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.
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".