Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics from a Phase I Study of PF-06863135, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Raje, Noopur; Jakubowiak, Andrzej; Gasparetto, Cristina; Cornell, Robert F.; Krupka, Heike I.; Navarro, Daniel; Forgie, Alison; Udata, Chandrasekhar; Basu, Cynthia; Chou, Jeffrey; Leung, Abraham; Lesokhin, Alexander M.

doi:10.1182/blood-2019-121805

Cited by 44 publications

(48 citation statements)

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“…There were mainly grade 1-2 AEs including CRS (24%), thrombocytopenia (24%), and anemia (18%). DLT of treatment-related febrile neutropenia was found in one patient on the highest dose level [168,174].…”

Section: Amg 420 (Bi 836909 Amgen)mentioning

confidence: 98%

BCMA-targeted immunotherapy for multiple myeloma

2020

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B cell maturation antigen (BCMA) is a novel treatment target for multiple myeloma (MM) due to its highly selective expression in malignant plasma cells (PCs). Multiple BCMA-targeted therapeutics, including antibody-drug conjugates (ADC), chimeric antigen receptor (CAR)-T cells, and bispecific T cell engagers (BiTE), have achieved remarkable clinical response in patients with relapsed and refractory MM. Belantamab mafodotin-blmf (GSK2857916), a BCMA-targeted ADC, has just been approved for highly refractory MM. In this article, we summarized the molecular and physiological properties of BCMA as well as BCMA-targeted immunotherapeutic agents in different stages of clinical development.

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Section: Amg 420 (Bi 836909 Amgen)mentioning

confidence: 98%

BCMA-targeted immunotherapy for multiple myeloma

2020

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“…Future studies will shed light on their role in the treatment of MM patients and on their efficacy when used earlier in the course of the disease; they will also explore how to improve their feasibility and treatment compliance, especially in relation to the continuous intravenous infusion characteristic of the BiTEs ® evaluated in MM thus far. In this field, the compounds showing the most encouraging preclinical results are bispecific antibodies with extended half-life such as the anti-BCMAs AMG701 and PF3135, which would allow a weekly administration [129,130]. Moreover, we still need to decipher the exact mechanisms of resistance and how to revert them, as well as the best drug-partners to enhance their efficacy in different settings.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma

Bonello

Mina

Boccadoro

2019

Cancers

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Immunotherapy is the latest innovation for the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) entered the clinical practice and are under evaluation in clinical trials. MAbs can target highly selective and specific antigens on the cell surface of MM cells causing cell death (CD38 and CS1), convey specific cytotoxic drugs (antibody-drug conjugates), remove the breaks of the immune system (programmed death 1 (PD-1) and PD-ligand 1/2 (L1/L2) axis), or boost it against myeloma cells (bi-specific mAbs and T cell engagers). Two mAbs have been approved for the treatment of MM: the anti-CD38 daratumumab for newly-diagnosed and relapsed/refractory patients and the anti-CS1 elotuzumab in the relapse setting. These compounds are under investigation in clinical trials to explore their synergy with other anti-MM regimens, both in the front-line and relapse settings. Other antibodies targeting various antigens are under evaluation. B cell maturation antigens (BCMAs), selectively expressed on plasma cells, emerged as a promising target and several compounds targeting it have been developed. Encouraging results have been reported with antibody drug conjugates (e.g., GSK2857916) and bispecific T cell engagers (BiTEs ® ), including AMG420, which re-directs T cell-mediated cytotoxicity against MM cells. Here, we present an overview on mAbs currently approved for the treatment of MM and promising compounds under investigation.Cancers 2020, 12, 15 2 of 24 Cancers 2020, 12, 15 3 of 24 (Bregs, which promote tumor growth and immune escape), as well as a subset of regulatory T cells (Tregs) express CD38, and their levels are reduced after daratumumab exposure. Conversely, daratumumab results in significant expansion of CD8+ cytotoxic and CD4+ helper T cells, likely following the depletion of regulatory cells. Remarkably, expanded effector T cells also show increased killing capacity due to augmented levels of granzyme B, which activates caspases and triggers cell apoptosis [23][24][25]. In addition, among the activities promoted by CD38, there is a nicotinamide adenine dinucleotide (NAD)-ase activity, which results in reduced levels of NAD+ in T cells, responsible for the loss of their effector functions (exhausted T cells). In murine models, anti-CD38 mAbs administration induced higher levels of NAD+ in T effector cells, thus enhancing their antitumor activity [23]. The main mechanisms of action of anti-CD38 monoclonal antibodies are summarized in Figure 1.

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“…For T cell redirecting BsAbs, the activation of large proportions of non-specific T cells can lead to significant toxicity and treatment-related adverse events (AEs) (12). Cytokine release syndrome (CRS) is among the most important AEs of BsAb treatment, with multiple instances recorded in clinical trials of blinatumomab, PF-0683135, CC-93269, and AMG420 (68,(72)(73)(74). CRS can present as a variety of symptoms, ranging from influenza-like symptoms to neurotoxicity and multi-organ failure; the recommended treatment depends on its grade of severity (68,75).…”

Section: Bispecific Antibodies: Overview Designs and Potential For MMmentioning

confidence: 99%

“…CRS primarily occurred after the first dose, was dose-dependent and resolved in all patients in less than 4 days. Dose escalation is ongoing as of early 2020, with plans to continue until the maximum tolerated dose is reached (73).…”

Section: Clinical Trials Of Bcma-targeting Bsabs Pf-06863135 (Pf-3135)mentioning

confidence: 99%

“…Preclinical findings in in vitro and in vivo models have shown effective tumor eradication. Additionally, preliminary clinical results of BCMA-targeting BsAbs PF-06863135 and AMG420 have been promising, with an absence of dose-limiting toxicity in PF-06863135 and six MRD-negative complete responses in AMG420 (73,74). As more study results materialize, BsAbs will continue to be refined to increase efficacy and safety.…”

Section: Future Directions and Conclusionmentioning

confidence: 99%

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Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions

et al. 2020

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Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematological neoplasm in adults, comprising 1.8% of all cancers. With an annual incidence of ∼30,770 cases in the United States, MM has a high mortality rate, leading to 12,770 deaths per year. MM is a genetically complex, highly heterogeneous malignancy, with significant inter-and intra-patient clonal variability. Recent years have witnessed dramatic improvements in the diagnostics, classification, and treatment of MM. However, patients with high-risk disease have not yet benefited from therapeutic advances. Highrisk patients are often primary refractory to treatment or relapse early, ultimately resulting in progression toward aggressive end-stage MM, with associated extramedullary disease or plasma cell leukemia. Therefore, novel treatment modalities are needed to improve the outcomes of these patients. Bispecific antibodies (BsAbs) are immunotherapeutics that simultaneously target and thereby redirect effector immune cells to tumor cells. BsAbs have shown high efficacy in B cell malignancies, including refractory/relapsed acute lymphoblastic leukemia. Various BsAbs targeting MM-specific antigens such as B cell maturation antigen (BCMA), CD38, and CD138 are currently in pre-clinical and clinical development, with promising results. In this review, we outline these advances, focusing on BsAb drugs, their targets, and their potential to improve survival, especially for high-risk MM patients. In combination with current treatment strategies, BsAbs may pave the way toward a cure for MM.

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Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics from a Phase I Study of PF-06863135, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Cited by 44 publications

References 0 publications

BCMA-targeted immunotherapy for multiple myeloma

BCMA-targeted immunotherapy for multiple myeloma

Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma

Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions

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