Daratumumab, bortezomib, cyclophosphamide and dexamethasone in newly diagnosed and relapsed multiple myeloma: <scp>LYRA</scp> study

Yimer, Habte; Melear, Jason M.; Faber, Edward A.; Bensinger, William I.; Burke, John M.; Narang, Mohit; Stevens, Don A.; Gunawardena, Sriya; Lutska, Yana; Qi, Keqin; Ukropec, Jon; Qi, Ming; Lin, Thomas S.; Rifkin, Robert M.

doi:10.1111/bjh.15806

Cited by 57 publications

(34 citation statements)

References 27 publications

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“…A split first dose of daratumumab is also under evaluation in the daratumumab plus KRd arm of this study in patients with NDMM 34 and in the phase 2 LYRA study of daratumumab plus cyclophosphamide, bortezomib, and dexamethasone in patients with NDMM or relapsed MM. 35 Similar reductions in the durations of first infusions were observed, suggesting that this may be an option to improve patient convenience and ease of outpatient administration for initial dosing. Based on the data from the present study, the split first daratumumab dosing regimen was recently approved.…”

Section: Discussionmentioning

confidence: 65%

Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma

Chari

Martínez‐López

Mateos

et al. 2019

Blood

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118

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K E Y P O I N T S l Daratumumab plus carfilzomib/ dexamethasone induced deep durable responses, regardless of prior treatment with lenalidomide. l Splitting the first dose of daratumumab was feasible, and the regimen was well tolerated.Patients with relapsed or refractory multiple myeloma (RRMM) have limited treatment options and poor survival outcomes. The increasing adoption of lenalidomide-based therapy for frontline treatment of multiple myeloma has resulted in a need for effective regimens for lenalidomide-refractory patients. This phase 1b study evaluated daratumumab plus carfilzomib and dexamethasone (D-Kd) in patients with RRMM after 1 to 3 prior lines of therapy, including bortezomib and an immunomodulatory drug; lenalidomiderefractory patients were eligible. Carfilzomib-and daratumumab-naïve patients (n 5 85) received carfilzomib weekly on days 1, 8, and 15 of each 28-day cycle (20 mg/m 2 initial dose, escalated to 70 mg/m 2 thereafter) and dexamethasone (40 mg/wk). Of these, 10 patients received the first daratumumab dose as a single infusion (16 mg/kg, day 1 cycle 1), and 75 patients received a split first dose (8 mg/kg, days 1-2 cycle 1). Subsequent dosing was per the approved schedule for daratumumab. Patients received a median of 2 (range, 1-4) prior lines of therapy; 60% were lenalidomide refractory. The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (31%), lymphopenia (24%), anemia (21%), and neutropenia (21%). Infusion-related reactions were observed in 60% and 43% of single and split first-dose patients, respectively. Overall response rate was 84% (79% in lenalidomide-refractory patients). Median progression-free survival (PFS) was not reached; 12-month PFS rates were 74% for all treated patients and 65% for lenalidomide-refractory patients. D-Kd was well tolerated with low neutropenia rates, and it demonstrated deep responses and encouraging PFS, including in patients refractory to lenalidomide.

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Section: Discussionmentioning

confidence: 65%

Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma

Chari

Martínez‐López

Mateos

et al. 2019

Blood

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118

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“…A comprehensive search of the Embase, Medline, the Science Citation Index, and Cochrane Controlled Trial Register attained 432 articles, of which 6 trials met the predefined inclusion criteria, covering 2674 untreated myeloma patients totally. [6][7][8][9][10][11][12][13][14][15] A diagram of the study flow is presented in Figure 1(1). Their characteristics were summarized in Table 1.…”

Section: Re Sultsmentioning

confidence: 99%

“…5 In those relapsed/refractory patients with multiple myeloma, daratumumab added to standard of care significantly prolonged progression-free survival and induced high response quality and had a favorable risk-benefit profile. 6,7 Meanwhile, there were some studies are investigating the use of daratumumab added to standard of care in untreated patients with multiple myeloma, [8][9][10][11][12][13] and most of them only enrolled small number of patients. To better characterize the benefit-to-risk profile of daratumumab combinations in untreated patients, we did this pooled analysis.…”

Section: Introductionmentioning

confidence: 99%

Daratumumab added to standard of care in patients with newly diagnosed multiple myeloma: A network meta‐analysis

