Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 113
Filter
Add more filters

Country/Region as subject
Publication year range
1.
Am J Hematol ; 96(5): 552-560, 2021 05 01.
Article in English | MEDLINE | ID: mdl-33650179

ABSTRACT

The MCRN-003/CCTGMYX.1 is a single arm phase II trial of weekly carfilzomib, cyclophosphamide and dexamethasone (wKCd), exploring a convenient immunomodulator (IMiD)-free regimen in relapsed myeloma. Weekly carfilzomib (20/70 mg/m2 ), dexamethasone 40 mg and cyclophosphamide 300 mg/m2 was delivered over 28-day cycles. The primary endpoint was overall response after four cycles. Secondary endpoints included toxicity, response depth, PFS and OS. Exploratory endpoints included the impact of cytogenetics, prior therapy exposure and serum free light chain (sFLC) escape; 76 patients were accrued. The ORR was 85% (68% ≥very good partial response [VGPR] and 29% ≥complete response [CR]). The median OS and PFS were 27 and 17 months respectively. High-risk cytogenetics conferred a worse ORR (75% vs. 97%, p = .013) and median OS (18 months vs. NR, p = .002) with a trend toward a worse median PFS (14 vs. 22 months, p = .06). Prior proteasome inhibitor (PI) or lenalidomide did not influence OS or PFS. The sFLC was noted in 15% of patients with a median PFS of 17 months when included as a progression event. The most common ≥ grade 3 non-hematologic adverse events were infectious (40%), vascular (17%) and cardiac (15%). The wKCD is a safe and effective regimen in relapse, especially for patients ineligible for lenalidomide-based therapies.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Multiple Myeloma/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cardiovascular Diseases/chemically induced , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Drug Administration Schedule , Dyspnea/chemically induced , Female , Hematologic Diseases/chemically induced , Humans , Infections/etiology , Kaplan-Meier Estimate , Male , Middle Aged , Multiple Myeloma/genetics , Myeloma Proteins/analysis , Oligopeptides/administration & dosage , Oligopeptides/adverse effects , Patient Selection , Prognosis , Progression-Free Survival , Recurrence , Salvage Therapy , Treatment Outcome
2.
Blood ; 131(3): 301-310, 2018 01 18.
Article in English | MEDLINE | ID: mdl-29150421

ABSTRACT

This FIRST trial final analysis examined survival outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with lenalidomide and low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). The primary endpoint was progression-free survival (PFS; primary comparison: Rd continuous vs MPT). Overall survival (OS) was a key secondary endpoint (final analysis prespecified ≥60 months' follow-up). Patients were randomized to Rd continuous (n = 535), Rd18 (n = 541), or MPT (n = 547). At a median follow-up of 67 months, PFS was significantly longer with Rd continuous vs MPT (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.59-0.79; P < .00001) and was similarly extended vs Rd18. Median OS was 10 months longer with Rd continuous vs MPT (59.1 vs 49.1 months; HR, 0.78; 95% CI, 0.67-0.92; P = .0023), and similar with Rd18 (62.3 months). In patients achieving complete or very good partial responses, Rd continuous had an ≈30-month longer median time to next treatment vs Rd18 (69.5 vs 39.9 months). Over half of all patients who received second-line treatment were given a bortezomib-based therapy. Second-line outcomes were improved in patients receiving bortezomib after Rd continuous and Rd18 vs after MPT. No new safety concerns, including risk for secondary malignancies, were observed. Treatment with Rd continuous significantly improved survival outcomes vs MPT, supporting Rd continuous as a standard of care for patients with transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as #NCT00689936 and EudraCT as 2007-004823-39.


Subject(s)
Antineoplastic Agents/therapeutic use , Multiple Myeloma/drug therapy , Antineoplastic Agents/adverse effects , Humans , Progression-Free Survival , Survival Analysis , Treatment Outcome
3.
Oncologist ; 23(3): 279-287, 2018 03.
Article in English | MEDLINE | ID: mdl-29192016

