scholarly journals Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study

Blood ◽  
2012 ◽  
Vol 119 (20) ◽  
pp. 4608-4613 ◽  
Author(s):  
Suzanne Lentzsch ◽  
Amy O'Sullivan ◽  
Ryan C. Kennedy ◽  
Mohammad Abbas ◽  
Lijun Dai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Response Rate ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Dose Escalation Study ◽  
Refractory Multiple Myeloma ◽  
One Year

Abstract This multicenter phase 1/2 trial investigated the combination of bendamustine, lenalidomide, and dexamethasone in repeating 4-week cycles as treatment for relapsed refractory multiple myeloma (MM). Phase 1 established maximum tolerated dose (MTD). Phase 2 assessed overall response rate at the MTD. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A total of 29 evaluable patients were enrolled. Median age was 63 years (range, 38-80 years). Median number of prior therapies was 3 (range, 1-6). MTD was bendamustine 75 mg/m2 (days 1 and 2), lenalidomide 10 mg (days 1-21), and dexamethasone 40 mg (weekly) of a 28-day cycle. Partial response rate was 52%, with very good partial response achieved in 24%, and minimal response in an additional 24% of patients. Median follow-up was 13 months; median OS has not been reached. One-year OS is 93% (95% confidence interval [CI], 59%-99%). Median PFS is 6.1 months (95% CI, 3.7-9.4 months) with one-year PFS of 20% (95% CI, 6%-41%). Grade 3/4 adverse events included neutropenia, thrombocytopenia, anemia, hyperglycemia, and fatigue. This first phase 1/2 trial testing bendamustine, lenalidomide, and dexamethasone as treatment of relapsed refractory MM was feasible and highly active. This study is registered at www.clinicaltrials.gov as #NCT01042704.

scholarly journals Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma

2021 ◽  
Vol 11 (2) ◽  
Author(s):  
Jacob P. Laubach ◽  
Sascha A. Tuchman ◽  
Jacalyn M. Rosenblatt ◽  
Constantine S. Mitsiades ◽  
Kathleen Colson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Dose Escalation Study ◽  
Refractory Multiple Myeloma ◽  
Duration Of Response ◽  
Label Dose ◽  
Grade 3

AbstractAdditional therapeutic options are needed for relapsed and refractory multiple myeloma (RRMM). We present data from a phase 1b, open-label, dose-escalation study (NCT01965353) of 20 patients with RRMM (median age: 63 years [range: 50–77]) and a median of four prior regimens (range: 2–14); 85% had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]). Patients received a median of six cycles (range: 1–74) of panobinostat (10 or 15 mg), lenalidomide 15 mg, bortezomib 1 mg/m2, and dexamethasone 20 mg (pano-RVd). Median follow-up was ~14 months. Six dose-limiting toxicities were reported (mostly hematological); maximum tolerated dose of panobinostat (primary endpoint) was 10 mg. Most common adverse events (AEs) were diarrhea (60%) and peripheral neuropathy (60%); all grade 1/2. Grade 3/4 AEs occurred in 80% of patients and included decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts, anemia (25%) and hypophosphatemia (25%). No treatment-related discontinuations or mortality occurred. In evaluable patients (n = 18), overall response rate was 44%, and clinical benefit rate was 61%. Median duration of response was 9.2 months; progression-free survival was 7.4 months; overall survival was not reached. Pano-RVd proved generally well-tolerated and demonstrated potential to overcome lenalidomide and/or bortezomib resistance.

Efficacy of Single-Agent Bortezomib Versus Thalidomide in Patients with Relapsed or Refractory Multiple Myeloma: A Systematic Review.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5160-5160
Author(s):  
Miles Prince ◽  
Michael Adena ◽  
Dell Kingsford Smith ◽  
Judy Hertel
Keyword(s):  
Systematic Review ◽  
Multiple Myeloma ◽  
Response Rate ◽  
English Literature ◽  
Progression Free Survival ◽  
Cochrane Library ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
One Year ◽  
Intent To Treat

