Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study

Usmani, Saad Z.; Quach, Hang; Mateos, María‐Victoria; Landgren, Ola; Leleu, Xavier; Siegel, David S.; Weisel, Katja; Gavriatopoulou, Maria; Oriol, Albert; Rabin, Neil; Nooka, Ajay K.; Qi, Ming; Beksaç, Meral; Jakubowiak, Andrzej; Ding, Bifeng; Zahlten-Kumeli, Anita; Yusuf, Akeem; Dimopoulos, Meletios A.

doi:10.1016/s1470-2045(21)00579-9

Cited by 113 publications

(96 citation statements)

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“…After a median follow-up of 16.9 months, the addition of daratumumab to Kd yielded a statistically significant improvement in median PFS (HR, 0.63; 95% CI 0.46–0.85; two-sided P = 0.0027) (Table 3 ) [ 75 ]. Results from the updated PFS analysis at a median follow-up of 27.8 months in the daratumumab-Kd group and 27.0 months in the Kd group showed a median PFS of 28.6 months (95% CI 22.7–not estimable) with daratumumab-Kd vs. 15.2 months (95% CI 11.1–19.9) with Kd (HR, 0.59, 95% CI 0.45–0.78, log-rank p < 0.0001) [ 76 ].…”

Section: Clinical Trial Resultsmentioning

confidence: 99%

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Anti-CD38 antibody therapy for patients with relapsed/refractory multiple myeloma: differential mechanisms of action and recent clinical trial outcomes

et al. 2022

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CD38 is a transmembrane glycoprotein that functions both as a receptor and an ectoenzyme, playing key roles in the regulation of calcium signaling and migration of immune cells to tumor microenvironments. High expression on multiple myeloma (MM) cells and limited expression on normal cells makes CD38 an ideal target for the treatment of MM patients. Two monoclonal antibodies directed at CD38, isatuximab and daratumumab, are available for use in patients with relapsed and/or refractory MM (RRMM); daratumumab is also approved in newly diagnosed MM and light-chain amyloidosis. Clinical experience has shown that anti-CD38 antibody therapy is transforming treatment of MM owing to its anti-myeloma efficacy and manageable safety profile. Isatuximab and daratumumab possess similarities and differences in their mechanisms of action, likely imparted by their binding to distinct, non-overlapping epitopes on the CD38 molecule. In this review, we present the mechanistic properties of these two antibodies and outline available evidence on their abilities to induce adaptive immune responses and modulate the bone marrow niche in MM. Further, we discuss differences in regulatory labeling between these two agents and analyze recent key clinical trial results, including evidence in patients with underlying renal impairment and other poor prognostic factors. Finally, we describe the limited existing evidence for the use of isatuximab or daratumumab after disease progression on prior anti-CD38 mono- or combination therapy, highlighting the need for additional clinical evaluations to define optimal anti-CD38 antibody therapy selection and sequencing in RRMM.

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Section: Clinical Trial Resultsmentioning

confidence: 99%

“…[75]. Results from the updated PFS analysis at a median follow-up of 27.8 months in the daratumumab-Kd group and 27.0 months in the Kd group showed a median PFS of 28.6 months (95% CI 22.7-not estimable) with daratumumab-Kd vs. 15.2 months (95% CI 11.1-19.9) with Kd (HR, 0.59, 95% CI 0.45-0.78, log-rank p < 0.0001)[76].…”

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confidence: 94%

Anti-CD38 antibody therapy for patients with relapsed/refractory multiple myeloma: differential mechanisms of action and recent clinical trial outcomes

et al. 2022

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“…However, one of the major limitations of this study is the lack of information in some of the important patient factors (e.g., ECOG performance status), tumorfactors (e.g., Revised International Staging System prognostic factors for MM 13 ), and treatment factors (e.g., the use of systemic therapy course of disease with availability of multiple systemic therapy options may warrant higher dose multifraction RT to provide more durable control, and this is different to a frail patient who is refractory to multiple lines of systemic therapy at the EOL. Nonetheless, it is important for radiation oncologists to stay abreast with advancement in systemic therapy options for MM, 15 as new combination systemic therapies (e.g., carfilzomib, daratumumab, and dexamethasone) have been shown to significantly improve outcomes, even in the setting of refractory MM, 16 and this may influence the decision making in RT fractionation prescribed.…”