ABSTRACT

BACKGROUND: Daratumumab (a human CD38-directed monoclonal antibody) and pomalidomide (an immunomodulatory drug) plus dexamethasone are both relatively new treatment options for patients with heavily pretreated multiple myeloma. A matching adjusted indirect comparison (MAIC) was used to compare absolute treatment effects of daratumumab versus pomalidomide + low-dose dexamethasone (LoDex; 40 mg) on overall survival (OS), while adjusting for differences between the trial populations. MATERIALS AND METHODS: The MAIC method reduces the risk of bias associated with naïve indirect comparisons. Data from 148 patients receiving daratumumab (16 mg/kg), pooled from the GEN501 and SIRIUS studies, were compared separately with data from patients receiving pomalidomide + LoDex in the MM-003 and STRATUS studies. RESULTS: The MAIC-adjusted hazard ratio (HR) for OS of daratumumab versus pomalidomide + LoDex was 0.56 (95% confidence interval [CI], 0.38-0.83; p = .0041) for MM-003 and 0.51 (95% CI, 0.37-0.69; p < .0001) for STRATUS. The treatment benefit was even more pronounced when the daratumumab population was restricted to pomalidomide-naïve patients (MM-003: HR, 0.33; 95% CI, 0.17-0.66; p = .0017; STRATUS: HR, 0.41; 95% CI, 0.21-0.79; p = .0082). An additional analysis indicated a consistent trend of the OS benefit across subgroups based on M-protein level reduction (≥50%, ≥25%, and <25%). CONCLUSION: The MAIC results suggest that daratumumab improves OS compared with pomalidomide + LoDex in patients with heavily pretreated multiple myeloma. IMPLICATIONS FOR PRACTICE: This matching adjusted indirect comparison of clinical trial data from four studies analyzes the survival outcomes of patients with heavily pretreated, relapsed/refractory multiple myeloma who received either daratumumab monotherapy or pomalidomide plus low-dose dexamethasone. Using this method, daratumumab conferred a significant overall survival benefit compared with pomalidomide plus low-dose dexamethasone. In the absence of head-to-head trials, these indirect comparisons provide useful insights to clinicians and reimbursement authorities around the relative efficacy of treatments.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Dexamethasone/therapeutic use , Multiple Myeloma/drug therapy , Multiple Myeloma/mortality , Thalidomide/analogs & derivatives , Aged , Bortezomib/therapeutic use , Clinical Trials as Topic , Drug Resistance, Neoplasm , Humans , Lenalidomide/therapeutic use , Middle Aged , Myeloma Proteins/metabolism , Survival Rate , Thalidomide/therapeutic use , Treatment Outcome
4.
N Engl J Med ; 373(7): 621-31, 2015 Aug 13.
Article in English | MEDLINE | ID: mdl-26035255

ABSTRACT

BACKGROUND: Elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), showed activity in combination with lenalidomide and dexamethasone in a phase 1b-2 study in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 3 study, we randomly assigned patients to receive either elotuzumab plus lenalidomide and dexamethasone (elotuzumab group) or lenalidomide and dexamethasone alone (control group). Coprimary end points were progression-free survival and the overall response rate. Final results for the coprimary end points are reported on the basis of a planned interim analysis of progression-free survival. RESULTS: Overall, 321 patients were assigned to the elotuzumab group and 325 to the control group. After a median follow-up of 24.5 months, the rate of progression-free survival at 1 year in the elotuzumab group was 68%, as compared with 57% in the control group; at 2 years, the rates were 41% and 27%, respectively. Median progression-free survival in the elotuzumab group was 19.4 months, versus 14.9 months in the control group (hazard ratio for progression or death in the elotuzumab group, 0.70; 95% confidence interval, 0.57 to 0.85; P<0.001). The overall response rate in the elotuzumab group was 79%, versus 66% in the control group (P<0.001). Common grade 3 or 4 adverse events in the two groups were lymphocytopenia, neutropenia, fatigue, and pneumonia. Infusion reactions occurred in 33 patients (10%) in the elotuzumab group and were grade 1 or 2 in 29 patients. CONCLUSIONS: Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-2 ClinicalTrials.gov number, NCT01239797.).


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Dexamethasone/therapeutic use , Multiple Myeloma/drug therapy , Receptors, Immunologic/antagonists & inhibitors , Thalidomide/analogs & derivatives , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Disease-Free Survival , Humans , Lenalidomide , Middle Aged , Multiple Myeloma/mortality , Recurrence , Signaling Lymphocytic Activation Molecule Family , Thalidomide/therapeutic use
5.
Blood ; 128(1): 37-44, 2016 07 07.
Article in English | MEDLINE | ID: mdl-27216216

ABSTRACT

The efficacy and favorable safety profile of daratumumab monotherapy in multiple myeloma (MM) was previously reported. Here, we present an updated pooled analysis of 148 patients treated with daratumumab 16 mg/kg. Data were combined from part 2 of a first-in-human phase 1/2 study of patients who relapsed after or were refractory to ≥2 prior therapies and a phase 2 study of patients previously treated with ≥3 prior lines of therapy (including a proteasome inhibitor [PI] and an immunomodulatory drug [IMiD]) or were double refractory. Among the pooled population, patients received a median of 5 prior lines of therapy (range, 2 to 14 prior lines of therapy), and 86.5% were double refractory to a PI and an IMiD. Overall response rate was 31.1%, including 13 very good partial responses, 4 complete responses, and 3 stringent complete responses. The median duration of response was 7.6 months (95% confidence interval [CI], 5.6 to not evaluable [NE]). The median progression-free survival (PFS) and overall survival (OS) were 4.0 months (95% CI, 2.8-5.6 months) and 20.1 months (95% CI, 16.6 months to NE), respectively. When stratified by responders vs stable disease/minimal response vs progressive disease/NE, median PFS was 15.0 months (95% CI, 7.4 months to NE) vs 3.0 months (95% CI, 2.8-3.7 months) vs 0.9 months (95% CI, 0.9-1.0 months), respectively, and median OS was NE (95% CI, NE to NE) vs 18.5 months (95% CI, 15.1-22.4 months) vs 3.7 months (95% CI, 1.7-7.6 months), respectively. No new safety signals were identified. In this pooled data set, daratumumab 16 mg/kg monotherapy demonstrated rapid, deep, and durable responses, with a clinical benefit that extended to patients with stable disease or better.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Multiple Myeloma/drug therapy , Multiple Myeloma/mortality , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Disease-Free Survival , Female , Follow-Up Studies , Humans , Male , Middle Aged , Recurrence , Remission Induction , Survival Rate
6.
Haematologica ; 103(12): 2088-2096, 2018 12.
Article in English | MEDLINE | ID: mdl-30237262

