A Phase I Study to Assess the Safety and Pharmacokinetics of Single-agent Lorvotuzumab Mertansine (IMGN901) in Patients with Relapsed and/or Refractory CD–56-positive Multiple Myeloma

Ailawadhi, Sikander; Kelly, Kevin R.; Vescio, Robert; Jagannath, Sundar; Wolf, Jeffrey; Gharibo, Mecide; Sher, Taimur; Bojanini, Leyla; Kirby, Maurice; Chanan‐Khan, Asher

doi:10.1016/j.clml.2018.08.018

Cited by 59 publications

(39 citation statements)

References 30 publications

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“…Another conjugate linked to a maytansine derivative, the anti-CD56 ADC lorvotuzumab mertansine (IMGN901; BB-10901), had been the focus of a phase I trial in CD56-positive RRMM patients (NCT00346255) but insufficient efficacy and dose-related toxicity reportedly led to discontinuation of further studies of this agent [112,113]. Other mAbs that have been dropped from further consideration in MM following demonstration of only modest efficacy and/or unacceptable toxicity in trials include the following (target in parentheses): dacetuzumab and lucatumumab (CD40); F50067 (CXCR-4); AVE1642 and figitumumab (IGF-R1); IPH 2101 (KIR); PAT-SM6 (GRP-78); BI 505 (intercellular adhesion molecule-1, ICAM-1), and siltuximab (IL-6).…”

Section: Additional Mabs and Their Targetsmentioning

confidence: 99%

Emerging Monoclonal Antibodies for the Treatment of Multiple Myeloma

Abramson¹

2021

Monoclonal Antibodies

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Therapeutic measures designed to treat multiple myeloma (MM) have undergone a fundamental shift over the past two decades as a number of small molecules that attack this cancer by different mechanisms, including proteasome blockade, immunomodulation, and histone deacetylase (HDAC) inhibition, have been introduced. The insertion of monoclonal antibodies (mAbs) into the mix began in 2015 with the U.S. Food and Drug Administration (FDA) approval of daratumumab and elotuzumab, which target CD38 and SLAMF7, respectively. In 2020, they were joined by another anti-CD38 mAb, isatuximab, and the bispecific antibody-drug conjugate (ADC) belantamab mafodotin, which targets the B-cell maturation antigen (BCMA). This review focuses on additional mAbs currently under clinical study for MM. These include several BCMAxCD3-directed bispecifics (AMG 420, AMG 701, REGN5458, REGN5459, teclistamab, and TNB-383B), the ADCs indatuximab ravtansine and STRO-001, and checkpoint inhibitors, although the future status of the latter is in a state of flux due to toxicity issues that arose in trials in which these drugs, especially PD-1 or PD-L1 blockers, were combined with immunomodulators.

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Section: Additional Mabs and Their Targetsmentioning

confidence: 99%

Emerging Monoclonal Antibodies for the Treatment of Multiple Myeloma

Abramson¹

2021

Monoclonal Antibodies

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“…This ADC consists of the cytotoxic maytansinoid DM1 payload (microtubule inhibitor) attached to the humanized anti-CD56 IgG1 antibody N901 via a disulfide linker (38)(39)(40)(41)(42). CD56, originally described as neuronal cell adhesion molecule (NCAM) (76)(77)(78), is a cell surface glycoprotein that has an important role in cell adhesion (76,79,80).…”

Section: Lorvotuzumab Mertansine (Imgn901)mentioning

confidence: 99%

“…The potent preclinical activity formed the rationale for a phase 1 trial in which lorvotuzumab mertansine was evaluated as a single agent in 37 relapsed/refractory patients (>3 prior treatment lines in 78% of patients) with CD56-positive MM (42). Patients received lorvotuzumab mertansine on days one and eight of a three-week cycle.…”

Section: Lorvotuzumab Mertansine (Imgn901)mentioning

confidence: 99%

Targeted Therapy With Immunoconjugates for Multiple Myeloma

2020

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The introduction of proteasome inhibitors (PI) and immunomodulatory drugs (IMiD) has markedly increased the survival of multiple myeloma (MM) patients. Also, the unconjugated monoclonal antibodies (mAb) daratumumab (anti-CD38) and elotuzumab (anti-SLAMF7) have revolutionized MM treatment given their clinical efficacy and safety, illustrating the potential of targeted immunotherapy as a powerful treatment strategy for MM. Nonetheless, most patients eventually develop PI-, IMiD-, and mAb-refractory disease because of the selection of resistant MM clones, which associates with a poor prognosis. Accordingly, these patients remain in urgent need of new therapies with novel mechanisms of action. In this respect, mAbs or mAb fragments can also be utilized as carriers of potent effector moieties to specifically target surface antigens on cells of interest. Such immunoconjugates have the potential to exert anti-MM activity in heavily pretreated patients due to their distinct and pleiotropic mechanisms of action. In addition, the fusion of highly cytotoxic compounds to mAbs decreases the off-target toxicity, thereby improving the therapeutic window. According to the effector moiety, immunoconjugates are classified into antibody-drug conjugates, immunotoxins, immunocytokines, or radioimmunoconjugates. This review will focus on the mechanisms of action, safety and efficacy of several promising immunoconjugates that are under investigation in preclinical and/or clinical MM studies. We will also include a discussion on combination therapy with immunoconjugates, resistance mechanisms, and future developments.

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“…In a phase I/II study, the objective response rate was only 5.7%, but stable disease or better was noted in 42.9% of patients treated with single agent lorvotuzumab mertansine, and the mDOR was 15.5 months. 209 Another ADC, milatuzumab doxorubicin (hLL1-DOX), which delivers a DNA-damaging anthracycline molecule to cells expressing CD74, also maintained stable disease for longer than 3 months in 5 out of 19 patients with RRMM in a multicenter dose-escalation study. 210 However, a subsequent trial of hLL1-DOX, completed in 2015 (NCT01101594) posted no results, and no further studies have been registered with the agent.…”

Section: Other Considerationsmentioning

confidence: 99%

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of multiple myeloma

Shah

Aiello

Avigan

et al. 2020

J Immunother Cancer

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Outcomes in multiple myeloma (MM) have improved dramatically in the last two decades with the advent of novel therapies including immunomodulatory agents (IMiDs), proteasome inhibitors and monoclonal antibodies. In recent years, immunotherapy for the treatment of MM has advanced rapidly, with the approval of new targeted agents and monoclonal antibodies directed against myeloma cell-surface antigens, as well as maturing data from late stage trials of chimeric antigen receptor CAR T cells. Therapies that engage the immune system to treat myeloma offer significant clinical benefits with durable responses and manageable toxicity profiles, however, the appropriate use of these immunotherapy agents can present unique challenges for practicing physicians. Therefore, the Society for Immunotherapy of Cancer convened an expert panel, which met to consider the current role of approved and emerging immunotherapy agents in MM and provide guidance to the oncology community by developing consensus recommendations. As immunotherapy evolves as a therapeutic option for the treatment of MM, these guidelines will be updated.

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A Phase I Study to Assess the Safety and Pharmacokinetics of Single-agent Lorvotuzumab Mertansine (IMGN901) in Patients with Relapsed and/or Refractory CD–56-positive Multiple Myeloma

Cited by 59 publications

References 30 publications

Emerging Monoclonal Antibodies for the Treatment of Multiple Myeloma

Emerging Monoclonal Antibodies for the Treatment of Multiple Myeloma

Targeted Therapy With Immunoconjugates for Multiple Myeloma

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of multiple myeloma

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