Abstract Aim: To perform a systematic review of the efficacy of monotherapy with bortezomib versus thalidomide in patients with relapsed or refractory multiple myeloma. Methods: Published English literature from 1966 to June 2005 (MEDLINE, EMBASE, Cochrane library), publication reference lists, Janssen-Cilag Pty Ltd data-on-file, and abstracts from recent multiple myeloma conferences were reviewed. Prospective studies containing at least a single arm of any treatment group with n ≥ 30 and using continuing or variable thalidomide dosing were included. Studies adding dexamethasone for non-responders were excluded. Outcomes were analysed on an intent-to-treat basis. Statistical pooling was performed where possible for the following outcome measures: primary outcome of response rate, defined by a serum M-protein reduction ≥50% (A) and strict (e.g. EBMT) criteria (B), and for the secondary outcomes of overall survival and progression-free survival. Results: One bortezomib (n=333, APEX, NEJM2005, 352; 2487–98) and 15 thalidomide (n=1007) studies were included. Patient baseline characteristics including age, gender, IgG:IgA, disease duration and β2M were well matched, except that 48% of bortezomib patients had received prior thalidomide. On an intent-to-treat basis, the overall estimate for response rate (A) was 53% for patients receiving bortezomib versus 32% for thalidomide (p<0.001, n=10 studies). For response rate (B) the estimate was 36% for patients receiving bortezomib versus 22% for thalidomide (p<0.001, n=4 studies). One-year survival was 81% for patients receiving bortezomib versus 67% for thalidomide (p<0.001, n=6 studies). Due to differences in disease monitoring and definitions of progression, it was not possible to compare results for progression-free survival. Conclusion: In patients with relapsed or refractory multiple myeloma, bortezomib achieved significantly higher response rates and longer one-year survival than thalidomide, despite 48% of bortezomib-treated patients having received prior thalidomide.

Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma

Blood ◽  
2006 ◽  
Vol 109 (7) ◽  
pp. 2767-2772 ◽  
Author(s):  
Antonio Palumbo ◽  
Maria Teresa Ambrosini ◽  
Giulia Benevolo ◽  
Patrizia Pregno ◽  
Norbert Pescosta ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Response Rate ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Free Survival ◽  
Grade 3 ◽  
Dose Levels ◽  
Initial Results

AbstractIn multiple myeloma (MM), the addition of thalidomide or bortezomib to the standard oral melphalan/prednisone combination significantly increased response rate and event-free survival. In this multicenter phase 1/2 trial, dosing, safety, and efficacy of the 4-drug combination, bortezomib, melphalan, prednisone, and thalidomide (VMPT) was determined. Bortezomib was administered at 3 dose levels (1.0 mg/m2, 1.3 mg/m2, or 1.6 mg/m2) on days 1, 4, 15, and 22; melphalan was given at a dose of 6 mg/m2 on days 1 through 5 and prednisone at 60 mg/m2 on days 1 through 5. Thalidomide was delivered at 50 mg on days 1 through 35. Each course was repeated every 35 days. The maximum tolerated dose of bortezomib was 1.3 mg/m2. Thirty patients with relapsed or refractory MM were enrolled; 20 patients (67%) achieved a partial response (PR) including 13 patients (43%) who achieved at least a very good PR. Among 14 patients who received VMPT as second-line treatment, the PR rate was 79% and the immunofixation-negative complete response rate 36%. The 1-year progression-free survival was 61%, and the 1-year survival from study entry was 84%. Grade 3 nonhematologic adverse events included infections (5 patients), fatigue (1), vasculitis (1), and peripheral neuropathy (2); no grade 4 toxicities were recorded. Initial results showed that VMPT is an effective salvage therapy with a very high proportion of responses. The incidence of neurotoxicities was unexpectedly low.

Phase I/II Trial Assessing Bortezomib and Melphalan Combination Therapy for the Treatment of Patients With Relapsed or Refractory Multiple Myeloma

2006 ◽  
Vol 24 (6) ◽  
pp. 937-944 ◽  
Author(s):  
James R. Berenson ◽  
Hank H. Yang ◽  
Karen Sadler ◽  
Supol G. Jarutirasarn ◽  
Robert A. Vescio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Free Survival ◽  
Dose Cohort ◽  
Refractory Multiple Myeloma ◽  
Promising Treatment ◽  
Grade 3 ◽  
Dose Limiting Toxicity

Purpose Bortezomib has shown synergy with melphalan in preclinical models. We assessed the safety, tolerability, and response rate in a dose-escalation study of this combination for relapsed or refractory multiple myeloma patients. Methods Bortezomib was administered from 0.7 to 1.0 mg/m2 on days 1, 4, 8, and 11 of a 28-day cycle for up to eight cycles. Oral melphalan was administered in escalating doses from 0.025 to 0.25 mg/kg on days 1 to 4. Results Thirty-five patients with relapsed or refractory myeloma were enrolled, 34 of whom were assessable for response. Dose-limiting toxicity of grade 4 neutropenia in two of six patients in the highest dose cohort led to the assignment of bortezomib 1.0 mg/m2 and melphalan 0.10 mg/kg as the maximum-tolerated dose (MTD). Responses (minimal [MR], partial [PR], or complete [CR]) occurred in 23 of 34 patients (68%), including two CRs (6%), three immunofixation-positive CRs (9%), 11 PRs (32%), and seven MRs (21%). Responses were observed in five of six assessable patients (83%) at the MTD. Median progression-free survival for all patients was 8 months (range, 2 to 18 months). Grade ≥ 3 toxicities were related mostly to myelosuppression. Among the 15 patients with grade 1/2 neuropathy at baseline, it resolved during treatment in one, worsened in four, and remained stable in 10 patients. Eight other patients developed grade 1/2 neuropathy during the study. Conclusion Bortezomib plus melphalan given on a 28-day schedule showed encouraging activity with manageable toxicity and represents a promising treatment for myeloma patients.