ABSTRACT

In the POLLUX study, daratumumab plus lenalidomide/dexamethasone significantly reduced risk of progression/death versus lenalidomide/dexamethasone alone in relapsed/refractory multiple myeloma. We provide one additional year of follow up and include the effect on minimal residual disease and in clinically relevant subgroups. After 25.4 months of follow up, daratumumab plus lenalidomide/dexamethasone prolonged progression-free survival versus lenalidomide/dexamethasone alone (median not reached vs 17.5 months; hazard ratio, 0.41; 95% confidence interval, 0.31-0.53; P<0.0001). The overall response rate was 92.9% versus 76.4%, and 51.2% versus 21.0% achieved a complete response or better, respectively (both P<0.0001). At the 10-5 sensitivity threshold, 26.2% versus 6.4% were minimal residual disease-negative, respectively (P<0.0001). Post hoc analyses of clinically relevant patient subgroups demonstrated that progression-free survival was significantly prolonged for daratumumab plus lenalidomide/dexamethasone versus lenalidomide/dexamethasone regardless of number of prior lines of therapy. Patients previously treated with lenalidomide or thalidomide and those refractory to bortezomib received similar benefits (all P<0.01). Treatment benefit with daratumumab plus lenalidomide/dexamethasone was maintained in high-risk patients (median progression-free survival 22.6 vs 10.2 months; hazard ratio, 0.53; 95% confidence interval, 0.25-1.13; P=0.0921) and patients with treatment-free intervals of >12 and ≤12 months and >6 and ≤6 months. No new safety signals were observed. In relapsed/refractory multiple myeloma patients, daratumumab plus lenalidomide/dexamethasone continued to improve progression-free survival and deepen responses versus lenalidomide/dexamethasone. Trial Registration: clinicaltrials.gov identifier: 02076009.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Multiple Myeloma/drug therapy , Neoplasm, Residual/diagnosis , Outcome Assessment, Health Care/statistics & numerical data , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Dexamethasone/administration & dosage , Drug Resistance, Neoplasm , Female , Humans , Kaplan-Meier Estimate , Lenalidomide/administration & dosage , Male , Middle Aged , Multiple Myeloma/pathology , Neoplasm Recurrence, Local , Outcome Assessment, Health Care/methods
7.
Eur J Haematol ; 101(4): 556-565, 2018 Oct.
Article in English | MEDLINE | ID: mdl-30027641

ABSTRACT

OBJECTIVE: The efficacy and safety of bortezomib-based therapy for relapsed/refractory multiple myeloma (RRMM) in clinical trials may differ from the oncology practice experience. The electronic VELCADE® OBservational Study was designed to prospectively evaluate bortezomib for multiple myeloma (MM) in real-world medical practice. METHOD: Patients scheduled to receive intravenous bortezomib for MM were eligible. The primary objective was to evaluate clinical outcomes, including response, time to response, time to next therapy, treatment-free interval, progression-free survival (PFS), and overall survival (OS). Secondary objectives included safety and healthcare resource utilization. RESULTS: In total, 873 patients with a median of two therapy lines prior to initiating bortezomib were included. The overall response rate (≥partial response) was 69%, including 37% complete response/near-complete response. Median time to response was 1.8 months, median time to next therapy was 9.7 months, and median treatment-free interval was 7.9 months. After 22.6 months' median follow-up, median PFS was 12.0 months and median OS was 36.1 months. The most common adverse events (AEs) were neuropathy not otherwise specified (19%), diarrhea NOS, and thrombocytopenia (each 17%); 230 (26%) patients discontinued bortezomib due to AEs. Of 689 (79%) patients without baseline peripheral neuropathy (PN), the rate of new-onset any-grade PN increased to 51% (12% grade 3/4) by cycle 8. Overall, 244 (28%) patients were hospitalized, 372 (43%) attended an outpatient visit, and 341 (39%) underwent a diagnostic/therapeutic procedure during bortezomib treatment. CONCLUSION: These prospective real-world data demonstrate the effectiveness and safety of bortezomib-based therapy for RRMM and confirm high response rates and long OS for this population.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bortezomib/administration & dosage , Combined Modality Therapy , Comorbidity , Drug Resistance, Neoplasm , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Multiple Myeloma/mortality , Recurrence , Retreatment , Treatment Outcome
8.
Br J Haematol ; 178(6): 896-905, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28677826

