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A. Spencer et al.
fidence interval, 0.12-0.29; P<0.0001). Daratumumab plus bortezomib and dexamethasone was also superior to bortezomib and dexamethasone alone in subgroups based on prior treatment exposure (bortezomib, thalidomide, or lenalidomide), lenalidomide-refractory status, time since last therapy (≤12, >12, ≤6, or >6 months), or cytogenetic risk. Minimal residual disease–negative rates were >2.5-fold high- er with daratumumab across subgroups. The safety profile of daratumumab plus bortezomib and dex- amethasone remained consistent with longer follow up. Daratumumab plus bortezomib and dexam- ethasone demonstrated significant clinical activity across clinically relevant subgroups and provided the greatest benefit to patients treated at first relapse. Trial registration: clinicaltrials.gov identifier: 02136134.
Introduction
As multiple myeloma (MM) progresses, a reduction in the duration and depth of response is observed with each treatment relapse, as a result of diminished sensitivity of heavily treated patients to subsequent therapies.1
Briefly, patients were randomized 1:1 to D-Vd or Vd. Randomization was balanced and stratified by International Staging System (I, II, or III) at screening (cen- tral laboratory results), number of prior lines of therapy (1 versus 2 or 3 versus >3), and prior bortezomib exposure (no versus yes). The study protocol was approved by an inde- pendent ethics committee or institutional review board at each study center, and was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. All patients provided written informed consent.
Patients
Procedures
Patients received 8 cycles of bortezomib (1.3 mg/m2 sub- cutaneously on Days 1, 4, 8, 11) and dexamethasone (20 mg orally on Days 1, 2, 4, 5, 8, 9, 11, 12) with or with- out daratumumab (16 mg/kg intravenously once weekly in Cycles 1-3, Day 1 of Cycles 4-8, then every 4 weeks until disease progression, unacceptable toxicity, or with- drawal of consent). Cycle durations were 21 days for Cycles 1 to 8 and 28 days for Cycle 9 onwards. A protocol amendment after the primary analysis allowed patients who progressed on Vd to receive daratumumab monotherapy.
Assessments and Endpoints
The primary endpoint was PFS; secondary endpoints included time to disease progression, overall response rate (ORR), minimal residual disease (MRD), and safety. This exploratory, post hoc, secondary analysis examined sub- populations according to prior lines of therapy (1, 2-3, >3, or 1-3), prior treatment exposure (bortezomib, thalido- mide, or lenalidomide), refractoriness to lenalidomide at the last prior line of therapy, time since last therapy (≤12, >12, ≤6, or >6 months), and cytogenetic risk assessed cen- trally by next-generation sequencing.19 Site investigators determined numbers of prior lines of therapy using IMWG guidelines.18 Time since last therapy was the dura- tion between the end date of the last line of prior therapy and the randomization date. PFS, ORR, and MRD-nega- tivity at 10–5 and 10–6 sensitivity thresholds were assessed for each subgroup. PFS based on MRD (10–5), and cytoge- netic risk status was also examined. Health-related quality
Proteasome inhibitors (PIs) are widely used due to their clinical effectiveness, manageable safety profile, and com- binability with other therapies.2 However, in several stud- ies of novel PI-based regimens in relapsed and/or refracto- ry MM (RRMM), deep clinical responses were uncom- mon.3-6 PI-based regimens that generate deeper responses in RRMM are an unmet need.
Daratumumab, a human IgGk monoclonal antibody tar- geting CD38, has a direct on-tumor and immunomodula- tory mechanism of action.7-12 In combination with stan- dard of care regimens, (bortezomib and dexamethasone [Vd; CASTOR] or lenalidomide and dexamethasone [Rd; POLLUX]), daratumumab induced rapid, deep, and durable responses, reducing the risk of disease progression or death by >60%, versus Vd or Rd in relapsed patients.13,14 Based on the superior progression-free survival (PFS) ben- efit, daratumumab-Vd (D-Vd) and daratumumab-Rd (D-Rd) were approved in the United States and Europe for MM patients who have received ≥1 prior therapy.15,16 In addition, daratumumab plus pomalidomide and dexam- ethasone was approved in the United States for MM patients after 2 prior therapies including lenalidomide and a PI.15 More recently, daratumumab in combination with bortezomib, melphalan, and prednisone was approved in the United States for patients with newly diagnosed MM who are ineligible for autologous stem cell transplanta- tion.15
Eligible patients had ≥1 prior line of therapy, achieved at least a partial response to ≥1 prior MM treatment, and had progressive disease per International Myeloma Working Group (IMWG) criteria17,18 on or after their last regimen. Patients refractory to bortezomib or another PI (ixazomib or carfilzomib following a protocol amendment) were ineligible.
At the time of the event-driven, pre-specified primary analysis (median follow up: 7.4 months) of the CASTOR study, PFS was significantly prolonged with D-Vd versus Vd (median: not reached versus 7.2 months; hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.28-0.53; P<0.0001).13 This updated analysis provides an additional 12 months of follow up for efficacy and safety compared with the primary analysis, including updated PFS in the intent-to-treat population, and presents an exploratory post hoc analysis of CASTOR to identify patient subgroups that may benefit most from D-Vd.
Methods
Study Design
CASTOR (clinicaltrials.gov
ongoing multi-center, open-label, randomized, active-con- trolled, phase 3 study of D-Vd versus Vd in patients with RRMM who received ≥1 prior line of therapy. The study design and primary results were previously published.13
identifier: 02136134)
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haematologica | 2018; 103(12)