High response rates with single-agent belantamab mafodotin in relapsed systemic AL amyloidosis.
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SUBMITTER: Khwaja J
PROVIDER: S-EPMC9445042 | biostudies-literature | 2022 Sep
REPOSITORIES: biostudies-literature
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High response rates with single-agent belantamab mafodotin in relapsed systemic AL amyloidosis.
Khwaja Jahanzaib J Bomsztyk Joshua J Mahmood Shameem S Wisniowski Brendan B Shah Raakhee R Tailor Anish A Yong Kwee K Popat Rakesh R Rabin Neil N Kyriakou Charalampia C Sive Jonathan J Esposti Simona Degli SD Larkin Daniel F P DFP Worthington Sarah S Hart Alyse A Dowling Emma E Correia Nuno N Bygrave Ceri C Rydzewski Andrzej A Jamroziak Krzysztof K Wechalekar Ashutosh D AD
Blood cancer journal 20220905 9
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Project description: Not available
| S-EPMC9431027 | biostudies-literature
Project description:Belantamab mafodotin (belamaf) is an antibody-drug conjugate (ADC) targeting B-cell maturation antigen (BCMA). Nonlinear mixed-effects models were developed to characterize the population pharmacokinetics (PopPK) of ADC, total monoclonal antibody (mAb), and cysteine-maleimidocaproyl-MMAF (cys-mcMMAF) after 0.03-4.6 mg/kg dosing every 3 weeks in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM; DREAMM-1, n = 73; DREAMM-2, n = 218). Sequential modeling methodology was used. Individual post hoc parameter estimates from the final ADC model were used to develop total mAb and cys-mcMMAF models. Formal covariate selection used a modified stepwise forward inclusion method with backward elimination. A linear, two-compartment PopPK model with a time-varying clearance (CL) described ADC PK. Initial ADC typical value for CL for a DREAMM-2 patient was 0.936 L/day with a half-life of 11.5 days, over time CL was reduced by 28% resulting in a half-life of 14.3 days. Time to 50% maximal CL change was ~ 50 days. Baseline soluble BCMA (sBCMA), immunoglobulin (IgG), albumin, and bodyweight impacted ADC CL. Cys-mcMMAF concentrations were described with a linear two-compartment model linked to ADC; input rate was governed by deconjugation/intracellular proteolytic degradation of ADC represented by an exponentially decreasing MMAF:mAb (drug antibody ratio [DAR]) after each dose. Time to 50% DAR reduction was 10.3 days. Baseline sBCMA and IgG impacted cys-mcMMAF central volume of distribution. In conclusion, ADC, total mAb, and cys-mcMMAF concentration-time profiles in RRMM were well-described by PopPK models, and exposure was most strongly impacted by disease-related characteristics.
| S-EPMC8376139 | biostudies-literature
Project description:CAN2007 was a phase 1/2 study of once- and twice-weekly single-agent bortezomib in relapsed primary systemic amyloid light chain amyloidosis (AL) amyloidosis. Seventy patients were treated, including 18 and 34 patients at the maximum planned doses on the once- and twice-weekly schedules. This prespecified final analysis provides mature response and long-term outcomes data after 3-year additional follow-up since the last report. In the once-weekly 1.6 mg/m(2) and twice-weekly 1.3 mg/m(2) bortezomib groups, final hematologic response rates were 68.8% and 66.7%; 80% of patients in each group sustained their response for ≥1 year. One-year progression-free rates were 72.2% and 76.8%. Median overall survival (OS) was 62.1 months and not reached; 4-year OS rates were 75.0% and 63.0%. Low baseline difference in κ/λ free light-chain level was associated with higher hematologic complete response rates and longer OS. At data cutoff, 40 (57%) patients had received subsequent therapy, including 19 (27%) retreated with bortezomib, 11 (58%) of whom achieved complete or partial hematologic responses. Four patients received prolonged bortezomib for between 3.5 and 5.6 years, with no new safety concerns, highlighting the feasibility of long-term therapy. Single-agent bortezomib produced durable hematologic responses and promising long-term OS in relapsed AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT00298766.