ABSTRACT

The randomized phase III ELOQUENT-2 study (NCT01239797) evaluated the efficacy and safety of elotuzumab + lenalidomide/dexamethasone (ELd) versus lenalidomide/dexamethasone (Ld) in relapsed/refractory multiple myeloma. ELd reduced the risk of disease progression/death by 30% versus Ld (hazard ratio [HR] 0·70). Median time from diagnosis was 3·5 years. We present extended 3-year follow-up data. Endpoints included progression-free survival (PFS), overall response rate (ORR) and interim overall survival (OS). Exploratory post-hoc analyses included impact of time from diagnosis and prior lines of therapy on PFS, and serum M-protein dynamic modelling. ORR was 79% (ELd) and 66% (Ld) (P = 0·0002). ELd reduced the risk of disease progression/death by 27% versus Ld (HR 0·73; P = 0·0014). Interim OS demonstrated a trend in favour of ELd (P = 0·0257); 1-, 2- and 3-year rates with ELd versus Ld were: 91% versus 83%, 73% versus 69% and 60% versus 53%. In patients with ≥ median time from diagnosis and one prior therapy, ELd resulted in a 53% reduction in the risk of progression/death versus Ld (HR 0·47). Serum M-protein dynamic modelling showed slower tumour regrowth with ELd. Adverse events were comparable between arms. ELd provided a durable and clinically relevant improvement in efficacy, with minimal incremental toxicity.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Multiple Myeloma/drug therapy , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Female , Follow-Up Studies , Humans , Immunoglobulins/blood , Kaplan-Meier Estimate , Lenalidomide , Male , Middle Aged , Multiple Myeloma/pathology , Recurrence , Thalidomide/administration & dosage , Thalidomide/adverse effects , Thalidomide/analogs & derivatives
9.
Lancet ; 387(10027): 1551-1560, 2016 Apr 09.
Article in English | MEDLINE | ID: mdl-26778538

ABSTRACT

BACKGROUND: New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma. METHODS: In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age ≥18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response [PR] + very good PR + complete response [CR] + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov, number NCT01985126. FINDINGS: The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2-14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29.2%, 95% CI 20.8-38.9)-three (2.8%, 0.6-8.0) had a stringent CR, ten (9.4%, 4.6-16.7) had a very good PR, and 18 (17.0%, 10.4-25.5) had a PR. The median time to first response was 1.0 month (range 0.9-5.6). Median duration of response was 7.4 months (95% CI 5.5-not estimable) and progression-free survival was 3.7 months (95% CI 2.8-4.6). The 12-month overall survival was 64.8% (95% CI 51.2-75.5) and, at a subsequent cutoff, median overall survival was 17.5 months (95% CI 13.7-not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) and anaemia (35 [33%]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation. INTERPRETATION: Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients. FUNDING: Janssen Research & Development.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Multiple Myeloma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Adult , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Canada , Disease-Free Survival , Drug Administration Schedule , Drug Resistance, Neoplasm , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Spain , Treatment Outcome , United States
10.
N Engl J Med ; 371(10): 906-17, 2014 Sep 04.
Article in English | MEDLINE | ID: mdl-25184863

ABSTRACT

BACKGROUND: The combination melphalan-prednisone-thalidomide (MPT) is considered a standard therapy for patients with myeloma who are ineligible for stem-cell transplantation. However, emerging data on the use of lenalidomide and low-dose dexamethasone warrant a prospective comparison of the two approaches. METHODS: We randomly assigned 1623 patients to lenalidomide and dexamethasone in 28-day cycles until disease progression (535 patients), to the same combination for 72 weeks (18 cycles; 541 patients), or to MPT for 72 weeks (547 patients). The primary end point was progression-free survival with continuous lenalidomide-dexamethasone versus MPT. RESULTS: The median progression-free survival was 25.5 months with continuous lenalidomide-dexamethasone, 20.7 months with 18 cycles of lenalidomide-dexamethasone, and 21.2 months with MPT (hazard ratio for the risk of progression or death, 0.72 for continuous lenalidomide-dexamethasone vs. MPT and 0.70 for continuous lenalidomide-dexamethasone vs. 18 cycles of lenalidomide-dexamethasone; P<0.001 for both comparisons). Continuous lenalidomide-dexamethasone was superior to MPT for all secondary efficacy end points, including overall survival (at the interim analysis). Overall survival at 4 years was 59% with continuous lenalidomide-dexamethasone, 56% with 18 cycles of lenalidomide-dexamethasone, and 51% with MPT. Grade 3 or 4 adverse events were somewhat less frequent with continuous lenalidomide-dexamethasone than with MPT (70% vs. 78%). As compared with MPT, continuous lenalidomide-dexamethasone was associated with fewer hematologic and neurologic toxic events, a moderate increase in infections, and fewer second primary hematologic cancers. CONCLUSIONS: As compared with MPT, continuous lenalidomide-dexamethasone given until disease progression was associated with a significant improvement in progression-free survival, with an overall survival benefit at the interim analysis, among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. (Funded by Intergroupe, Francophone du Myélome and Celgene; FIRST ClinicalTrials.gov number, NCT00689936; European Union Drug Regulating Authorities Clinical Trials number, 2007-004823-39.).


