Real‐world outcomes of daratumumab monotherapy (DM) for relapsed/refractory multiple myeloma (RRMM) have remained unclear. We conducted a multicentre retrospective study of 107 patients receiving DM for RRMM. The cohort included 64 trial‐unfit patients whose characteristics could not meet inclusion criteria in two previous clinical trials (GEN501 and SIRIUS). The overall response rate (ORR), and median first and second progression‐free survival (PFS1 and PFS2) and overall survival were 42·1%, and 3·6, 8·1 and 11·9 months, respectively. Refractoriness to carfilzomib and/or lenalidomide, and neutropenia (<1.0 × 109/l) resulted in poorer ORRs. An Eastern Cooperative Oncology Group Performance Status of ≥3, neutropenia (<1.0 × 109/l), thrombocytopenia (<75 × 109/l), and renal failure (glomerular filtration rate of <20 ml/min/1·73 m2) were associated with poor PFS1 and PFS2 in respective univariate analysis. The modified trial‐unfit group, based on the above factors, showed significantly negative impacts on PFS1 and PFS2 (hazard ratio 2·823 and 3·677, all P < 0·001) in multivariate analysis despite having a 34% ORR. Fatal infections occurred more often in the modified trial‐unfit group than in the others (16·1% vs. 4·3%; P = 0·099). Despite failure of DM, subsequent therapy with pomalidomide‐based therapy or carfilzomib‐dexamethasone provided a 66·6% ORR. Real‐world DM showed favourable efficacies for RRMM and, potentially, additional benefits with subsequent therapies. However, characteristics corresponding with trial‐unfitness might offset the efficacy of DM.

2021-02-01·Leukemia1区 · 医学

Deep immune profiling of patients treated with lenalidomide and dexamethasone with or without daratumumab

1区 · 医学

Article

作者: van de Donk, Niels W C J ; Rusbuldt, Joshua ; Chiu, Christopher ; Bald, Jaime ; Adams, Homer C ; Lysaght, Andrew ; Avet-Loiseau, Herve ; Casneuf, Tineke ; Stevenaert, Frederik ; Smets, Tina ; Foulk, Brad ; Usmani, Saad Z ; Bahlis, Nizar J ; Ceulemans, Hugo ; Axel, Amy ; Mutis, Tuna ; Plesner, Torben ; Abraham, Yann ; Vanhoof, Greet ; Nijhof, Inger ; Van der Borght, Koen ; Nielsen, Karl C ; Schecter, Jordan M

Abstract:

CD38-targeted antibody, daratumumab, is approved for the treatment of multiple myeloma (MM). Phase 1/2 studies GEN501/SIRIUS revealed a novel immunomodulatory mechanism of action (MOA) of daratumumab that enhanced the immune response, reducing natural killer (NK) cells without affecting efficacy or safety. We further evaluated daratumumab’s effects on immune cells in whole blood samples of relapsed/refractory MM patients from both treatment arms of the phase 3 POLLUX study (lenalidomide/dexamethasone [Rd] or daratumumab plus Rd [D-Rd]) at baseline (D-Rd, 40; Rd, 45) and after 2 months on treatment (D-Rd, 31; Rd, 33) using cytometry by time-of-flight. We confirmed previous reports of NK cell reduction with D-Rd. Persisting NK cells were phenotypically distinct, with increased expression of HLA-DR, CD69, CD127, and CD27. The proportion of T cells increased preferentially in deep responders to D-Rd, with a higher proportion of CD8+versus CD4+T cells. The expansion of CD8+T cells correlated with clonality, indicating generation of adaptive immune response with D-Rd. D-Rd resulted in a higher proportion of effector memory T cells versus Rd. D-Rd reduced immunosuppressive CD38+regulatory T cells. This study confirms daratumumab’s immunomodulatory MOA in combination with immunomodulatory drugs and provides further insight into immune cell changes and activation status following daratumumab-based therapy.

2020-06-01·The Lancet. Haematology1区 · 医学

Daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma: final results from the phase 2 GEN501 and SIRIUS trials

1区 · 医学

Article

作者: Weiss, Brendan M ; Nahi, Hareth ; Plesner, Torben ; Belch, Andrew ; Wang, Jianping ; Voorhees, Peter M ; Qi, Ming ; Uhlar, Clarissa M ; Ahmadi, Tahamtan ; Bahlis, Nizar J ; Feng, Huaibao ; Usmani, Saad Z ; Richardson, Paul G ; Lonial, Sagar ; Laubach, Jacob P ; van de Donk, Niels W C J

BACKGROUND:

Daratumumab showed encouraging efficacy as monotherapy in patients with heavily pretreated multiple myeloma in the GEN501 and SIRIUS studies. Here we report a pooled, post-hoc final analysis of these two studies.

METHODS:

GEN501 was an open-label, multicentre, phase 1-2, dose escalation and expansion study done in the Netherlands, the USA, Sweden, and Denmark. Eligible patients had multiple myeloma and had relapsed or were refractory to 2 or more previous lines of treatment that included a proteasome inhibitor or an immunomodulatory drug. SIRIUS was an open-label, multicentre, phase 2 study done in Canada, Spain, and the USA, in which eligible patients with multiple myeloma had received 3 or more previous lines of therapy, including a proteasome inhibitor or an immunomodulatory drug, or were double refractory. In both studies, eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group performance status of 2 or less. In part 2 of GEN501, patients were given intravenous daratumumab 16 mg/kg once per week for 8 weeks, twice per month for 8 doses, and then once per month until disease progression. In part 2 of SIRIUS, patients received intravenous daratumumab 16 mg/kg once per week for 8 weeks, twice per month for 16 weeks, and once per month until disease progression. The primary endpoints (safety in GEN501 and overall response rate in SIRIUS) have previously been reported. These trials are registered on ClinicalTrials.gov, NCT00574288 (GEN501) and NCT01985126 (SIRIUS).

FINDINGS:

Patients were enrolled in GEN501 from March 27, 2008, until May 30, 2014, and in SIRIUS from Sept 30, 2013, until May 5, 2014. The combined analysis included 148 patients who received daratumumab 16 mg/kg (42 patients in GEN501 part 2; 106 patients in SIRIUS), with a median follow-up of 36·6 months (IQR 34·5-38·2). Patients had received a median of 5 previous lines of therapy (IQR 4-7), and 128 (87%) of 148 patients were double refractory. The overall response rate was 30·4% (95% CI 23·1-38·5), including 20 (14%) of 148 patients with very good partial response or better (8·5-20·1) and seven (5%) patients reporting complete response or better (1·9-9·5). Among 45 responders, the median duration of response was 8·0 months (95% CI 6·5-14·7). Median overall survival was 20·5 months (95% CI 16·6-28·1), with a 3-year overall survival rate of 36·5% (28·4-44·6). The most common grade 3-4 treatment-emergent adverse events (TEAEs) were anaemia (grade 3, 26 [18%] of 148 patients; no grade 4 events) and thrombocytopenia (grade 3, 13 [9%] of 148 patients; grade 4, 8 [5%] of 148 patients). Serious drug-related TEAEs occurred in 13 (9%) of 148 patients. There were no treatment-related deaths.

INTERPRETATION:

In this analysis, daratumumab 16 mg/kg monotherapy showed durable responses and there were no new safety concerns with longer follow-up.

FUNDING:

Janssen Research & Development.

100 项与 GEN-501 相关的药物交易

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