Phase 1 open label trial of intraperitoneal paclitaxel (IPP) in combination with intravenous cisplatin (C) and oral capecitabine (X) in patients with advanced gastric cancer and peritoneal metastases.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4061-4061
Author(s):  
Sina Vatandoust ◽  
Tim F Bright ◽  
M Nazim Abbas ◽  
Amitesh Chandra Roy ◽  
David I. Watson ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Survival Data ◽  
Response Rate ◽  
Standard Dose ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Phase 2 ◽  
Open Label ◽  
Genetic Pool

4061 Background: IPP is a potential treatment option in patients with gastric cancer with peritoneal metastasis. IPP with a dose of 20 mg/m2 is well tolerated in combination with S1; however, this has been achieved in a specific genetic pool (Japanese population), and S1 is not available in some countries. We investigated the Maximum Tolerated Dose (MTD) of IPP in addition to a standard chemotherapy combination in an Australian population. Methods: Study population included synchronous or metachronous metastatic HER-2 non-amplified gastric adenocarcinoma with histologically/cytologically proven peritoneal involvement and adequate organ function. Intra-peritoneal catheter was placed surgically. 3 + 3 standard dose-escalation design was used. MTD was defined as the highest dose level at which ≤ 33% of patients had Dose Limiting Toxicity (DLT). DLT was defined within the first 3 cycles. Recommended Phase-2 Dose was defined as equal to the MTD, or cohort-3 dose if MTD was not reached. Treatment: maximum of six 21-day cycles of C (80mg/m2 IV day 1) + X (1000mg/m2 PO BD days 1-14) + IPP (days 1 and 8). IPP doses for Cohort-1, 2 and 3 were 10, 20 and 30mg/m2 respectively. Primary endpoint was the MTD of IPP. Secondary endpoints included safety, tolerability, overall response rate, ascites response rate, progression free survival and overall survival. Results: 15 patients were recruited in 3 cohorts: 9 males (60%), median age at study entry: 61y (range 32-82). All had synchronous metastatic disease and were chemo-naïve. Cohort-1 expanded to 6 patients due to 1 DLT (grade 3 diarrhea), cohort-2 included 3 patients (no DLT) and cohort-3 was expanded to 6 patients as planned and 1 DLT occurred (febrile neutropenia). MTD was not reached and Recommended Phase 2 Dose was determined as 30mg/m2. 8 patients (53%) completed all 6 cycles of treatment. The last patient on the study has completed 3 cycles and is expected to complete 6 cycles by April 2019. No grade 4 or 5 toxicity was recorded. Conclusions: MTD of IPP was not reached. IPP is safe in combination with C + X and the Recommended Phase 2 Dose is 30 mg/m2. Survival data will be presented when available. Clinical trial information: ACTRN12614001063606.

scholarly journals A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma

Blood ◽  
2012 ◽  
Vol 120 (3) ◽  
pp. 552-559 ◽  
Author(s):  
Jeffrey A. Zonder ◽  
Ann F. Mohrbacher ◽  
Seema Singhal ◽  
Frits van Rhee ◽  
William I. Bensinger ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Stable Disease ◽  
Plasma Cells ◽  
Phase 1 ◽  
Human Study ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose

Abstract This multicenter, first-in-human study evaluated the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of the anti-CS1 monoclonal antibody elotuzumab. A standard 3 + 3 design was used to determine maximum tolerated dose; dose-limiting toxicities were assessed during cycle 1. Thirty-five patients with relapsed/refractory multiple myeloma were treated with intravenous elotuzumab at doses ranging from 0.5 to 20 mg/kg every 2 weeks. Patients who achieved at least stable disease after 4 treatments could receive another 4 treatments. No maximum tolerated dose was identified up to the maximum planned dose of 20 mg/kg. The most common adverse events, regardless of attribution, were cough, headache, back pain, fever, and chills. Adverse events were generally mild to moderate in severity, and adverse events attributed to study medication were primarily infusion-related. Plasma elotuzumab levels and terminal half-life increased with dose whereas clearance decreased, suggesting target-mediated clearance. CS1 on bone marrow–derived plasma cells was reliably saturated (≥ 95%) at the 10-mg/kg and 20-mg/kg dose levels. Using the European Group for Bone and Marrow Transplantation myeloma response criteria, 9 patients (26.5%) had stable disease. In summary, elotuzumab was generally well tolerated in this population, justifying further exploration of this agent in combination regimens.

