RG6234, a GPRC5DxCD3 T-Cell Engaging Bispecific Antibody, Is Highly Active in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Updated Intravenous (IV) and First Subcutaneous (SC) Results from a Phase I Dose-Escalation Study

Carlo‐Stella, Carmelo; Mazza, Rita; Manier, Salomon; Facon, Thierry; Yoon, Sung‐Soo; Koh, Youngil; Harrison, Simon; Er, Jeremy; Pinto, Antonio; Volzone, Francesco; Perrone, Giulia; Corradini, Paolo; Cazaubiel, Titouan; Hulin, Cyrille; Touzeau, Cyrille; Moreau, Philippe; Ocio, Enrique M.; Gaisan, Carmen Maria Montes; Popat, Rakesh; Leong, Sarah; Offner, Fritz; Otero, Paula Rodríguez; Bröske, Ann-Marie; Dekhtiarenko, Iryna; Helms, Hans‐Joachim; Belli, Sara; Rossmann, Eva; Fauti, Tanja; Eckmann, Jan; Moore, Tom; Schneider, Meike; Jacob, Wolfgang; Weisser, Martin; Hutchings, Martin; Riley, Caroline Hasselbalch

doi:10.1182/blood-2022-157988

Cited by 40 publications

(16 citation statements)

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“…Forimtamig (RG6234) is another GPRC5D T‐cell engaging BsAb with a 2:1 (GPRC5D:CD3) configuration, which increased the potency compared to the 1:1 configuration [49]. Forimtamig induced rapid responses in heavily pretreated MM patients (≥PR with IV administration: 71.4%; ≥PR with SC administration: 63.6%) [49]. The toxicity profile of forimtamig is comparable to that observed with talquetamab [49].…”

Section: Gprc5d‐targeting Bsabsmentioning

confidence: 99%

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T‐cell redirecting bispecific antibodies in multiple myeloma: Current landscape and future directions

O'Neill

Donk

2023

eJHaem

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T‐cell engaging bispecific antibodies (BsAbs) have substantial activity in heavily pretreated patients with multiple myeloma (MM). The overall response rate obtained with B‐cell maturation antigen (BCMA)‐targeting BsAbs is approximately 60%–70%, including a high proportion of patients achieving very good partial response or complete response. Comparable efficacy is seen with BsAbs targeting GPRC5D or FcRH5. Cytokine release syndrome is frequently observed with BsAb treatment, but mostly during the step‐up doses and the first full dose. Early intervention with IL‐6 receptor blocking antibodies (e.g., tocilizumab) prevents escalation to severe manifestations. Infections are also common during treatment and related to the extent of exposure to immune suppressive anti‐MM agents, as well as development of hypogammaglobulinemia due to elimination of normal plasma cells, and probably because of T‐cell exhaustion resulting from continuous BsAb‐mediated T‐cell activation. Adequate monitoring for infections and institution of infectious prophylaxis are essential. Patients treated with GPRC5D‐targteing BsAbs often develop skin and nail disorders and loss of taste, which is likely related to GPRC5D expression in cells that produce hard keratin. Currently ongoing studies are aiming at further improving these results by evaluating BsAbs in combination with other drugs, such as immunomodulatory agents and anti‐CD38 antibodies, as well as the application of BsAbs in earlier lines of therapy, including patients with newly diagnosed disease. We expect that the outcomes of patients with MM will further improve by the introduction of this novel type of T‐cell immunotherapy.

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Section: Gprc5d‐targeting Bsabsmentioning

confidence: 99%

“…Forimtamig induced rapid responses in heavily pretreated MM patients (≥PR with IV administration: 71.4%; ≥PR with SC administration: 63.6%) [49]. The toxicity profile of forimtamig is comparable to that observed with talquetamab [49].…”

Section: Gprc5d‐targeting Bsabsmentioning

confidence: 99%

T‐cell redirecting bispecific antibodies in multiple myeloma: Current landscape and future directions

O'Neill

Donk

2023

eJHaem

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“…[44][45][46][47] Likewise, the GPRC5D/CD3 BsAbs talquetamab and RG6234 have demonstrated ORRs in the 60%-70% range. 31,32 Finally, Fc receptorlike 5 (FcRH5) has also proven to be a target of interest in MM. 49 A phase I study of cevostamab, a BsAb directed against FcRH5/CD3, has shown an ORR of 57% at higher dose levels.…”