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Dexamethasone/administration & dosage , Multiple Myeloma/drug therapy , Thalidomide/analogs & derivatives , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Dexamethasone/adverse effects , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Lenalidomide , Male , Melphalan/administration & dosage , Middle Aged , Multiple Myeloma/immunology , Prednisone/administration & dosage , Thalidomide/administration & dosage , Thalidomide/adverse effects
11.
Immunol Cell Biol ; 95(7): 611-619, 2017 08.
Article in English | MEDLINE | ID: mdl-28303902

ABSTRACT

MS4A4A is a member of the membrane-spanning, four domain family, subfamily A (MS4A) that includes CD20 (MS4A1), FcRß (MS4A2) and Htm4 (MS4A3). Like the first three members of this family, transcription of MS4A4A appears to be limited to hematopoietic cells. To evaluate expression of the MS4A4A protein in hematopoietic cell lineages and subsets we generated monoclonal antibodies against extracellular epitopes for use in flow cytometry. In human peripheral blood we found that MS4A4A is expressed at the plasma membrane in monocytes but not in granulocytes or lymphocytes. In vitro differentiation of monocytes demonstrated that MS4A4A is expressed in immature but not activated dendritic cells, and in macrophages generated in the presence of interleukin-4 ('alternatively activated' or M2 macrophages) but not by interferon-γ and lipopolysaccharide ('classically' activated or M1 macrophages). MS4A4A was expressed in the U937 monocytic cell line only after differentiation. In normal bone marrow, MS4A4A was expressed in mature monocytes but was undetected, or detected at only a low level, in myeloid/monocytic precursors, as well as their malignant counterparts in patients with various subtypes of myeloid leukemia. Although MS4A4A was not expressed in healthy B lymphocytes, it was highly expressed in normal plasma cells, CD138+ cells from multiple myeloma patients, and bone marrow B cells from a patient with mantle cell lymphoma. These findings suggest immunotherapeutic potential for MS4A4A antibodies in targeting alternatively activated macrophages such as tumor-associated macrophages, and in the treatment of multiple myeloma and mantle cell lymphoma.


Subject(s)
Cell Membrane/metabolism , Macrophages/metabolism , Membrane Proteins/metabolism , Plasma Cells/metabolism , B-Lymphocytes/drug effects , B-Lymphocytes/metabolism , Biomarkers/metabolism , Blood Cells/drug effects , Blood Cells/metabolism , Bone Marrow/metabolism , Cell Differentiation/drug effects , Cell Lineage/drug effects , Cell Membrane/drug effects , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Granulocyte Colony-Stimulating Factor/pharmacology , Humans , Leukemia, Myeloid/immunology , Leukemia, Myeloid/pathology , Macrophages/drug effects , Membrane Proteins/blood , Monocytes/drug effects , Monocytes/metabolism , Plasma Cells/drug effects , Tetradecanoylphorbol Acetate/pharmacology , U937 Cells , Up-Regulation/drug effects
12.
Blood ; 125(13): 2068-74, 2015 03 26.
Article in English | MEDLINE | ID: mdl-25628469

ABSTRACT

We conducted a pooled analysis of 869 individual newly diagnosed elderly patient data from 3 prospective trials. At diagnosis, a geriatric assessment had been performed. An additive scoring system (range 0-5), based on age, comorbidities, and cognitive and physical conditions, was developed to identify 3 groups: fit (score = 0, 39%), intermediate fitness (score = 1, 31%), and frail (score ≥2, 30%). The 3-year overall survival was 84% in fit, 76% in intermediate-fitness (hazard ratio [HR], 1.61; P = .042), and 57% in frail (HR, 3.57; P < .001) patients. The cumulative incidence of grade ≥3 nonhematologic adverse events at 12 months was 22.2% in fit, 26.4% in intermediate-fitness (HR, 1.23; P = .217), and 34.0% in frail (HR, 1.74; P < .001) patients. The cumulative incidence of treatment discontinuation at 12 months was 16.5% in fit, 20.8% in intermediate-fitness (HR, 1.41; P = .052), and 31.2% in frail (HR, 2.21; P < .001) patients. Our frailty score predicts mortality and the risk of toxicity in elderly myeloma patients. The International Myeloma Working group proposes this score for the measurement of frailty in designing future clinical trials. These trials are registered at www.clinicaltrials.gov as #NCT01093136 (EMN01), #NCT01190787 (26866138MMY2069), and #NCT01346787 (IST-CAR-506).