Section: Discussionmentioning

confidence: 99%

Large variation in radiation therapy fractionation for multiple myeloma in Australia

Ong

MacManus

Milne

et al. 2022

Asia-Pac J Clncl Oncology

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Aim:To evaluate the patterns of use of different radiation therapy (RT) fractionation for multiple myeloma (MM) bone disease.Methods: This is a population-based cohort of patients with MM who had RT between 2012 and 2017 as captured in the statewide Victorian Radiotherapy Minimum Data Set in Australia. Data linkage was performed to identify subsets of RT delivered within 3 months of death. RT fractionation was classified into four groups: single-fraction (SFRT), 2-5, 6-10, and > 10 fractions. Changes in RT fractionation use over time were evaluated with the Cochran-Armitage test for trend. Factors associated with RT fractionation were evaluated using multivariate logistic regressions.Results: Nine hundred and sixty-seven courses of RT were delivered in 623 patients.The proportion of SFRT, 2-5, 6-10 and > 10 fractions RT was 18%, 47%, 28%, and 7%, respectively. There was an increase in the use of 2-5 fractions, from 48% in 2012 to 60% in 2017 (p-trend < .001), with corresponding decrease in the use of 6-10 fractions, from 26% in 2012 to 20% in 2017 (p-trend = .003). Nine percent (40/430) of RT courses at private institutions were SFRT, compared to 25% (135/537) in public institutions (p < .001). In multivariate analyses, treatment in private institution was the strongest predictor of multifraction RT use. SFRT use was more common closer to the end of life--18%, 14%, and 33% of RT within 2-3, 1-2, < 1 month of death, respectively. Conclusion:There is increasing use of shorter course RT (2-5 fractions) for MM over time. SFRT use remains low, with large variation in practice. INTRODUCTIONBone involvement is common in patients with multiple myeloma (MM), with up to 80% of patients with newly diagnosed MM presenting with osteolytic lesions, with high risk of skeletal-related events, such asThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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“…CFZ has been approved by FDA as single agent or as part of combination regimens for treating relapsed and refractory MM patients who have already received other therapies [ 92 , 139 ]. Additional studies conducted in relapsed and refractory MM demonstrated that patients treated with CFZ, dexamethasone, and the anti-CD38 monoclonal antibody daratumumab showed an extended PFS as well as a favorable benefit risk profile compared to patients treated with CFZ and dexamethasone [ 140 ]. Additional clinical trials testing CFZ in MM or relapsed and refractory MM are still ongoing (NCT03934684; NCT02970747; NCT02199665; NCT02899052; NCT04813653; NCT04176718; NCT04263480; etc).…”

Section: Therapeutic Targeting Of the Nf-κb Pathway In Cancermentioning

confidence: 99%

The NF-κB Pharmacopeia: Novel Strategies to Subdue an Intractable Target

et al. 2022

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NF-κB transcription factors are major drivers of tumor initiation and progression. NF-κB signaling is constitutively activated by genetic alterations or environmental signals in many human cancers, where it contributes to almost all hallmarks of malignancy, including sustained proliferation, cell death resistance, tumor-promoting inflammation, metabolic reprogramming, tissue invasion, angiogenesis, and metastasis. As such, the NF-κB pathway is an attractive therapeutic target in a broad range of human cancers, as well as in numerous non-malignant diseases. Currently, however, there is no clinically useful NF-κB inhibitor to treat oncological patients, owing to the preclusive, on-target toxicities of systemic NF-κB blockade. In this review, we discuss the principal and most promising strategies being developed to circumvent the inherent limitations of conventional IκB kinase (IKK)/NF-κB-targeting drugs, focusing on new molecules that target upstream regulators or downstream effectors of oncogenic NF-κB signaling, as well as agents targeting individual NF-κB subunits.

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Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study

Cited by 113 publications

References 17 publications

Anti-CD38 antibody therapy for patients with relapsed/refractory multiple myeloma: differential mechanisms of action and recent clinical trial outcomes

Anti-CD38 antibody therapy for patients with relapsed/refractory multiple myeloma: differential mechanisms of action and recent clinical trial outcomes

Large variation in radiation therapy fractionation for multiple myeloma in Australia

The NF-κB Pharmacopeia: Novel Strategies to Subdue an Intractable Target

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