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The Lancet. Haematology Oct 2023Multiple myeloma remains incurable, and heavily pretreated patients with relapsed or refractory disease have few good treatment options. Belantamab mafodotin showed... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of single-agent belantamab mafodotin versus pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM-3): a phase 3, open-label, randomised study.
BACKGROUND
Multiple myeloma remains incurable, and heavily pretreated patients with relapsed or refractory disease have few good treatment options. Belantamab mafodotin showed promising results in a phase 2 study of patients with relapsed or refractory multiple myeloma at second or later relapse and a manageable adverse event profile. We aimed to assess the safety and efficacy of belantamab mafodotin in a phase 3 setting.
METHODS
In the DREAMM-3 open-label phase 3 study, conducted at 108 sites across 18 countries, adult patients were enrolled who had confirmed multiple myeloma (International Myeloma Working Group criteria), ECOG performance status of 0-2, had received two or more previous lines of therapy, including two or more consecutive cycles of both lenalidomide and a proteasome inhibitor, and progressed on, or within, 60 days of completion of the previous treatment. Participants were randomly allocated using a central interactive response technology system (2:1) to receive belantamab mafodotin 2·5 mg/kg intravenously every 21 days, or oral pomalidomide 4·0 mg daily (days 1-21) and dexamethasone 40·0 mg (20·0 mg if >75 years) weekly in a 28-day cycle. Randomisation was stratified by previous anti-CD38 therapy, International Staging System stage, and number of previous therapies. The primary endpoint was progression-free survival in all patients who were randomly allocated. The safety population included all randomly allocated patients who received one or more doses of study treatment. This trial is registered with ClinicalTrials.gov, NCT04162210, and is ongoing. Data cutoff for this analysis was Sept 12, 2022.
FINDINGS
Patients were recruited between April 2, 2020, and April 18, 2022. As of September, 2022, 325 patients were randomly allocated (218 to the belantamab mafodotin group and 107 to the pomalidomide-dexamethasone group); 184 (57%) of 325 were male and 141 (43%) of 325 were female, 246 (78%) of 316 were White. Median age was 68 years (IQR 60-74). Median follow-up was 11·5 months (5·5-17·6) for belantamab mafodotin and 10·8 months (5·6-17·1) for pomalidomide-dexamethasone. Median progression-free survival was 11·2 months (95% CI 6·4-14·5) for belantamab mafodotin and 7·0 months (4·6-10·6) for pomalidomide-dexamethasone (hazard ratio 1·03 [0·72-1·47]; p=0·56). Most common grade 3-4 adverse events were thrombocytopenia (49 [23%] of 217) and anaemia (35 [16%]) for belantamab mafodotin, and neutropenia (34 [33%] of 102) and anaemia (18[18%]) for pomalidomide-dexamethasone. Serious adverse events occurred in 94 (43%) of 217 and 40 (39%) of 102 patients, respectively. There were no treatment-related deaths in the belantamab mafodotin group and one (1%) in the pomalidomide-dexamethasone group due to sepsis.
INTERPRETATION
Belantamab mafodotin was not associated with statistically improved progression-free survival compared with standard-of-care, but there were no new safety signals associated with its use. Belantamab mafodotin is being tested in combination regimens for relapsed or refractory multiple myeloma.
FUNDING
GSK (study number 207495).
Topics: Aged; Female; Humans; Male; Anemia; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Multiple Myeloma; Neoplasm Recurrence, Local; Middle Aged
PubMed: 37793771
DOI: 10.1016/S2352-3026(23)00243-0 -
Blood Jun 2016The International Myeloma Working Group consensus updates the definition for high-risk (HR) multiple myeloma based on cytogenetics Several cytogenetic abnormalities such...