| S-EPMC4199951 | biostudies-literature
Project description:DREAMM-2 (NCT03525678) is an ongoing global, open-label, phase 2 study of single-agent belantamab mafodotin (belamaf; GSK2857916), a B-cell maturation antigen-targeting antibody-drug conjugate, in a frozen-liquid presentation in patients with relapsed/refractory multiple myeloma (RRMM). Alongside the main study, following identical inclusion/exclusion criteria, a separate patient cohort was enrolled to receive belamaf in a lyophilised presentation (3.4 mg/kg, every 3 weeks) until disease progression/unacceptable toxicity. Primary outcome was independent review committee-assessed overall response rate (ORR). Twenty-five patients were enrolled; 24 received ≥1 dose of belamaf. As of 31 January 2020, ORR was 52% (95% CI: 31.3-72.2); 24% of patients achieved very good partial response. Median duration of response was 9.0 months (2.8-not reached [NR]); median progression-free survival was 5.7 months (2.2-9.7); median overall survival was not reached (8.7 months-NR). Most common grade 3/4 adverse events were keratopathy (microcyst-like corneal epithelial changes, a pathological finding seen on eye examination [75%]), thrombocytopenia (21%), anaemia (17%), hypercalcaemia and hypophosphatemia (both 13%), neutropenia and blurred vision (both 8%). Pharmacokinetics supported comparability of frozen-liquid and lyophilised presentations. Single-agent belamaf in a lyophilised presentation (intended for future use) showed a deep and durable clinical response and acceptable safety profile in patients with heavily pre-treated RRMM.
| S-EPMC7584571 | biostudies-literature
Project description:Belantamab mafodotin is an antibody-drug conjugate comprising a humanized anti-B-cell maturation antigen (BCMA) monoclonal antibody conjugated to monomethyl auristatin F (MMAF) via a protease-resistant maleimidocaproyl linker. Single-agent belantamab mafodotin showed clinically meaningful activity and manageable safety in patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM) in the phase I DREAMM-1 and phase II DREAMM-2 studies and is approved by the US Food and Drug Administration and European Medicines Agency for RRMM treatment. To support monotherapy dose selection, the relationship between Cycle 1 exposure (derived using a population pharmacokinetic model) and clinical response (for multiple efficacy and safety end points) was explored. In DREAMM-2, efficacy end points (probability of response (PoR) and progression-free survival (PFS)) were associated with exposure in univariate evaluation; however, once disease burden factors were included in the model (e.g., baseline soluble BCMA, ß2 -microglobulin), exposure was no longer significant. Patients with higher disease burden had lower exposure. In DREAMM-1, belantamab mafodotin exposure was the only variable to correlate with PoR and PFS. Probability of corneal events (keratopathy), but not dry eye or blurred vision, was strongly associated with belantamab mafodotin exposure (DREAMM-2). Higher cys-mcMMAF maximum plasma drug concentration (Cmax ) and lower baseline platelet count were associated with increased probability of thrombocytopenia (DREAMM-1 and DREAMM -2). In general, safety end points were more strongly associated with belantamab mafodotin exposure than efficacy end points, particularly after disease factors and patient characteristics were taken into account. Overall, these findings supported the monotherapy dose recommendation of belantamab mafodotin as 2.5 mg/kg every 3 weeks in patients with RRMM who have received four or more prior therapies.
| S-EPMC9293327 | biostudies-literature
Project description:BackgroundOn the basis of the DREAMM-2 study (ClinicalTrials.gov identifier NCT03525678), single-agent belantamab mafodotin (belamaf) was approved for patients with relapsed or refractory multiple myeloma (RRMM) who received ≥4 prior therapies, including anti-CD38 therapy. The authors investigated longer term efficacy and safety outcomes in DREAMM-2 after 13 months of follow-up among patients who received belamaf 2.5 mg/kg.MethodsDREAMM-2 is an ongoing, phase 2, open-label, 2-arm study investigating belamaf (2.5 or 3.4 mg/kg) in patients with RRMM who had disease progression after ≥3 lines of therapy and were refractory to immunomodulatory drugs and proteasome inhibitors and refractory and/or intolerant to an anti-CD38 therapy. The primary outcome was the proportion of patients that achieved an overall response, assessed by an independent review committee.ResultsAs of January 31, 2020, 10% of patients still received belamaf 2.5 mg/kg. Thirty-one of 97 patients (32%; 97.5% confidence interval [CI], 21.7%-43.6%) achieved an overall response, and 18 responders achieved a very good partial response or better. Median estimated duration of response, overall survival, and progression-free survival were 11.0 months (95% CI, 4.2 months to not reached), 13.7 months (95% CI, 9.9 months to not reached), and 2.8 months (95% CI, 1.6-3.6 months), respectively. Response and survival outcomes in patients who had high-risk cytogenetics or renal impairment were consistent with outcomes in the overall population. Outcomes were poorer in patients with extramedullary disease. In patients who had a clinical response and prolonged dose delays (>63 days; mainly because of corneal events), 88% maintained or deepened responses during their first prolonged dose delay. Overall, there were no new safety signals during this follow-up.ConclusionsExtended follow-up confirms sustained clinical activity without new safety signals with belamaf in this heavily pretreated patient population with RRMM.