Subject(s)
Antineoplastic Agents/adverse effects , Frail Elderly , Geriatric Assessment , Multiple Myeloma/drug therapy , Multiple Myeloma/mortality , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Clinical Trials as Topic , Cohort Studies , Humans , Prognosis , Withholding Treatment/statistics & numerical data
13.
Cell Biol Toxicol ; 33(2): 83-97, 2017 04.
Article in English | MEDLINE | ID: mdl-27761761

ABSTRACT

Cancer heterogeneity is a significant factor in response to treatment and escape leading to relapse. Within an individual cancer, especially blood cancers, there exists multiple subclones as well as distinct clonal expansions unrelated to the clinically detected, dominant clone. Over time, multiple subclones and clones undergo emergence, expansion, and extinction. Although sometimes this intra-clonal and inter-clonal heterogeneity can be detected and/or quantified in tests that measure aggregate populations of cells, frequently, such heterogeneity can only be detected using single cell analysis to determine its frequency and to detect minor clones that may subsequently emerge to become drug resistant and dominant. Most genetic/genomic tests look at the pooled tumor population as a whole rather than at its individual cellular components. Yet, minor clones and cancer stem cells are unlikely to be detected against the background of expanded major clones. Because selective pressures are likely to govern much of what is seen clinically, single cell analysis allows identification of otherwise cryptic compartments of the malignancy that may ultimately mediate progression and relapse. Single cell analysis can track intra- or inter-clonal heterogeneity and provide useful clinical information, often before changes in the disease are detectable in the clinic. To a very limited extent, single cell analysis has already found roles in clinical care. Because inter- and intra-clonal heterogeneity likely occurs more frequently than can be currently appreciated on a clinical level, future use of single cell analysis is likely to have profound clinical utility.


Subject(s)
Hematologic Neoplasms/pathology , Single-Cell Analysis/methods , Animals , Clinical Decision-Making , Clone Cells , Hematologic Neoplasms/therapy , Humans
14.
Genes Chromosomes Cancer ; 55(12): 962-974, 2016 12.
Article in English | MEDLINE | ID: mdl-27509849

ABSTRACT

Many B-cell malignancies are characterized by chromosomal translocations involving IGH and a proto-oncogene. For translocations to occur, spatial proximity of translocation-prone genes is necessary. Currently, it is not known how such genes are brought into proximity with one another. Although decondensed chromosomes occupy definitive, non-random spaces in the interphase nucleus known as chromosome territories (CTs), chromatin at the edges of CTs can intermingle, and specific genomic regions from some chromosomes have been shown to "loop out" of their respective CTs. This extra-territorial positioning of specific genomic regions may provide a mechanism whereby translocation-prone genes are brought together in the interphase nucleus. FGFR3 and MAF recurrently participate in translocations with IGH at different frequencies. Using 3D, 4-color FISH, and 3D analysis software, we show frequent extra-territorial positioning of FGFR3 and significantly less frequent extra-territorial positioning of MAF. Frequent extra-territorial positioning may be characteristic of FGFR3 in B-cells from healthy adult donors and non-malignant B-cells from patients, but not in hematopoietic stem cells from patients with translocations. The frequency of extra-territorial positioning of FGFR3 and MAF in B-cells correlates with the frequency of translocations in the patient population. Most importantly, in patient B-cells, we demonstrate a significant proportion of extra-territorial FGFR3 participating in close loci pairs and/or colocalizing with IGH. This preliminary work suggests that in patient B-cells, extra-territorial positioning of FGFR3 may provide a mechanism for forming close loci pairs and/or colocalization with IGH; indirectly facilitating translocation events involving these two genes. © 2016 Wiley Periodicals, Inc.


Subject(s)
Cell Nucleus/genetics , Immunoglobulin Heavy Chains/genetics , Interphase/genetics , Multiple Myeloma/genetics , Receptor, Fibroblast Growth Factor, Type 3/genetics , Repressor Proteins/genetics , Adult , B-Lymphocytes , Biomarkers, Tumor/genetics , Case-Control Studies , Chromosomes, Human, Pair 14/genetics , Chromosomes, Human, Pair 4/genetics , Female , Follow-Up Studies , Humans , In Situ Hybridization, Fluorescence , Male , Multiple Myeloma/pathology , Proto-Oncogene Mas , Translocation, Genetic
15.
Blood ; 123(12): 1826-32, 2014 Mar 20.
Article in English | MEDLINE | ID: mdl-24421329

ABSTRACT

This multicenter, open-label, randomized phase 2 study assessed the efficacy and safety of pomalidomide (POM) with/without low-dose dexamethasone (LoDEX) in patients with relapsed/refractory multiple myeloma (RRMM). Patients who had received ≥2 prior therapies (including lenalidomide [LEN] and bortezomib [BORT]) and had progressed within 60 days of their last therapy were randomized to POM (4 mg/day on days 1-21 of each 28-day cycle) with/without LoDEX (40 mg/week). The primary end point was progression-free survival (PFS). In total, 221 patients (median 5 prior therapies, range 1-13) received POM+LoDEX (n = 113) or POM (n = 108). With a median follow-up of 14.2 months, median PFS was 4.2 and 2.7 months (hazard ratio = 0.68, P = .003), overall response rates (ORRs) were 33% and 18% (P = .013), median response duration was 8.3 and 10.7 months, and median overall survival (OS) was 16.5 and 13.6 months, respectively. Refractoriness to LEN, or resistance to both LEN and BORT, did not affect outcomes with POM+LoDEX (median PFS 3.8 months for both; ORRs 30% and 31%; and median OS 16 and 13.4 months). Grade 3-4 neutropenia occurred in 41% (POM+LoDEX) and 48% (POM); no grade 3-4 peripheral neuropathy was reported. POM+LoDEX was effective and generally well tolerated and provides an important new treatment option for RRMM patients who have received multiple prior therapies. This trial was registered at www.clinicaltrials.gov as #NCT00833833.