The International Myeloma Working Group consensus updates the definition for high-risk (HR) multiple myeloma based on cytogenetics Several cytogenetic abnormalities such as t(4;14), del(17/17p), t(14;16), t(14;20), nonhyperdiploidy, and gain(1q) were identified that confer poor prognosis. The prognosis of patients showing these abnormalities may vary with the choice of therapy. Treatment strategies have shown promise for HR cytogenetic diseases, such as proteasome inhibition in combination with lenalidomide/pomalidomide, double autologous stem cell transplant plus bortezomib, or combination of immunotherapy with lenalidomide or pomalidomide. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. Cross-trial comparisons may provide insight into the effect of new drugs in patients with cytogenetic abnormalities. However, to achieve this, consensus on definitions of analytical techniques, proportion of abnormal cells, and treatment regimens is needed. Based on data available today, bortezomib and carfilzomib treatment appear to improve complete response, progression-free survival, and overall survival in t(4;14) and del(17/17p), whereas lenalidomide may be associated with improved progression-free survival in t(4;14) and del(17/17p). Patients with multiple adverse cytogenetic abnormalities do not benefit from these agents. FISH data are implemented in the revised International Staging System for risk stratification.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Chromosome Aberrations; Combined Modality Therapy; Consensus; Cytogenetics; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Multiple Myeloma; Prognosis; Risk Factors; Thalidomide; Transplantation, Autologous
PubMed: 27002115
DOI: 10.1182/blood-2016-01-631200 -
Nature Medicine Feb 2024Due to evolving treatment standards for newly diagnosed multiple myeloma, many patients will be triple-class exposed after initial relapses and have poor survival. Novel...
Due to evolving treatment standards for newly diagnosed multiple myeloma, many patients will be triple-class exposed after initial relapses and have poor survival. Novel therapies and combinations are therefore required to improve outcomes. B cell maturation antigen (BCMA)-targeted biologics have emerged as an important new area of therapeutics for relapsed multiple myeloma. The two-part ALGONQUIN trial evaluated various doses and schedules of the anti-BCMA antibody-drug conjugate belantamab mafodotin plus pomalidomide and dexamethasone for patients who are lenalidomide refractory and proteosome inhibitor exposed. The primary endpoints, including evaluating dose-limiting toxicities, establishing the recommended Part 2 dose (RP2D) and overall response rate for patients treated at the RP2D, were met. Secondary efficacy endpoints included progression-free survival and overall survival. Patients treated on study (N = 87) had a median of three previous regimens and 55.2% were triple-class refractory. At the RP2D the most common adverse events were decrease in best-corrected visual acuity (71.1%), keratopathy (65.8%), fatigue (57.9%), infection (47.4%; 7.9% grade ≥3), neutropenia (39.5%) and thrombocytopenia (39.5%). For RP2D patients (n = 38), the overall response rate was 85.3%, ≥very good partial response 75.7% and estimated two-year progression-free survival 52.8% (95% confidence interval, 33.9% to 82.4%), at a median follow-up of 13.9 months. The RP2D schedule was associated with manageable antibody-drug conjugate-associated corneal adverse events and improved tolerability without compromising efficacy. Belantamab mafodotin plus pomalidomide and dexamethasone induced durable responses with promising overall survival in relapsed multiple myeloma, the results of which are yet to be confirmed in the phase 3 DREAMM-8 study. ClinicalTrials.gov Identifier: NCT03715478 .
Topics: Humans; Multiple Myeloma; Treatment Outcome; Dexamethasone; Antineoplastic Combined Chemotherapy Protocols; Immunoconjugates; Thalidomide; Antibodies, Monoclonal, Humanized
PubMed: 38177852
DOI: 10.1038/s41591-023-02703-y -
Immunology Letters Jul 2018The fist in class CD38-targeting antibody, daratumumab, is currently approved as single agent and in combination with standards of care for the treatment of relapsed and... (Review)
Review
The fist in class CD38-targeting antibody, daratumumab, is currently approved as single agent and in combination with standards of care for the treatment of relapsed and refractory multiple myeloma. Based on the high activity and favorable toxicity profile of daratumumab, other CD38 antibodies, such as isatuximab, MOR202, and TAK-079, are being evaluated in MM and other malignancies. The CD38-targeting antibodies have classic Fc-dependent immune effector mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). These mechanisms of action are dependent on CD38 expression on the tumor cells. There is increasing evidence that CD38 antibodies also improve host-anti-tumor immune response by eliminating CD38-positive immune suppressor cells, including regulatory T cells, regulatory B cells, and myeloid-derived suppressor cells. Indeed, daratumumab treatment results in a marked increase in T cell numbers and activity. CD38-targeting antibodies probably also reduce adenosine production in the bone marrow microenvironment, which may contribute to improved T cell activity. Preclinical and clinical studies have demonstrated that CD38-targeting antibodies have synergistic activity with several other anti-cancer drugs, including various agents with immune stimulating activity, such as lenalidomide and pomalidomide, as well as PD1/PD-L1 inhibitors.
