A Phase I–II Trial of Bortezomib (Velcade) (Vc) and Oral Cyclophosphamide (CY) Plus Prednisone (P) for Relapsed/Refractory Multiple Myeloma (MM).
Bibliographic record
Abstract
Abstract We have previously reported that a simple, well-tolerated regimen of weekly oral CY (500mg) and alternate day prednisone (50–100mg) produced partial responses (PR) in 40% of 56 patients (pts) in relapse after ASCT; median progression-free survival was 18.6 months (Blood2004; 104[11]: 311b). To build upon these favorable results, we have designed an ongoing phase I–II trial adding Vc to this regimen. CY was given p.o. once weekly on days 1,8,15 and 22 of each 28 day cycle while prednisone was given every other morning. CY was given before Vc on appropriate days. A maximum of 8 cycles was administered. Sixteen pts have been entered so far. Patients characteristics: Median age was 59 (48–74) years; 9 were male. The Ig subtypes were: IgG kappa:lambda = 9:2, IgA kappa:lambda = 1:2; kappa light chain = 2. All had received VAD, i.v. CY (2.5 g/m2) + G-CSF mobilization followed by ASCT and 2 had undergone a second ASCT; other prior regimens included melphalan and prednisone in 5 pts, thalidomide in 10, lenalidomide in 1, α-interferon in 3, vaccine therapy in 1 and oral CY + P in 8. The median pretreament ß2-microglobulin level was 279 (147 – 875) nm/L, albumin 39 (30–42) g/L and creatinine 91 (60–112) umol/L. The dose escalation schedule to date is as follows: Dose Level N P dose CY dose (mg/m2) Vc dose (mg/m2) 1 6 100 150 0.7 d 1,8,15 2 3 100 300 0.7 d 1,8,15 3 3 100 300 1.0 d 1,8,15 4 4 100 300 1.0 d 1,4,8,11 Three further dose escalations to a maximum Vc dose of 1.5 mg/m2 days 1,8, and 15 are allowed if dose limiting toxicity does not occur. Toxicities during cycle 1: All pts have completed cycle 1. Three episodes of grade (gr) 3 sinopulmonary infection occurred during a community outbreak at dose level 1; levofloxacin prophylaxis during the first cycle was added and no further infections during the initial cycle were observed. One pt at dose level 3 experienced transient gr 4 hypophosphatemia which reversed without therapy. At dose level 4, cycle 1 was interrupted in one pt due to gr 4 leukopenia (gr 3 neutropenia and thrombocytopenia) related to disease, while a second pt developed grade 4 elevation in transaminases which recovered quickly when Vc was held on d 8. Pt accrual continues. Toxicities of subsequent cycles: To date, 47 additional cycles have been given. SAE’s consisted of pneumonia during cycle 2 in the same 3 patients with infection during cycle 1 and one of these with progressive disease had another bout during cycle 3. Gr 3 toxicities included anemia in 2 cycles, leucopenia in 2, neutropenia in 4, hypophosphatemia in 1 and hyperglycemia in 2; reversible gr 4 hypophosphatemia recurred in the pt mentioned above in 1 other cycle. No liver or other organ toxicity was observed. Maximum gr of peripheral neuropathy was 1. Responses: Responses were assessed after cycles 2, 4, 6 and 8. Best response included near CR (1), PR (4), MR (4), stable disease (5), progression (1) and too early (1). Two pts have completed all 8 cycles, while 4 have progressed; 10 remain on study. Preliminary Conclusions: 1) Vc can be added to a continuous program of oral CY + P with acceptable hematologic toxicity; 2) no neurotoxicity > gr 1 has been observed; 3) the maximum tolerated dose (MTD) of this combination regimen has not yet been defined; 4) future plans include a randomized National Cancer Institute of Canada trial comparing the the MTD of this combination to Vc in relpased MM pts.
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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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".