Subject(s)
Dexamethasone/administration & dosage , Multiple Myeloma/drug therapy , Thalidomide/analogs & derivatives , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols , Boronic Acids/administration & dosage , Bortezomib , Disease-Free Survival , Drug Resistance, Neoplasm , Female , Humans , Immunologic Factors/administration & dosage , Lenalidomide , Male , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Neutropenia/chemically induced , Pyrazines/administration & dosage , Thalidomide/administration & dosage , Thalidomide/adverse effects , Treatment Outcome
16.
Cancer ; 121(5): 716-23, 2015 Mar 01.
Article in English | MEDLINE | ID: mdl-25355245

ABSTRACT

BACKGROUND: Patients with T-cell lymphomas face a poorer prognosis compared with patients with B-cell lymphomas. New therapeutic approaches need to be developed to improve outcomes for these patients. METHODS: Forty patients with recurrent and refractory T-cell lymphomas other than mycosis fungoides and patients with untreated T-cell lymphoma who were not candidates for combination chemotherapy were prescribed oral lenalidomide at a dose of 25 mg daily on days 1 to 21 of each 28-day cycle, with standardized dose reductions for toxicity. The primary endpoint was overall response rate (ORR), and secondary endpoints were complete and partial response rates, progression-free survival (PFS), overall survival (OS), and safety. The authors also determined duration of response (DoR). RESULTS: A total of 40 patients were enrolled in the current study; 1 patient was subsequently deemed ineligible. The ORR was 10 of 39 patients (26%); 3 patients (8%) achieved complete responses and 7 patients achieved partial responses. Three patients had stable disease for ≥5 cycles. The median OS was 12 months (range <1 month to ≥69 months), the median PFS was 4 months (range, <1 month to ≥50 months), and the median DoR was 13 months (range 2 months to ≥37 months), including 5 responses that lasted >1 year. Toxicity was in keeping with the known safety profile of lenalidomide. Among the patients who had recurrent/refractory peripheral T-cell lymphoma (29 patients), the ORR was 24%, the median OS was 12 months, the median PFS was 4 months, and the median DoR was 5 months (range, 2 months to ≥37 months). CONCLUSIONS: In the current study, the use of oral lenalidomide monotherapy demonstrated clinically relevant efficacy among patients with systemic T-cell lymphomas. It appears to have excellent potential as an agent in combination therapy for patients with T-cell lymphoma.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/therapeutic use , Immunologic Factors/therapeutic use , Lymphoma, T-Cell, Peripheral/drug therapy , Thalidomide/analogs & derivatives , Adult , Aged , Aged, 80 and over , Angiogenesis Inhibitors/adverse effects , Antineoplastic Agents/adverse effects , Disease-Free Survival , Drug Administration Schedule , Female , Humans , Immunologic Factors/adverse effects , Immunomodulation/drug effects , Lenalidomide , Male , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Remission Induction , Thalidomide/adverse effects , Thalidomide/therapeutic use
17.
Br J Haematol ; 168(4): 511-7, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25302852

ABSTRACT

Venous thromboembolism (VTE) has an increased incidence in patients with multiple myeloma (MM), especially during chemotherapy. Mechanisms including upregulation of procoagulant factors, such as factor VIII, have been postulated. The National Cancer Institute of Canada Clinical Trials Group MY.10 phase III clinical trial compared thalidomide-prednisone to observation for 332 patients with MM post-autologous stem cell transplantation (ASCT), with a primary endpoint of overall survival and various secondary endpoints including the incidence of VTE. One hundred and fifty-three patients had biomarker data, including D-dimer, factor VIII and thrombin anti-thrombin (TAT) levels collected post-ASCT at baseline and 2 months after intervention investigating in-vivo thrombin generation. Differences between the time-points included a significant reduction over time in D-dimer, factor VIII and TAT levels in the observation group and sustained elevation of D-dimer, significant increase in factor VIII and reduction in TAT levels in the thalidomide-prednisone group. Eight VTE events were reported in this subset of study patients, all in the thalidomide-prednisone arm, with a trend to increase in D-dimer levels over time in those patients with VTE. This study provides physiological and clinical evidence for an increased risk of VTE associated with thalidomide-prednisone maintenance therapy post-ASCT for MM.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antithrombin III/analysis , Factor VIII/analysis , Fibrin Fibrinogen Degradation Products/analysis , Hematopoietic Stem Cell Transplantation , Multiple Myeloma/therapy , Peptide Hydrolases/analysis , Thrombin/biosynthesis , Thrombophilia/chemically induced , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Combined Modality Therapy , Female , Follow-Up Studies , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Maintenance Chemotherapy , Male , Middle Aged , Multiple Myeloma/blood , Multiple Myeloma/drug therapy , Prednisone/administration & dosage , Thalidomide/administration & dosage , Thalidomide/adverse effects , Thrombophilia/blood , Transplantation, Autologous , Venous Thromboembolism/epidemiology , Venous Thromboembolism/prevention & control
18.
Blood ; 121(9): 1517-23, 2013 Feb 28.
Article in English | MEDLINE | ID: mdl-23297129