Section: Efficacymentioning

confidence: 99%

“…48,68 Studies conducted to date using either GPRC5D-directed CAR T cells or BsAbs have reported skin and nail changes, rash, and oral-related adverse events, including dysgeusia, dry mouth, and dysphagia (Table 3), which are presumably related to GPRC5D expression in these tissues. 31,32,44,45 Strategies to minimize these toxicities and improve long-term tolerability of these therapies are needed.…”

Section: Toxicitymentioning

confidence: 99%

“…Until that time, there are substantial uncertainties regarding the optimal sequencing of these BCMA-directed therapies. As discussed earlier, GPRC5D-and FcRH5-directed CAR T-cell and/or BsAb therapies are showing efficacy in patients with previous BCMA-directed therapy, [31][32][33]44,45 but again whether optimal sequencing should involve options within the same class (eg, BsAb to BsAb) or should involve switching classes (eg, CAR T-cell to BsAb) will need to be investigated.…”

Section: Sequencingmentioning

confidence: 99%

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Chimeric Antigen Receptor T-Cell and Bispecific Antibody Therapy in Multiple Myeloma: Moving Into the Future

Holstein

Grant

Wildes

2023

JCO

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Historically, the outcomes for individuals with triple-class refractory and penta-drug refractory multiple myeloma (MM) have been poor because of a dearth of effective treatment options. However, the advent of chimeric antigen receptor (CAR) T-cell and T-cell redirecting bispecific antibody (BsAb) therapies has led to unprecedented response rates and durations of response in heavily relapsed/refractory (R/R) populations. Currently, two B-cell maturation antigen (BCMA)–directed CAR T-cell therapies (idecabtagene vicleucel and ciltacabtagene autoleucel) as well as one BCMA/CD3 BsAb (teclistamab) have been approved for late-line (greater than four previous lines) R/R MM in the United States. The purpose of this review is to analyze the recent data for these approved therapies as well as provide an overview of other related CAR T-cell and BsAb therapies under development, including non–BCMA-targeting agents. We review efficacy and safety considerations, with particular focus on cytokine release syndrome, neurotoxicity, and infection risk. The relative merits and limitations of each class of therapy are discussed, as well as the areas of unmet need with respect to optimal sequencing and supportive care measures. We examine the factors that challenge equitable access to these novel therapies across minoritized racial, ethnic, and socioeconomic populations. Although it is evident that CAR T-cell and BsAb therapies will transform treatment paradigms in MM for years to come, significant work remains to identify the optimal utilization of these novel therapies and ensure equitable access.

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Beyond BCMA, why GPRC5D could be the right way: treatment strategies with immunotherapy at relapse after anti-BCMA agents

Del Giudice,

Galimberti,

Buda

2023

Cancer Immunol Immunother

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Multiple Myeloma remains incurable, and there is a need for therapies with novel mechanisms of action. Recently, B cell maturation antigen targeted therapy has demonstrated deep and durable responses in a largely treated population. However, the relapse rate of myeloma patients after anti-BCMA treatment strategies is increasing worldwide, and one of the most challenging issues for them is to choose the best therapy sequencing. After anti-BCMA treatment, retreatment with anti-BCMA drugs remains an option, but new targets are emerging strongly. One of them is G protein-coupled receptor, class C group 5 member D (GPRC5D), that due to the very promising data from the use of chimeric antigen receptor T-cells (CAR-T) and bispecific antibodies (BsAb) seems to be the ideal candidate in the relay of myeloma treatment at relapse. In this literature review, we discuss data from treatment with the new drugs at relapse after anti-BCMA therapies, observing an undeniable benefit from the use of drugs directed against GPRC5D.

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RG6234, a GPRC5DxCD3 T-Cell Engaging Bispecific Antibody, Is Highly Active in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Updated Intravenous (IV) and First Subcutaneous (SC) Results from a Phase I Dose-Escalation Study

Cited by 40 publications

References 0 publications

T‐cell redirecting bispecific antibodies in multiple myeloma: Current landscape and future directions

T‐cell redirecting bispecific antibodies in multiple myeloma: Current landscape and future directions

Chimeric Antigen Receptor T-Cell and Bispecific Antibody Therapy in Multiple Myeloma: Moving Into the Future

Beyond BCMA, why GPRC5D could be the right way: treatment strategies with immunotherapy at relapse after anti-BCMA agents

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