Initial Clinical Activity and Safety of BFCR4350A, a FcRH5/CD3 T-Cell-Engaging Bispecific Antibody, in Relapsed/Refractory Multiple Myeloma

Cohen, Adam D.; Harrison, Simon; Krishnan, Amrita; Fonseca, Rafaël; Forsberg, Peter; Spencer, Andrew; Berdeja, Jesús G.; Laubach, Jacob P.; Li, Mengsong; Choeurng, Voleak; Vaze, Anjali; Samineni, Divya; Sumiyoshi, Teiko; Cooper, James N.; Fine, Bernard M.; Trudel, Suzanne

doi:10.1182/blood-2020-136985

Cited by 74 publications

(67 citation statements)

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“…Preclinical studies have demonstrated that FcHR5 is expressed at higher levels among patients with MM harboring +1q21 compared to those without +1q21 106 . Cevostamab is a bispecific antibody targeting FcHR5 and has shown promising activity in Phase 1 studies 107 . Although data among patients with +1q21 are unknown in that study, it will be interesting to see whether these patients have increased sensitivity to targeting by cevostamab.…”

Section: Management Implicationsmentioning

confidence: 99%

Chromosome 1q21 abnormalities in multiple myeloma

2021

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Gain of chromosome 1q (+1q) is one of the most common recurrent cytogenetic abnormalities in multiple myeloma (MM), occurring in approximately 40% of newly diagnosed cases. Although it is often considered a poor prognostic marker in MM, +1q has not been uniformly adopted as a high-risk cytogenetic abnormality in guidelines. Controversy exists regarding the importance of copy number, as well as whether +1q is itself a driver of poor outcomes or merely a common passenger genetic abnormality in biologically unstable disease. Although the identification of a clear pathogenic mechanism from +1q remains elusive, many genes at the 1q21 locus have been proposed to cause early progression and resistance to anti-myeloma therapy. The plethora of potential drivers suggests that +1q is not only a causative factor or poor outcomes in MM but may be targetable and/or predictive of response to novel therapies. This review will summarize our current understanding of the pathogenesis of +1q in plasma cell neoplasms, the impact of 1q copy number, identify potential genetic drivers of poor outcomes within this subset, and attempt to clarify its clinical significance and implications for the management of patients with multiple myeloma.

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Section: Management Implicationsmentioning

confidence: 99%

Chromosome 1q21 abnormalities in multiple myeloma

2021

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“…Fc receptor-homolog 5 (FcRH5) is a type I membrane protein expressed on B cells and PC with a near 100% prevalence. At the last ASH Meeting Cohen et al 64 reported the initial results from a dose-escalation phase 1 trial. Fifty-three patients, with a median of six prior lines of therapy, 72% triple-refractory and 45% penta-refractory, received BFCR4350A by IV infusion every 21 days.…”

Section: “Old” Generation Immunotherapiesmentioning

confidence: 99%

Novel Experimental Drugs for Treatment of Multiple Myeloma

Offidani

Corvatta²,

Morè

et al. 2021

JEP

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Multiple myeloma (MM) is the second most frequent hematological malignancy characterized by bone marrow aberrant plasma cells proliferation leading to a genetic complex and heterogeneous disease, with a median survival ranging from two to more than 10 years. By using new drugs such as proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs) in different combinations and high-dose therapy followed by auto-transplantation, there has been an amazing improvement in the outcome of this disease in recent years. Despite this, MM is still considered an incurable disease, characterized by remission periods alternated with relapse/progression episodes finally leading to resistant disease. In particular, patients who become refractory to PIs, IMiDs and mAbs have a very poor outcome. Moreover, to overcome resistant residual disease, a large combination of drugs will be increasingly used in early lines of therapy; this further reduces the therapeutic options at each relapse. This natural history means that MM always needs new drugs/strategies to overcome the incoming resistance. New combinations of naked mAbs are becoming the therapy of choice for patients refractory to lenalidomide and/or PI; conjugated mAbs will be useful in triple- and more-refractory patients; CAR-T cells and bispecific mAbs have shown relevant results in very advanced stages of disease. In this review, we reported the results of these new therapies and explored their potential applications. Personalized and precision medicine seem to be the new frontier of cancer treatment. Although no single or few factors have been identified as disease drivers in MM, recurrent gene mutations were recognized and specific compounds targeting these alterations were developed and studied. Therefore, we reviewed these targeted drugs to try to understand what the best therapeutic strategy in MM is.

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“…BFCR4350A, a humanized immunoglobulin G-based T-cell-engaging bispecific antibody, targets the most membrane-proximal domain of FcRH5 on myeloma cells and CD3 on T cells, resulting in T-cell activation and killing of myeloma cells. GO39775 (NCT03275103) is an ongoing, phase I trial evaluating BFCR4350A monotherapy in patients with RRMM for whom no other effective therapy is available or feasible [ 67 ]. Patients receive BFCR4350A by IV infusion in 21-day cycles (Q3W).…”

Section: Bispecific Monoclonal Antibodies: Design and Mechanism Ofmentioning

confidence: 99%

Drug Conjugated and Bispecific Antibodies for Multiple Myeloma: Improving Immunotherapies off the Shelf

et al. 2021

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The impressive improvement of overall survival in multiple myeloma (MM) patients in the last years has been mostly related to the availability of new classes of drugs with different mechanisms of action, including proteasome inhibitors (PI), immunomodulating agents (IMiDs), and monoclonal antibodies. However, even with this increased potence of fire, MM still remains an incurable condition, due to clonal selection and evolution of neoplastic clone. This concept underlines the importance of immunotherapy as one of the most relevant tools to try to eradicate the disease. In line with this concept, active and passive immunotherapies represent the most attractive approach to this aim. Antibody-drug conjugate(s) (ADCs) and bispecific antibodies (BsAbs) include two innovative tools in order to limit neoplastic plasma cell growth or even, if used at the time of the best response, to potentially eradicate the tumoral clone. Following their promising results as single agent for advanced disease, at the recent 62nd ASH meeting, encouraging data of several combinations, particularly of ADC(s) with PI or IMiDs, have been reported, suggesting even better results for patients treated earlier. In this paper, we reviewed the characteristics, mechanism of action, and clinical data available for most relevant ADC(s) and BsAbs.

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Initial Clinical Activity and Safety of BFCR4350A, a FcRH5/CD3 T-Cell-Engaging Bispecific Antibody, in Relapsed/Refractory Multiple Myeloma

Cited by 74 publications

References 0 publications

Chromosome 1q21 abnormalities in multiple myeloma

Chromosome 1q21 abnormalities in multiple myeloma

Novel Experimental Drugs for Treatment of Multiple Myeloma

Drug Conjugated and Bispecific Antibodies for Multiple Myeloma: Improving Immunotherapies off the Shelf

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