Targeting GPRC5D in multiple myeloma

ABSTRACT

Introduction

The prognosis of multiple myeloma (MM) continues to improve. Recent progress in therapies, using immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies, has greatly improved patients’ outcomes. Despite these advancements, relapses still happen often, and patients can become resistant to the usual treatments. Newer treatments, such as chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies (BsAbs) targeting B-cell maturation antigen (BCMA), have resulted in excellent outcomes in patients with limited treatment options. G protein – coupled receptor, class C group 5 member D (GPRC5D) is considered a very promising target with early results from clinical trials showing high response rates in patients with relapsed or refractory multiple myeloma.

Areas Covered

This review covers the efficacy and safety of CAR-T and BsAbs targeting GPRC5D in MM, focusing on talquetamab – the inaugural FDA-approved BsAb targeting GPRC5D. Talquetamab has exhibited promising response rates alongside a distinctive side effect profile. Additionally, ongoing trials examining talquetamab in combination with agents like daratumumab and teclistamab are discussed.

Expert Opinion

We offer insights into the potential utilization of various GPRC5D-based therapies in the treatment paradigm for MM, either independently or in combination with established therapies.

KEYWORDS:

• Talquetamab
• multiple myeloma
• GPRC5D
• bispecific antibodies
• CAR-T
• adverse events

Article highlights

• Managing triple class refractory multiple myeloma presents a substantial challenge due to the poor outcomes.

• Targeting GPRC5D in multiple myeloma is promising given the high response rates in patients with relapsed refractory disease.

• In a phase 1 study assessing talquetamab’s safety and effectiveness in heavily treated relapsed or refractory multiple myeloma patients, the intravenous and subcutaneous administration showed encouraging overall response rates of 70% and 64%, respectively.

• Talquetamab exhibited a distinct safety profile in patients with relapsed refractory multiple myeloma. Common adverse events included cytokine release syndrome, skin-related adverse events, weight loss and dysgeusia.

• CAR-T therapy targeting GPRC5D are under development and early clinical trials are showing promising results.

Declaration of interest

S Al Hadidi has received consulting fees from Jansen, Sanofi, Pfizer, and Galapagos. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

SE reports no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties. SAH reports receiving consulting fees from Jansen, Sanofi, Pfizer, and Galapagos.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.