Early Normalization of Serum Free Light Chain Is Associated with Prolonged Time to Progression Following Bortezomib ± Pegylated Liposomal Doxorubicin Treatment of Relapsed/Refractory Multiple Myeloma.
Bibliographic record
Abstract
Abstract Multiple myeloma (MM), like other monoclonal gammopathies, frequently causes impairment of the κ/λ serum free light chain (sFLC) ratio. Based on a short serum half-life of FLC as compared to the complete immunoglobulin (hours versus days), early normalization of κ/λ could predict for response to treatment. As part of a randomized, controlled study, we examined the association between normalization of the κ/λ ratio after one or two 21-day cycles of treatment with bortezomib (B) ± pegylated liposomal doxorubicin (PLD) among patients with relapsed/refractory multiple myeloma. Patients with ≥1 prior therapy were randomized to receive PLD 30 mg/m2 on day 4 and B 1.3 mg/m2 on days 1, 4, 8, and 11, or B alone for up to eight 21-day cycles, or at least 2 cycles beyond complete response (CR) or optimal response, unless disease progression or unacceptable toxicities occurred (Orlowski, JCO 2007). κ/λ measurements were carried out prior to the start of therapy and at the end of each cycle through the entire study period using an immunoassay (Freelite, The Binding Sites, Birmingham, UK). Serial sFLC κ/λ measurements were available on sera from 487 patients with baseline values out of a total of 646 study patients. At baseline, 458/487 patients (94%) had an abnormal κ/λ ratio (<0.26 or >1.65). The percentage of patients with normal κ/λ ratio increased from 6% at baseline to 12% after cycle 1, 17% after cycle 2 and 23% by the end of the study. Among patients with a normal κ/λ ratio after cycle 1 (n=54), the median time to progression (TTP) was 345 days compared to 225 days in patients with abnormal ratios (n=395, p=0.0005, HR=0.47 favoring normalization). Following cycle 2, TTP was 325 days vs. 224 days (p≤0.001) in patients with normal (n=72) vs. abnormal (n=348) ratios, respectively. Additionally, patients with normalized sFLC ratios showed significantly higher overall response rates as compared to those with persistently abnormal ratios (≥ partial response [PR] 73% vs. 47%, p=0.001 following cycle 1, and 77% vs. 48%, p<0.0001 following cycle 2, respectively). Similarly, CR + very good PR rates were significantly higher among patients with normalized sFLC ratios after cycles 1 and 2 (p<0.0001 and p<0.001 respectively). As reported previously, both treatments, B + PLD and B alone, were well tolerated (Orlowski, JCO 2007). Normalization of the sFLC ratio as early as after cycle 1 of B + PLD, or B alone, was associated with a prolonged TTP and higher response rates. Additional analyses are undertaken to evaluate whether Freelite data: predict treatment outcome earlier than electrophoresis, and correlate with 24-hour urine M-protein.
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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 | 0.002 |
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".