexamethasone and/or thalidomide are favored. Nevertheless, since response to these agents is often short lived novel therapeutic regimens are required. In this regard the early clinical study of targeted FGFR-3 tyrosine kinase inhibitors which have shown pre-clinical promise is encouraged.