| S-EPMC8597112 | biostudies-literature
Project description:Daratumumab, a monoclonal CD38 antibody, is approved in the treatment of myeloma, but its efficacy and safety in light-chain (AL) amyloidosis has not been formally studied. This prospective phase 2 trial of daratumumab monotherapy for the treatment of AL amyloidosis was designed to determine the safety, tolerability, and hematologic and clinical response. Daratumumab 16 mg/kg was administered by IV infusion once weekly for weeks 1 to 8, every 2 weeks for weeks 9 to 24, and every 4 weeks thereafter until progression or unacceptable toxicity, for up to 24 months. Twenty-two patients with previously treated AL amyloidosis were enrolled. The majority of the patients had received high-dose melphalan and stem cell transplantation and/or treatment with a proteasome inhibitor. The median time between prior therapy and trial enrollment was 9 months (range, 1-180 months). No grade 3-4 infusion-related reactions occurred. The most common grade ≥3 adverse events included respiratory infections (n = 4; 18%) and atrial fibrillation (n = 4, 18%). Hematologic complete and very-good-partial response occurred in 86% of patients. The median time to first and best hematologic response was 4 weeks and 3 months, respectively. Renal response occurred in 10 of 15 patients (67%) with renal involvement and cardiac response occurred in 7 of 14 patients (50%) with cardiac involvement. In summary, daratumumab is well tolerated in patients with relapsed AL amyloidosis and leads to rapid and deep hematologic responses and organ responses. This trial was registered at www.clinicaltrials.gov as #NCT02841033.
| S-EPMC7193185 | biostudies-literature
Project description:Belantamab mafodotin (belamaf) is a first-in-class anti-B-cell maturation antigen (BCMA) antibody-drug conjugate (ADC) that recently gained regulatory approval for the treatment of relapsed and/or refractory multiple myeloma (RRMM) patients who have received at least four prior therapies including an anti-CD38 monoclonal antibody (mAb), a proteasome inhibitor (PI), and an immunomodulatory drug (IMiD). As the first BCMA-targeted therapy to be approved in multiple myeloma along with its "off-the-shelf" outpatient administration, belamaf addresses a significant unmet need in RRMM that is refractory to IMiD, PI, and anti-CD38 mAb therapy, otherwise known as triple-class refractory myeloma. Belamaf is also associated with frequent corneal ocular adverse events, which represents a unique toxicity in multiple myeloma therapeutics, and its administration requires a multidisciplinary approach with oncologists and eye care specialists to safely and effectively manage patients on belamaf therapy. In this review, we discuss the preclinical and clinical data leading to the regulatory approval of belamaf, the monitoring and mitigation strategies of corneal ocular adverse events, and its current and future role in the RRMM treatment landscape.
| S-EPMC7739070 | biostudies-literature
Project description:Systemic immunoglobulin light chain (AL) amyloidosis is a disorder characterized by the production of clonal serum free light chains that misfold, aggregate, and deposit in vital organs. Treatment of this disease is typically targeted at the abnormal plasma cell clone in the bone marrow which is the source of the amyloidogenic light chain. First-line therapies in this disease are well established, but in the relapsed or refractory setting, there are many treatment options, including immunomodulatory agents, proteasome inhibitors, alkylating agents, and monoclonal antibodies. Decisions regarding treatment choice should be made by a multidisciplinary team with consideration of the patient's functional status, disease stage, degree of organ dysfunction, and potential treatment toxicities. Herein we review the current treatment options available for patients with relapsed or refractory AL amyloidosis.
| S-EPMC6815750 | biostudies-literature
Project description: Not available
| S-EPMC10428262 | biostudies-literature