Multiple Myeloma Requires Multiple Targets

In the last year, results of several phase 1 clinical trials testing trispecific antibodies—proteins engineered to bind to 3 different targets—in the treatment of multiple myeloma (MM) have been presented at major medical meetings, generating excitement about this new class of therapy.

With different targets, each of these therapies is looking to take the concept of combination therapy and make it available through a single drug.

For example, recent results of the RedirecTT-1 trial showed that combining the G protein–coupled receptor, class C, group 5, member D (GPRC5D)–targeting talquetamab and the B-cell maturation antigen (BCMA)–targeting teclistamab yielded a 78.9% response rate in patients with relapsed MM with extramedullary disease.¹

“Trispecifics ask, ‘Can we avoid the use of two drugs and use just one drug? Can we improve the tolerability of this?’” said Joshua Richter, MD, associate professor of medicine at The Tisch Cancer Institute at Icahn School of Medicine at Mount Sinai. “We are really excited to see where that is going.”

Recent Progress

The first well-documented case of MM occurred almost 200 years ago, with the patient receiving treatment with a rhubarb pill and an infusion of orange peel.²

“We have come a long way since then,” said Muhamed Baljevic, MD, associate professor of medicine, Division of Hematology-Oncology at Vanderbilt University Medical Center. “Our current standards of care have significantly improved, and we now live in an era of front-line so-called quadruplet regimens for both transplant-eligible and -ineligible patients.”

These quadruplet regimens—comprising a monoclonal antibody, a proteasome inhibitor, an immunomodulatory drug, and a corticosteroid—provide a “functional cure for a subset of patients,” Dr. Baljevic said, “so that patients diagnosed later in life can achieve a ‘near-normal’ lifespan.”

“Unfortunately, despite this progress, we are still not in a place where we can say that we reliably cure the majority of patients,” Dr. Baljevic said.

For patients with relapsed or refractory MM (RRMM), similar progress has been made with the introduction of therapies that engage immune T cells. Chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies have both become important options for patients.

Two CAR T-cell therapies are currently being used for patients with MM previously treated with other agents: idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), both targeting BCMA.³ Four bispecific therapies are approved by the FDA: three targeting CD3 and BCMA (teclistamab, elranatamab, linvoseltamab) and talquetamab, which targets CD3 and GPRC5D.^4,5

These new classes of drugs have again transformed the treatment landscape for patients with MM, Dr. Richter said.

“The traditional teaching for myeloma is that every remission will be shorter than the one before,” Dr. Richter said. “In the era of bispecifics and CAR T-cell therapy, that concept has been inverted. Some people in their third relapse will have 6-month relapse-free survival, but in their fourth, they will get 18 months because the bispecific is better than the treatment they received third-line.”

Long-term results of the CARTITUDE-1 trial of cilta-cel showed a median overall survival of more than 5 years. One-third of patients were alive and progression free for 5 years or longer after undergoing CAR T-cell therapy.⁶

“Historically, this was impossible to imagine,” Dr. Baljevic said. “But we need to do much better for the other two-thirds of patients.”

Trispecifics

A multitude of trispecific or “multi”-specific antibodies are under investigation for MM, with several targeting MM having phase 1 results read out in the last year.

SAR442257 is a trispecific antibody targeting CD3 and CD28, with a myeloma cell–directed third target of CD38. Results from a phase 1 study of SAR442257 were presented at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition, detailing treatment of 40 patients with RRMM. The overall response rate (ORR) was 5% with a disease control rate of 60%. However, the study was terminated during dose escalation because of safety concerns, including high rates of cytokine release syndrome (CRS), Epstein-Barr virus, and cytomegalovirus reactivations.⁷

Another trispecific under investigation is ISB-2001, which targets CD3 and two targets on the myeloma cells, CD38 and BCMA.

“This molecule can potentially overcome the resistance mechanism associated with traditional bispecific therapies,” said Hang Quach, MBBS, clinical professor of haematology at the University of Melbourne.

Dr. Quach presented results of a phase 1 first-in-human study of ISB 2001 at the 2024 American Society of Hematology Annual Meeting & Exposition.⁸ The study tested subcutaneous ISB 2001 administered with two step-up doses on cycle 1 days 1 and 4 before administering the full target dose in cycle 1 on day 8.

“Among patients who had ISB 2001 at 50 micrograms per kilogram or more, we saw a response rate of 83% with a very good partial response—that is reduction of myeloma burden by 90%—in around one-quarter of patients and a complete response in around in 23% of patients,” Dr. Quach said.

Another remarkable finding, Dr. Quach said, was a response rate of about 90% among patients who had no prior treatment with CAR T-cell therapy or bispecific T-cell engagers. “For some perspective,” Dr. Quach said, “we would expect a response rate in the order of about 60% with the traditional bispecific antibodies in this group of patients.”

Among patients who had prior CAR T-cell therapy or treatment with T-cell engagers, the response rate was about 75%.

Overall, the drug was well tolerated, Dr. Quach said, with a rate of infection and hematologic toxicity that was “much lower than anticipated with T-cell engagers in general,” leaving room for potential combination treatment in the future.

A third trispecific under investigation in MM is JNJ-5322, which binds to BCMA, GPRC5D, and CD3.⁹ According to Dr. Baljevic, JNJ-5322 may be the “most exciting of the bunch” based on follow-up data and the number of patients treated.

A phase 1 trial of JNJ-5322 included 126 patients who received the drug every 4 weeks with one step-up dose of 5 mg. Thirty-six patients received the recommended phase 2 dose with an ORR of 86.1%. Among the 27 patients with no prior BCMA- or GPRC5D-directed therapies, the ORR was 100% with the phase 2 dose.^9,10

“In terms of safety, there was a lower incidence of GPRC5D-related adverse events compared with the bispecific, with minimal to no weight loss,” Dr. Baljevic said. In addition, CRS rates (59%) were all grade 1 or grade 2, and only 28% of patients had grade 3 or higher infections.^9,10

Fewer step-up doses and the relatively manageable safety profile make JNJ-5322 particularly appealing for use in the community, Dr. Baljevic said.

Here to Stay?

In the future, approaching MM by going after multiple targets will play a role in effective treatment.

“I think there are two big things we are going to see in the next few years,” Dr. Richter said. “One is that trispecifics are definitely going to come into play. The other is that MM, in my mind, is about dance partners.Meaning, although many drugs get approved as monotherapies, there is usually ongoing work to partner those drugs with others to make effective combination therapy approaches.” For example, the MonumenTAL-2 study is testing the combination of talquetamab with other anti-myeloma agents.

In addition, like most new classes of drugs that are first tested in the multiply relapsed or refractory setting, bispecifics are slowly making their way to earlier lines of treatment, including frontline approaches.

“We have no reason to think they won’t be successful in that area,” Dr. Baljevic said. “We do want to make sure there are no treatment-related issues in terms of high toxicities or even deaths in the newly diagnosed patient space. We have fantastic data already and do want to improve on it, but [we are] being mindful about requirements for optimal safety and acceptable cost.”

Dr. Richter said, “If more therapies look to target both BCMA and GPC5D, researchers must ask, what is the next big target?”

“To me, that is cevostamab,” he added, mentioning an Fc receptor–homolog 5 (FcRH5) bispecific antibody that “facilitates T-cell–mediated killing of multiple myeloma cells.”

Last year, Dr. Richter and colleagues presented data from a phase 1 study of cevostamab in patients with heavily pretreated RRMM and found that the drug demonstrated “clinically meaningful activity.”¹¹

“The message here is that we used to cure no one,” Dr. Richter said. “Now we cure some, and we are not going to stop until we cure all.”