ABSTRACT

We conducted a randomized, controlled trial comparing thalidomide-prednisone as maintenance therapy with observation in 332 patients who had undergone autologous stem cell transplantation with melphalan 200 mg/m2. The primary end point was overall survival (OS); secondary end points were myeloma-specific progression-free survival,progression-free survival, incidence of venous thromboembolism, and health-related quality of life (HRQoL). With a median follow-up of 4.1 years, no differences in OS between thalidomide-prednisone and observation were detected (respective 4-year estimates of 68% vs 60%, respectively; hazard ratio = 0.77; P = .18); thalidomide-prednisone was associated with superior myeloma-specific progression-free survival and progression-free survival (for both outcomes, the 4-year estimates were 32% vs 14%; hazard ratio = 0.56; P < .0001) and more frequent venous thromboembolism (7.3% vs none; P = .0004). Median survival after first disease recurrence was 27.7 months with thalidomide-prednisone and 34.1 months in the observation group. Nine second malignancies were observed with thalidomide-prednisone versus 6 in the observation group. Those allocated to thalidomide-prednisone reported worse HRQoL with respect to cognitive function, dyspnea, constipation, thirst, leg swelling, numbness, dry mouth, and balance problems. We conclude that maintenance therapy with thalidomide-prednisone after autologous stem cell transplantation improves the duration of disease control, but is associated with worsening of patient-reported HRQoL and no detectable OS benefit.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hematopoietic Stem Cell Transplantation , Maintenance Chemotherapy/methods , Multiple Myeloma/therapy , Prednisone/administration & dosage , Thalidomide/administration & dosage , Academies and Institutes , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Canada/epidemiology , Female , Humans , Male , Medical Oncology/organization & administration , Middle Aged , Multiple Myeloma/drug therapy , Multiple Myeloma/mortality , Prednisone/adverse effects , Quality of Life , Survival Analysis , Thalidomide/adverse effects , Transplantation, Autologous , Treatment Outcome
19.
Blood ; 119(24): 5661-70, 2012 Jun 14.
Article in English | MEDLINE | ID: mdl-22555973

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/m(2) for all treatment cycles, and Cohort 2, scheduled to receive 20 mg/m(2) for cycle 1 and then 27 mg/m(2) 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.


Subject(s)
Antineoplastic Agents/therapeutic use , Boronic Acids/therapeutic use , Multiple Myeloma/drug therapy , Oligopeptides/therapeutic use , Pyrazines/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Bortezomib , Cohort Studies , Demography , Disease-Free Survival , Female , Humans , Male , Middle Aged , Oligopeptides/administration & dosage , Oligopeptides/adverse effects , Recurrence , Time Factors , Treatment Outcome
20.
Genes Chromosomes Cancer ; 52(6): 523-37, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23460268

ABSTRACT

Gene organization in nonmalignant B cells from t(4;14) and t(11;14) multiple myeloma (MM) patients differs from that of healthy donors. Among recurrent IGH translocations in MM, the frequency of t(4;14) (IGH and FGFR3) or t(11;14) (IGH and CCND1) is greater than the frequency of t(14;16) (IGH and MAF). Gene organization in t(14;16) patients may influence translocation potential of MAF with IGH. In patients, three-dimensional FISH revealed the positions of IGH, CCND1, FGFR3, and MAF in nonmalignant B cells that are likely similar to those when MM first arose, compared with B cells from healthy donors. Overall, IGH occupies a more central nuclear position while MAF is more peripherally located. However, for B cells from t(4;14) and t(11;14) patients, IGH and FGFR3, or IGH and CCND1 are found in spatial proximity: IGH and MAF are not. This differs in B cells from t(14;16) patients and healthy donors where IGH is approximately equidistant to FGFR3, CCND1, and MAF, suggesting that gene organization in t(14;16) patients is different from that in t(4;14) or t(11;14) patients. Translocations between IGH and MAF may arise only in the absence of close proximity to the more frequent partners, as appears to be the case for individuals who develop t(14;16) MM.


Subject(s)
B-Lymphocytes/pathology , Biomarkers, Tumor/genetics , Chromosomes, Human, Pair 11/genetics , Chromosomes, Human, Pair 14/genetics , Chromosomes, Human, Pair 16/genetics , Chromosomes, Human, Pair 4/genetics , Multiple Myeloma/genetics , Translocation, Genetic/genetics , B-Lymphocytes/metabolism , Genetic Loci , Humans , Immunoglobulin Heavy Chains/genetics , In Situ Hybridization, Fluorescence , Oncogene Proteins, Fusion/genetics , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins c-maf/genetics , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Receptor, Fibroblast Growth Factor, Type 3/genetics , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/genetics , Reverse Transcriptase Polymerase Chain Reaction
SELECTION OF CITATIONS
SEARCH DETAIL