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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Elotuzumab and daratumumab are two relatively new mAbs approved by the FDA in 2015 for treatment of patients with relapsed or refractory MM. Elotuzumab targets directly the glycoprotein receptor SLAMF7 (Signalling Lymphocyte Activation Molecule Family Member 7) that is overexpressed on the surface of myeloma and NK cells but is not found on normal cells. It exerts a dual effect in that it activates NK cells directly and also mediates antibody-dependent cell-mediated cytotoxicity (ADCC) by recruiting activated NK cells on MM cells (Lonial et al., 2015). Daratumumab is a human anti-CD38 IgG1 (κ subclass) antibody. It targets the protein CD38 (also an enzyme that catalyzes the metabolism of cyclic adenosine diphosphate ribose and nicotinic acid adenine dinucleotide phosphate) that is overexpressed on multiple myeloma cells and also expressed on many types of immune cells. Its antimyeloma effect mainly relies on its prominent ADCC and complement-dependent cytotoxicity (CDC) activities (Phipps et al., 2015). This topic is discussed in more detail in Section 21.2.3.4.3.
Plasma Cell Neoplasms
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
The licensing of the first monoclonal antibody, as a monotherapy for the treatment of relapsed-and-refractory myeloma, daratumumab, which targets CD38, an antigen uniformly expressed in all myeloma cells, has generally been considered to be a breakthrough. The antibody when used as a single agent in patients who have had at least three previous treatments, accorded about 30% responses rates and a survival benefit. This remarkable activity appears to be arise from the drug, triggering long-term memory T-cell function, and the associated anti-MM immunity, by targeting the CD38 immunosuppressive cells. This is unprecedented in patients with relapsed-and-refractory disease, and there is much enthusiasm to test the agent in first-line setting in combination with a chemotherapy-free regimen. The challenge in the first-line use is of course formidable, given an overall survival of about 88% at 3 years with VRD. A second monoclonal antibody, elotuzumab, which targets the signalling lymphocytic activation molecule F7 (SLAMF7) has also been approved for use as a combination for relapsed-and-refractory myeloma. Panobinostat, a deacetylase inhibitor, is also licensed for this indication, and in a randomized trial in combination with VD had a longer progression-free survival and more near or complete responses, compared to VD plus placebo. The principal side effect appears to be grade 3 diarrhoea, which occurs in about a quarter of all patients.
Multiple myeloma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
A number of monoclonal antibodies are showing promise in MM. Daratumumab is an anti-CD38 antibody that is showing efficacy and good tolerability in early phase trials. Elotuzumab is a humanized anti-CS1 monoclonal antibody that enhances natural killer cell activity and is already being incorporated into combination regimens. Histone deacetylase inhibitors such as vorinostat and panobinostat have been used in combination with bortezomib predominantly and also lenalidomide and clearly show improved efficacy with the addition of an HDAC inhibitor.155 Other novel agents include ARRY-50, a novel kinesin spindle protein inhibitor, other monoclonal antibodies and heat shock protein inhibitors.
Safety and efficacy of Elotuzumab combination therapy for patients with multiple myeloma: A systematic review and meta-analysis
Published in Expert Review of Anticancer Therapy, 2023
Maryam Noori, Farimah Fayyaz, Nima Rezaei
In conclusion, the constant development of novel treatment approaches in patients with MM in recent years promises a more prolonged survival and lower mortality in these patients. The completion of multiple RCTs on the Elotuzumab combination therapy and the publication of their updated results with long median follow-ups prompted a pooled analysis. Our findings showed that Elotuzumab combination therapy significantly prolongs OS and PFS compared to non-Elotuzumab treatments in patients with MM, particularly those with relapsed/refractory disease. However, further investigations are required to establish the most effective combination of the Elotuzumab regimen, taking patients’ drug resistance and comorbidities into account. Moreover, identifying response markers that determine patients more likely to benefit from Elotuzumab therapies could optimize treatment regimen selection for each individual.
Advances in maintenance strategy in newly diagnosed multiple myeloma patients eligible for autologous transplantation
Published in Expert Review of Hematology, 2020
Ahsan Wahab, Abdul Rafae, Muhammad Salman Faisal, Kamran Mushtaq, Hamid Ehsan, Maria Khakwani, Afia Ashraf, Tayyab Rehan, Zahoor Ahmed, Zunairah Shah, Aslam Khan, Faiz Anwer
Lenalidomide has been successfully combined with other agents [36–38]. In a pooled study of two RCTs (GIMEMA-RV-MM-PI-209 and RV-MM-EMN-441), lenalidomide combination with prednisone was better in terms of m-PFS (71% vs. 41%) and OS (86% vs. 75%) compared to lenalidomide alone [36]. Elotuzumab, a monoclonal antibody, has been successfully combined with lenalidomide in post-myeloablative phase. The preliminary results of this phase-II trial (3-Yr PFS:81%, OS:96%) support future trials on this combination [38]. Lenalidomide was also safely combined with vorinostat in 2015 in a dose-escalation phase-I trial which showed improved responses in 7 of 15 participants [37]. Sharma et al. reported long-term results of this trial with m-PFS of 64.3 months (range: 21.7-months-NR) at a median follow-up of 89.8 months. Median-OS was not reached but 2, 4 and 6 year OS estimates were 94%, 88%, and 69%, respectively, [39].
The safety of current and emerging therapies for multiple myeloma
Published in Expert Opinion on Drug Safety, 2020
Omar Nadeem, Kenneth C. Anderson
Elotuzumab is administered intravenously at a dose of 10 mg/kg weekly for the first 2 cycles. It is then administered every 2 weeks if in combination with lenalidomide or monthly at a dose of 20 mg/kg if in combination with pomalidomide. Grade 3 or greater hematologic adverse effects when used in combination with lenalidomide included lymphopenia (77%), anemia (19%), thrombocytopenia (19%), and neutropenia (34%). Grade 3 or greater non-hematologic adverse events were uncommon and included fatigue (8%), pyrexia (3%), and diarrhea (5%). Infections were reported in 81% of patients in the Elo-Ld group vs 74% in the Ld group. IRR were reported in 10% of patients, mostly grades 1–2, and the majority occurred during the first infusion. The AE profile was similar when combined with pomalidomide, with the exception of lower hematologic toxicity.