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Daratumumab Plus Bortezomib and Dexamethasone Regimen Significantly Prolongs OS in Patients with Relapsed or Refractory Multiple Myeloma

Long-term overall survival results from the CASTOR study
30 Nov 2022
Anticancer agents & Biologic therapy;  Haematologic malignancies

Updated efficacy and safety results show at the final analysis for overall survival (OS) in multicentre, randomised, open-label, phase III CASTOR study, after a median follow-up of 72.6 months, that daratumumab plus bortezomib and dexamethasone regimen significantly prolonged OS in patients with relapsed or refractory multiple myeloma with a 26% reduction in the risk of death versus bortezomib and dexamethasone alone. Median OS was 49.6 months with daratumumab plus bortezomib and dexamethasone versus 38.5 months with bortezomib and dexamethasone. Prespecified subgroup analyses showed OS improvement with daratumumab plus bortezomib and dexamethasone across most patient subgroups, with the greatest benefit observed in patients with one prior line of treatment. Findings are published by Dr. Pieter Sonneveld of the Erasmus MC Cancer Institute in Rotterdam, the Netherlands and colleagues on 22 November 2022 in the JCO.

Daratumumab is a human monoclonal antibody targeting CD38 with a direct on-tumour and immunomodulatory mechanism of action. In phase III studies among newly diagnosed and relapsed or refractory multiple myeloma, the addition of daratumumab to standard of care regimens significantly reduced the risk of disease progression or death and achieved deep and durable responses, including significantly higher complete response or better (≥ CR) rates and minimal residual disease (MRD)-negativity rates, versus standard of care alone.

At the primary analysis of the phase III CASTOR study with a median follow-up of 7.4 months, daratumumab plus bortezomib and dexamethasone significantly prolonged progression-free survival (PFS) with hazard ratio (HR) of 0.39 (95% confidence interval [CI] 0.28 to 0.53; p < 0.001) and induced higher rates of deeper responses than bortezomib and dexamethasone alone.

After longer follow-up with a mmedian of 19.4 months, daratumumab plus bortezomib and dexamethasone reduced the risk of disease progression or death by 69% with median PFS of 16.7 versus 7.1 months (HR 0.31, 95% CI 0.24 to 0.39; p < .0001) and responses deepened, resulting in higher ≥ CR rates (28.8% versus 9.8%; p < 0.0001) and MRD-negativity rates (10−5 sensitivity, 11.6% versus 2.4%; p = 0.000034) compared with bortezomib and dexamethasone.

In the most recent analysis of the study performed at a median follow-up of 50.2 months, daratumumab plus bortezomib and dexamethasone continued to demonstrate significant efficacy benefits versus bortezomib and dexamethasone alone, inducing deep and more durable responses and improved MRD-negativity rates. Efficacy benefits were most pronounced in patients who received one prior line of treatment, regardless of prior treatment with lenalidomide.

In the latest article, published in the JCO, the authors report updated efficacy and safety results at the time of the final OS analysis in CASTOR after approximately 6 years of follow-up. CASTOR was a multicentre, randomised, open-label, phase III study during which eligible patients with at least one line of prior treatment were randomly assigned to up to eight cycles of bortezomib and dexamethasone with or without daratumumab until disease progression. After positive primary analysis and protocol amendment, patients receiving bortezomib and dexamethasone were offered daratumumab monotherapy after disease progression.

At a median follow-up of 72.6 months (range, 0.0-79.8), significant OS benefit was observed with daratumumab plus bortezomib and dexamethasone (HR 0.74, 95% CI 0.59 to 0.92; p = 0.0075). Median OS was 49.6 months with daratumumab plus bortezomib and dexamethasone versus 38.5 months with bortezomib and dexamethasone.

Prespecified subgroup analyses demonstrated an OS advantage with daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone for most subgroups, including patients age ≥ 65 years and patients with one or two prior lines of treatment, International Staging System stage III disease, high-risk cytogenetic abnormalities, and prior bortezomib treatment.

The most common (≥ 10%) grade 3/4 treatment-emergent adverse events with daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone were thrombocytopenia (46.1% versus 32.9%), anaemia (16.0% versus 16.0%), neutropenia (13.6% versus 4.6%), lymphopenia (10.3% versus 2.5%), and pneumonia (10.7% versus 10.1%).

The authors concluded that these results, together with the OS benefit observed with daratumumab plus lenalidomide and dexamethasone in the phase III POLLUX study, demonstrate for the first time an OS benefit with daratumumab-containing regimens in relapsed or refractory multiple myeloma, with the greatest benefit observed in patients with one prior line of treatment.

The study was supported by Janssen Research & Development, LLC.

Reference

Sonneveld P, Chanan-Khan A, Weisel K, et al. Overall Survival With Daratumumab, Bortezomib, and Dexamethasone in Previously Treated Multiple Myeloma (CASTOR): A Randomized, Open-Label, Phase III Trial. JCO; Published online 22 November 2022. DOI: 10.1200/JCO.21.02734

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