Molecular Quantification of Pre-Treatment Bone Marrow Clonal Cells in Multiple Myeloma Is a Novel Predictive Indicator of Remission Length.
Bibliographic record
Abstract
Abstract Multiple myeloma (MM) is a clonal B-cell malignancy with an accumulation of plasma cells in the bone marrow (BM). Newer treatments continue to increase remission occurrence and decrease side effects, however, relapse invariably occurs. Current diagnostic and monitoring criteria such as bone marrow plasmacytosis (BMPC) and serum M-protein levels (Mpr) fail to predict the length of remission for a given patient. The clonal IgH VDJ gene rearrangement provides a molecular method of measuring the MM disease burden. This unique biomarker can identify and quantify the number of malignant cells through analysis of genomic DNA with quantitative PCR. Here we use SYBR Green real-time quantitative PCR (rqPCR) to measure the level of clonal cells, termed VDJ%, in 91 previously untreated and 51 relapsed pre-treatment BM aspirates from MM patients. Kaplan-Meier analysis showed that VDJ%s lower than the median were associated with longer event free survivals (EFSs) (p=0.0077, HR=0.57). These patients were treated with a variety of different regimens (including VAD, ASCT, Melphalan, Prednisone, Thalidomide, Dexamethasone, Velcade or Revlimid). A modest correlation between the VDJ% and the BMPC was observed (p=0.0003, r2=0.099) but, the BMPC was not able to stratify these patients into groups with significantly different EFSs (p=0.1153, HR=0.6521) as was the VDJ%. This result confirms the BMPC’s poor association with outcome. The Mpr was not significantly correlated with VDJ% (p=2312, r2=0.012). The IMWG response subcategories correlated well with EFS where the poorer the response the shorter the EFS. However, there was no significant correlation between the pre-treatment VDJ% and the response subcategories. In addition to the pre-treatment BM samples, the tumor burden in 30 remission BM samples was quantified. To date, neither the remission VDJ% nor the reduction in VDJ% relative to the pre-treatment VDJ% was associated with EFS in a Kaplan-Meier analysis. The remission VDJ% had a significant yet modest correlation with the remission BMPC (p=0.014, r2=0.27) and nadir Mpr (p=0.0001, r2=0.61). Additionally, the IMWG response subcategory correlated with the proportionate reduction of the remission BM (p=0.036). Taken together these results indicate that VDJ% in pre-treatment BMs, but not the matched BMPC or Mpr, is a significant measure of outcome. The percent of clonal cells as measured in BM aspirates with rqPCR could be developed as a novel tool for predicting outcome by placing patients into a high risk or low risk category for EFS. Patients with a higher than median VDJ% have a shorter EFS than patients with a VDJ% below the median. RqPCR enumerates all cells containing the clonal sequence and thus may include relevant cells types not counted in the BMPC or reflected in the protein electrophoresis and not proportionally represented in remission BMs. The predictive value of pre-treatment VDJ% occurred despite varying types of therapy and tumor response, suggesting that these factors might provide independent prognostic information.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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 | 0.001 |
| 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".