Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma

Palumbo, Antônio; Chanan‐Khan, Asher; Weisel, Katja; Nooka, Ajay K.; Masszi, Tamás; Beksaç, Meral; Špıčka, Ivan; Hungria, Vânia; Mun, Yeung Chul; Mateos, María‐Victoria; Mark, Tomer M.; Qi, Ming; Schecter, Jordan M.; Amin, Himal; Qin, Xiang; Deraedt, William; Ahmadi, Tahamtan; Spencer, Andrew; Sonneveld, Pieter

doi:10.1056/nejmoa1606038

Cited by 1,314 publications

(1,247 citation statements)

References 32 publications

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“…2 Two phase 3 studies of daratumumab in combination with standard-of-care regimens in patients treated with at least 1 prior line of therapy (POLLUX and CASTOR) have demonstrated a significant benefit to progression-free survival (PFS). 10,11 The reduction in the risk of disease progression or death was more than 60% compared with active controls. In these studies, patients refractory to the standard-of-care regimens were not eligible for enrollment.…”

Section: Introductionmentioning

confidence: 99%

Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma

Chari

Suvannasankha

Fay

et al. 2017

Blood

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• No new safety signals were observed with daratumumab plus pomalidomide and dexamethasone, except for increased neutropenia.• Daratumumab plus pomalidomide and dexamethasone induced rapid, deep, and durable responses in heavily treated patients with multiple myeloma.Daratumumab plus pomalidomide and dexamethasone (pom-dex) was evaluated in patients with relapsed/refractory multiple myeloma with ‡2 prior lines of therapy who were refractory to their last treatment. Patients received daratumumab 16 mg/kg at the recommended dosing schedule, pomalidomide 4 mg daily for 21 days of each 28-day cycle, and dexamethasone 40 mg weekly. Safety was the primary end point. Overall response rate (ORR) and minimal residual disease (MRD) by next-generation sequencing were secondary end points. Patients (N 5 103) received a median (range) of 4 (1-13) prior therapies; 76% received ‡3 prior therapies. The safety profile of daratumumab plus pomdex was similar to that of pom-dex alone, with the exception of daratumumab-specific infusion-related reactions (50%) and a higher incidence of neutropenia, although without an increase in infection rate. Common grade ‡3 adverse events were neutropenia (78%), anemia (28%), and leukopenia (24%). ORR was 60% and was generally consistent across subgroups (58% in double-refractory patients). Among patients with a complete response or better, 29% were MRD negative at a threshold of 10 25 . Among the 62 responders, median duration of response was not estimable (NE; 95% confidence interval [CI], 13.6-NE). At a median follow-up of 13.1 months, the median progression-free survival was 8.8 (95% CI, 4.6-15.4) months and median overall survival was 17.5 (95% CI, 13.3-NE) months. The estimated 12-month survival rate was 66% (95% CI, 55.6-74.8). Aside from increased neutropenia, the safety profile of daratumumab plus pom-dex was consistent with that of the individual therapies. Deep, durable responses were observed in heavily treated patients. The study was registered at www.clinicaltrials.gov as #NCT01998971. (Blood. 2017;130(8):974-981)

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Section: Introductionmentioning

confidence: 99%

Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma

Chari

Suvannasankha

Fay

et al. 2017

Blood

Self Cite

405

311

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“…158 In both examples, the ability of a specific agent (e.g., oxaliplatin, cyclophosphamide) but not one of its alike (e.g., cisplatin, melphalan) to drive ICD can be explained by the differential activation of ER stress (and hence differential exposure of CALR in the course of RCD). 100,[157][158][159] Well established ICD inducers include commonly employed anticancer chemotherapeutics such as: (1) (6) bortezomib, a proteasomal inhibitor approved for the therapy MM and mantle cell lymphoma (MCL); [171][172][173][174][175][176][177][178][179][180][181] (7) cyclophosphamide, a DNA-alkylating agent approved for use in patients with chronic myeloid leukemia (CML), AML, ALL, chronic lymphocytic leukemia, MM, ovarian carcinoma, breast carcinoma, mycosis fungoides, lymphoma, neuroblastoma, and retinoblastoma; 177,[182][183][184][185][186][187][188][189][190][191] and (8) oxaliplatin, a platinum-derivative licensed for the therapy of advanced colorectal carcinoma in combination with 5-fluorouracil and folinic acid. 156,157,[192][193][194][195][196][197][198] Moreover, there is some evidence that microtubule-targeting agents including taxanes and vinca alkaloids (which are commonly used for the treatment of multiple carcinomas) can stimulate ICD.…”

Section: Introductionmentioning

confidence: 99%

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

et al. 2017

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The expression "immunogenic cell death" (ICD) refers to a functionally unique form of cell death that facilitates (instead of suppressing) a T cell-dependent immune response specific for dead cell-derived antigens. ICD critically relies on the activation of adaptive responses in dying cells, culminating with the exposure or secretion of immunostimulatory molecules commonly referred to as "damage-associated molecular patterns". Only a few agents can elicit bona fide ICD, including some clinically established chemotherapeutics such as doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin. In this Trial Watch, we discuss recent progress on the development of ICD-inducing chemotherapeutic regimens, focusing on studies that evaluate clinical efficacy in conjunction with immunological biomarkers.

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“…The synergistic efficacy of these two classes of agent has been confirmed in the phase III CASTOR study comparing daratumumab plus bortezomib and dexamethasone vs. bortezomib and dexamethasone. In a pre-specified interim analysis, treatment with daratumumab led to a significant increase in median PFS compared with bortezomib and dexamethasone treatment alone (NR vs. 7.2 months; HR, 0.39; P < 0.001) (Palumbo et al, 2016). Grade 3-4 AEs in the daratumumab group and the bortezomib and G. Cook et al Critical Reviews in Oncology / Hematology 121 (2018) 74-89 dexamethasone only group included thrombocytopenia, anaemia and neutropenia (Table 1).…”

Section: Combining Pis and Mabsmentioning

confidence: 99%

A question of class: Treatment options for patients with relapsed and/or refractory multiple myeloma

Cook

Mateos

Suzan

et al. 2018

Critical Reviews in Oncology/Hematology

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A B S T R A C TMultiple classes of agent with distinct mechanisms of action are now available for the treatment of patients with relapsed and/or refractory multiple myeloma (RRMM), including immunomodulatory agents, proteasome inhibitors, histone deacetylase inhibitors and monoclonal antibodies. Additionally, several different drugs may be available within each agent class, each with their own specific efficacy and safety profile. This expansion of the treatment landscape has dramatically improved outcomes for patients. However, as the treatment options for RRMM become more complex, choosing the class of agent or combination of agents to use in the relapsed setting becomes increasingly challenging. Furthermore, treatment options for specific patient populations such as the elderly, those with high-risk cytogenetic abnormalities and those with refractory disease are yet to be defined in the current treatment landscape. When choosing an appropriate treatment approach, physicians must consider multiple criteria including both patient-related and disease-related factors. The aim should be to provide patientspecific treatment in order to gain a clinical benefit while minimizing toxicity. This review provides an overview of the mechanism of action and efficacy and safety profiles of each class of agent and of treatment regimens that combine different classes of agent, with a special focus on treating specific patient populations.

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Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma

Cited by 1,314 publications

References 32 publications

Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma

Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

A question of class: Treatment options for patients with relapsed and/or refractory multiple myeloma

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