Mezigdomide (CC-92480), a Potent, Novel Cereblon E3 Ligase Modulator (CELMoD), Combined with Dexamethasone (DEX) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Preliminary Results from the Dose-Expansion Phase of the CC-92480-MM-001 Trial

Richardson, Paul G.; Trudel, Suzanne; Quach, Hang; Popat, Rakesh; Lonial, Sagar; Orłowski, Robert Z.; Kım, Kihyun; Mateos, María‐Victoria; Pawlyn, Charlotte; Ramasamy, Karthik; Martínez‐López, Joaquín; Spirlí, Alessia; Casas-Avilés, Ignacio; Gong, Jing; Amatangelo, Michael; Katz, Jessica; Maciag, Paulo; Peluso, Teresa; Bahlis, Nizar J.

doi:10.1182/blood-2022-157945

Cited by 23 publications

(20 citation statements)

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“…Furthermore, the activity of an anti-BCMA BsAb in a murine MM model was improved by the addition of pomalidomide, leading to increased levels of circulating lytic T-cells, even in lenalidomide-resistant cases, although T-cell exhaustion was noted [ 49 ]. Iberdomide and mezigdomide are novel cereblon E3 ligase modulators (CELMoDs) which have more potent tumoricidal and immunogenic effects than the IMiDs and produce greater MM cell killing [ 55 , 56 ]. The asymmetric 2-arm, humanized IgG BsAb alnuctamab [ 57 ] was assessed in a preclinical model, combined with pomalidomide, iberdomide or mezigdomide.…”

Section: Imidsmentioning

confidence: 99%

Bispecific Antibodies in Multiple Myeloma: Opportunities to Enhance Efficacy and Improve Safety

Swan

Murphy

Glavey

et al. 2023

Cancers

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Multiple myeloma (MM) is the second most common haematological neoplasm of adults in the Western world. Overall survival has doubled since the advent of proteosome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies. However, patients with adverse cytogenetics or high-risk disease as determined by the Revised International Staging System (R-ISS) continue to have poorer outcomes, and triple-refractory patients have a median survival of less than 1 year. Bispecific antibodies (BsAbs) commonly bind to a tumour epitope along with CD3 on T-cells, leading to T-cell activation and tumour cell killing. These treatments show great promise in MM patients, with the first agent, teclistamab, receiving regulatory approval in 2022. Their potential utility is hampered by the immunosuppressive tumour microenvironment (TME), a hallmark of MM, which may limit efficacy, and by undesirable adverse events, including cytokine release syndrome (CRS) and infections, some of which may be fatal. In this review, we first consider the means of enhancing the efficacy of BsAbs in MM. These include combining BsAbs with other drugs that ameliorate the effect of the immunosuppressive TME, improving target availability, the use of BsAbs directed against multiple target antigens, and the optimal time in the treatment pathway to employ BsAbs. We then discuss methods to improve safety, focusing on reducing infection rates associated with treatment-induced hypogammaglobulinaemia, and decreasing the frequency and severity of CRS. BsAbs offer a highly-active therapeutic option in MM. Improving the efficacy and safety profiles of these agents may enable more patients to benefit from these novel therapies and improve outcomes for patients with high-risk disease.

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Section: Imidsmentioning

confidence: 99%

Bispecific Antibodies in Multiple Myeloma: Opportunities to Enhance Efficacy and Improve Safety

Swan

Murphy

Glavey

et al. 2023

Cancers

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“…Mezigdomide (CC-92480) is another potent CELMoD, that has a significantly higher degradation efficiency compared to either lenalidomide or pomalidomide, having shown a 55% ORR in a heavily pre-treated RRMM population enrolled in the phase I CC-92480 trial [ 236 ]. Efficacy data in triple-class refractory RRMM, including patients with prior BCMA-targeted therapies are promising, showing 40% and 50% ORR, respectively [ 237 ]. Selinexor is a first-in-class, selective exportin-1 inhibitor, that is approved in the EU and USA for the treatment of adult patients with MM who have received at least one prior therapy.…”