Topics: ADP-ribosyl Cyclase 1; Adenosine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibody-Dependent Cell Cytotoxicity; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes, Regulatory; B7-H1 Antigen; Humans; Immunologic Factors; Lenalidomide; Membrane Glycoproteins; Multiple Myeloma; Myeloid-Derived Suppressor Cells; Programmed Cell Death 1 Receptor; T-Lymphocytes, Regulatory; Thalidomide
PubMed: 29702148
DOI: 10.1016/j.imlet.2018.04.005 -
Critical Reviews in Oncology/hematology Aug 2023Treatment of multiple myeloma (MM) has seen great advances in recent years, and a key contributor to this change has been the effective use of combination therapies,... (Review)
Review
Treatment of multiple myeloma (MM) has seen great advances in recent years, and a key contributor to this change has been the effective use of combination therapies, which have improved both the depth and duration of patient responses. Immunomodulatory drug (IMiD) agents (lenalidomide and pomalidomide) have both tumoricidal and immunostimulatory functions, and due to their multiple mechanisms of action have become the backbone of numerous combination treatments in the newly diagnosed and relapsed/refractory settings. Although IMiD agent-based combination regimens provide improved clinical outcomes for patients with MM, the mechanisms underpinning these combinations are not well understood. In this review we describe the potential mechanisms of synergy leading to the enhanced activity observed when IMiD agents and other drug classes are used in combination through interrogation of the current knowledge surrounding their mechanism of actions.
Topics: Humans; Multiple Myeloma; Lenalidomide; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Immunomodulation
PubMed: 37268176
DOI: 10.1016/j.critrevonc.2023.104041 -
Blood Advances Dec 2023
Topics: Humans; Multiple Myeloma; Bortezomib; Thalidomide; Renal Insufficiency; Dexamethasone
PubMed: 37922425
DOI: 10.1182/bloodadvances.2023011428 -
Blood Cancer Journal May 2023
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Multiple Myeloma; POEMS Syndrome; Thalidomide
PubMed: 37253713
DOI: 10.1038/s41408-023-00859-x -
Targeted Oncology Sep 2021Isatuximab (Sarclisa; isatuximab-irfc in the USA) is an anti-CD38 monoclonal antibody (mAb) approved for use in the treatment of adults with multiple myeloma (MM): in... (Review)
Review
Isatuximab (Sarclisa; isatuximab-irfc in the USA) is an anti-CD38 monoclonal antibody (mAb) approved for use in the treatment of adults with multiple myeloma (MM): in combination with pomalidomide and dexamethasone for those with relapsed and refractory MM (RRMM) who have received ≥ 2 prior therapies, including lenalidomide and a proteasome inhibitor; and in combination with carfilzomib and dexamethasone for those with relapsed MM who have received ≥ 1 prior therapy. In phase III studies, the addition of isatuximab to pomalidomide and dexamethasone significantly prolonged progression-free survival (PFS) and improved the depth of tumour response in patients with RRMM, as did the addition of isatuximab to carfilzomib and dexamethasone in patients with relapsed or refractory MM. Health-related quality of life was maintained when isatuximab was combined with these other therapies. Isatuximab-based combination therapies were generally well tolerated and demonstrated a manageable safety profile with no new safety signals. Although mature overall survival data are awaited, available evidence indicates that the combinations of isatuximab with pomalidomide and dexamethasone and isatuximab with carfilzomib and dexamethasone are important additional treatment options for RRMM and relapsed MM, respectively.
Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Quality of Life
PubMed: 34351561
DOI: 10.1007/s11523-021-00827-0 -
Future Oncology (London, England) Feb 2017
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Humans; Immunologic Factors; Multiple Myeloma; Retreatment; Thalidomide
PubMed: 28116940
DOI: 10.2217/fon-2016-0559 -
American Journal of Therapeutics
Topics: Dexamethasone; Humans; Lung Diseases; Multiple Myeloma; Thalidomide
PubMed: 33369914
DOI: 10.1097/MJT.0000000000000870