A phase 1, open-label, dose-escalation study of pralatrexate in combination with bortezomib in patients with relapsed/refractory multiple myeloma

2016 ◽  
Vol 173 (2) ◽  
pp. 253-259
Author(s):  
Tamara J. Dunn ◽  
Shira Dinner ◽  
Elizabeth Price ◽  
Steven E. Coutré ◽  
Jason Gotlib ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Escalation ◽  
Phase 1 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Refractory Multiple Myeloma ◽  
Label Dose

scholarly journals A phase 2, open-label, multicenter study of ixazomib plus lenalidomide and dexamethasone in adult Japanese patients with relapsed and/or refractory multiple myeloma

2021 ◽  
Author(s):  
Shinsuke Iida ◽  
Tohru Izumi ◽  
Takuya Komeno ◽  
Yasuhito Terui ◽  
Takaaki Chou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Confidence Interval ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Japanese Patients ◽  
Open Label ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Good Partial Response

Abstract Background TOURMALINE-MM1 was a global study that demonstrated a significant improvement in progression-free survival with ixazomib plus lenalidomide and dexamethasone compared with placebo plus lenalidomide and dexamethasone, in patients with relapsed and/or refractory multiple myeloma. The current study was conducted to evaluate further the efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients. Methods This phase 2, open-label, single-arm, multicenter study enrolled patients aged ≥ 20 years with relapsed and/or refractory multiple myeloma at 16 sites in Japan. Patients refractory to lenalidomide or proteasome inhibitor-based therapy at any line were excluded. The primary endpoint was the rate of very good partial response or better in the response-evaluable analysis set. Secondary endpoints were progression-free survival, overall response rate, duration of response, time to progression, overall survival and safety. Results In total, 34 patients were enrolled. The rate of very good partial response or better was 50.0% (95% confidence interval 31.9–68.1) and the overall response rate was 84.4% (95% confidence interval 67.2–94.7). Median progression-free survival was 22.0 months (95% confidence interval 17.3–not evaluable) and median overall survival was not estimable. The safety profile of ixazomib plus lenalidomide and dexamethasone in this study was similar to that in the TOURMALINE-MM1 study. Conclusions The efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients with relapsed and/or refractory multiple myeloma are comparable with reported TOURMALINE-MM1 study results. Clinicaltrials.gov identifier NCT02917941; date of registration September 28, 2016.

scholarly journals An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma

Blood ◽  
2012 ◽  
Vol 119 (24) ◽  
pp. 5661-5670 ◽  
Author(s):  
Ravi Vij ◽  
Michael Wang ◽  
Jonathan L. Kaufman ◽  
Sagar Lonial ◽  
Andrzej J. Jakubowiak ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase 1 ◽  
Single Agent ◽  
Phase 2 ◽  
Open Label ◽  
Refractory Multiple Myeloma ◽  
Overall Response ◽  
To Receive

Abstract Carfilzomib is a selective proteasome inhibitor that binds irreversibly to its target. In phase 1 studies, carfilzomib elicited promising responses and an acceptable toxicity profile in patients with relapsed and/or refractory multiple myeloma (R/R MM). In the present phase 2, multicenter, open-label study, 129 bortezomib-naive patients with R/R MM (median of 2 prior therapies) were separated into Cohort 1, scheduled to receive intravenous carfilzomib 20 mg/m2 for all treatment cycles, and Cohort 2, scheduled to receive 20 mg/m2 for cycle 1 and then 27 mg/m2 for all subsequent cycles. The primary end point was an overall response rate (≥ partial response) of 42.4% in Cohort 1 and 52.2% in Cohort 2. The clinical benefit response (overall response rate + minimal response) was 59.3% and 64.2% in Cohorts 1 and 2, respectively. Median duration of response was 13.1 months and not reached, and median time to progression was 8.3 months and not reached, respectively. The most common treatment-emergent adverse events were fatigue (62.0%) and nausea (48.8%). Single-agent carfilzomib elicited a low incidence of peripheral neuropathy—17.1% overall (1 grade 3; no grade 4)—in these pretreated bortezomib-naive patients. The results of the present study support the use of carfilzomib in R/R MM patients. This trial is registered at www.clinicaltrials.gov as NCT00530816.

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