Sun

et al. 2019

European J of Haematology

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Purpose: To investigate the activity and safety of daratumumab added to standard of care and evaluate the relative efficacy of DRd vs DVMP and other regimens on survival endpoints for untreated myeloma, we undertook this meta-analysis. Methods:We searched published reports that described the activity and safety of daratumumab added to standard of care for untreated myeloma. Results: Six daratumumab trials were identified, covering 5106 subjects. Daratumumab containing combinations for untreated myeloma attained an impressive complete response or better (≥CR) rate of 24%, very good partial response or better (≥VGPR) rate of 67%, overall response rate (ORR) of 92%. Daratumumab added to standard of care significantly improved progression free survival (PFS): the HR for PFS was 0.52 [0.44, 0.61], P < .001. The HR for overall survival (OS) was 0.73 [0.52, 1.04], P = .09. In the network meta-analysis for patients ineligible for autologous stem-cell transplantation (ASCT), DRd regimen produced significant PFS advantage vs other first-line treatments (VMP HR:0.39 P < .001, Rd HR:0.55 P < .001, MPT HR:0.38 P < .001, and MP HR:0.22 P < .001); DVMP regimen also produced significant PFS advantage vs VMP (HR:0.50 P < .001), MPT (HR:0.49 P < .001), and MP (HR:0.28 P < .001). Among these first-line regimens (DRd, DVMP, VMP, Rd, MPT, and MP), DRd regimen had the highest probability to be the best intervention, with 83.4% and 91.0% probability to reach the longest PFS and OS, respectively. Toxicity consisted primarily of myelosuppression. And, the vital non-hematologic adverse events (AEs) were peripheral sensory neuropathy (41% of all grades) and upper respiratory tract infection (39% of all grades).Conclusions: Daratumumab added to standard of care could produce clinical benefits in newly diagnosed patients with multiple myeloma. DRd and DVMP could be good combination options for those patients ineligible for ASCT. K E Y W O R D Sdaratumumab, front-line, meta-analysis, multiple myeloma

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“…The split first dose was associated with a shorter infusion duration on Day 1 and did not increase the rate of infusion reactions compared with the single first dose regimen [28], supporting the use of split first dosing in patients with MM. Several clinical studies using the split first dosing of daratumumab are also ongoing, including the phase 2 LYRA (NCT02951819) study of daratumumab in combination with cyclophosphamide, bortezomib, and dexamethasone in newly diagnosed MM and relapsed MM [29] and the phase 3 CANDOR (NCT03158688) study of D-Kd versus Kd in patients with relapsed/ refractory MM.…”

Section: Discussionmentioning

confidence: 99%

Split First Dose Administration of Intravenous Daratumumab for the Treatment of Multiple Myeloma (MM): Clinical and Population Pharmacokinetic Analyses

Moreau

Usmani

et al. 2020

Adv Ther

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Introduction: Daratumumab, a human immunoglobulin Gj monoclonal antibody targeting CD38, is approved as monotherapy and in combination with standard-of-care regimens for multiple myeloma. In clinical studies, the median durations of the first, second, and subsequent intravenous infusions of daratumumab were 7.0, 4.3, and 3.4 h, respectively. Splitting the first intravenous infusion of daratumumab over 2 days is an approved alternative dosing regimen to reduce the duration of the first infusion and provide flexibility for patients and healthcare providers. Methods: The feasibility of splitting the first 16-mg/kg infusion into two separate infusions of 8 mg/kg on Days 1 and 2 of the first treatment cycle was investigated in two cohorts [daratumumab, carfilzomib, and dexamethasone (D-Kd) and daratumumab, carfilzomib, lenalidomide, and dexamethasone (D-KRd)] of the phase 1b MMY1001 study. Additionally, a population pharmacokinetic (PK) analysis and simulations were used to compare the PK Enhanced Digital Features To view enhanced digital features for this article go to https://doi.org/10.6084/ m9.figshare.11673591.

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Daratumumab, bortezomib, cyclophosphamide and dexamethasone in newly diagnosed and relapsed multiple myeloma: LYRA study

Cited by 57 publications

References 27 publications

Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma

Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma

Daratumumab added to standard of care in patients with newly diagnosed multiple myeloma: A network meta‐analysis

Split First Dose Administration of Intravenous Daratumumab for the Treatment of Multiple Myeloma (MM): Clinical and Population Pharmacokinetic Analyses

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