Section: Precision Medicine and Next Generation Therapiesmentioning

confidence: 99%

Current Main Topics in Multiple Myeloma

Morè¹,

Corvatta²,

Manieri³

et al. 2023

Cancers

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Multiple Myeloma (MM) remains a difficult to treat disease mainly due to its biological heterogeneity, of which we are more and more knowledgeable thanks to the development of increasingly sensitive molecular methods that allow us to build better prognostication models. The biological diversity translates into a wide range of clinical outcomes from long-lasting remission in some patients to very early relapse in others. In NDMM transplant eligible (TE) patients, the incorporation of mAb as daratumumab in the induction regimens, followed by autologous stem cell transplantation (ASCT) and consolidation/maintenance therapy, has led to a significant improvement of PFS and OS.; however, this outcome remains poor in ultra-high risk MM or in those who did not achieve a minimal residual disease (MRD) negativity. Several trials are exploring cytogenetic risk-adapted and MRD-driven therapies in these patients. Similarly, quadruplets-containing daratumumab, particularly when administered as continuous therapies, have improved outcome of patients not eligible for autologous transplant (NTE). Patients who become refractory to conventional therapies have noticeably poor outcomes, making their treatment a difficult challenge in need of novel strategies. In this review, we will focus on the main points regarding risk stratification, treatment and monitoring of MM, highlighting the most recent evidence that could modify the management of this still incurable disease.

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“…R f = 0.36 (5% methanol−dichloromethane, UV). 1 (6). Reaction of 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (25.0 mg, 0.10 mmol, 1.00 equiv) with 3phenoxybenzaldehyde (57.3 mg, 0.29 mmol, 3.00 equiv) in the presence of sodium cyanoborohydride (18.2 mg, 0.29 mmol, 3.00 equiv), for 16 h by Standard Procedure A afforded compound 6 (24.6 mg, 58% yield).…”

Section: -(5-((naphthalen-2-ylmethyl)amino)-1-oxoisoindolin-2-yl)pipe...mentioning

confidence: 99%

“…1−4 The therapeutic efficacy of lenalidomide can be attributed in part to the recruitment and eventual degradation of targets such as zinc fingers Ikaros (IKZF1) and Aiolos (IKZF3) in the context of multiple myeloma 2,3 and casein kinase 1 alpha (CK1α) in the context of del(5q) myelodysplastic syndrome (del5Q MDS). 4 The clinical success of thalidomide derivatives has also fueled efforts to develop more potent CRBN ligands against IKZF1 and IKZF3 5,6 and additional targets such as G1 to S phase transition 1 enzyme (GSPT1) 7,8 and Helios (IKZF2). 9,10 Thalidomide derivatives that recruit substrates to CRBN do so via recognition of an exposed β-hairpin motif in the substrate.…”

Section: ■ Introductionmentioning

confidence: 99%

“…2H, H 9 /H 11 ),6.93 (d, J = 7 6. Hz, H 14 ),6.88 (dd, J = 8.1, 2.1 Hz, 1H, H 12 ), 6.69 (d, J = 9.7 Hz, 1H, H 7 ), 6.63 (s, 1H, H 6 ), 5.07 (s, 2H, H 15 ), 5.00 (dd, J = 13.3, 5.1 Hz, 1H, H 4 ), 4.32 (d, J = 5.9 Hz, 2H, H 10 ), 4.23 (d, J = 16.8 Hz, 1H, H 5 ), 4.10 (d, J = 16.8 Hz, 1H, H 5 ), 2.93−2.84 (m, 1H, H 2 ), 2.59−2.55 (m, 1H, H 2 ), 2.87−2.26 (m, 1H, H 3 ), 1.94− 1.91 (m, 1H, H 3 ).…”

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confidence: 99%

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Design and Development of IKZF2 and CK1α Dual Degraders

Miyamoto,

Curnutt,

Park

et al. 2023

J. Med. Chem.

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Mezigdomide (CC-92480), a Potent, Novel Cereblon E3 Ligase Modulator (CELMoD), Combined with Dexamethasone (DEX) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Preliminary Results from the Dose-Expansion Phase of the CC-92480-MM-001 Trial

Cited by 23 publications

References 0 publications

Bispecific Antibodies in Multiple Myeloma: Opportunities to Enhance Efficacy and Improve Safety

Bispecific Antibodies in Multiple Myeloma: Opportunities to Enhance Efficacy and Improve Safety

Current Main Topics in Multiple Myeloma

Design and Development of IKZF2 and CK1α Dual Degraders

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