A 'Whole Different Ballgame' for Myeloma Treatment

For more than seven years, 58-year- old Cindy Brown of Trabuco Canyon, California, had tried numerous therapies for multiple myeloma, but her disease had always relapsed.

Then, in March 2020, her oncologist at the City of Hope Comprehensive Cancer Center in Los Angeles asked her to consider joining a clinical trial evaluating Tecvayli (teclistamab-cqyv), an immunotherapy drug that is a human bispecific monoclonal antibody, or bispecific T-cell engager, a highly specialized molecule that, by binding to two different proteins, focuses the immune system on two distinct targets to attack the cancer. Tecvayli activates the immune system by binding to both a receptor called CD3 on the surface of T cells and a protein expressed specifically on multiple myeloma cells called the B-cell maturation antigen (BCMA). Brown has been in remission since she started taking the drug.

“It’s been remarkable for me in terms of success. It’s super well-tolerated,” Brown says. “If you met me and didn’t know who I was, you would have no idea I was sick.”

Targeting BCMA

Bispecific antibodies are a type of immunotherapy designed to bring two cells or proteins on a cell together, since proximity helps initiate the immune cascade. Using therapies that specifically recognize a target signal such as myeloma-specific BCMA and act only on those cells “is a much more specific way of targeting the bad cells we’re trying to get rid of, as opposed to therapy that can attack a lot of different types of cells and then cause side effects,” says Dr. Nisha Joseph, an oncologist at Emory Winship Cancer Institute and an assistant professor of hematology and medical oncology at Emory University School of Medicine in Atlanta. “It’s almost like a homing device.”

Only a few such therapies have been approved by the Food and Drug Administration (FDA), generally as fourth-line therapy after other treatments have not worked, and more are in clinical trials. However, study results have been impressive, according to Dr. Krina Patel.

“Heavily pretreated patients who otherwise would have probably not done very well, and [with whom] we would have discussed hospice, are now living longer using these therapies,” says Patel, an associate professor in the department of lymphoma and myeloma at The University of Texas MD Anderson Cancer Center in Houston. “We’re improving overall survival [the time a patient lives following treatment] with these therapies, which is pretty phenomenal.”

Over the past decade, the FDA has approved treatments for multiple myeloma that have had a response rate (patients whose disease responded partially or completely to treatment) varying between 23% and 30%, adds Dr. Joshua Richter, director of multiple myeloma at the Blavatnik Family Chelsea Medical Center at Mount Sinai and an associate professor of medicine at the Tisch Cancer Institute in New York.

“Now you look at these drugs being used, and the bispecifics are getting 60% to 80% response rates, and some CAR-T (chimeric antigen receptor-T cell therapy treatments) are pushing 90% to 100%. It’s a whole different ballgame,” Richter says.

Take Brown’s case: She first received a diagnosis of multiple myeloma at age 48 after having debilitating leg and hip pain for months. She underwent a chemotherapy regimen of Revlimid (lenalidomide), Velcade (bortezomib) and dexamethasone.

During a three-week break from treatment leading into a planned stem cell transplant, Brown had a nearly complete relapse and had to be admitted to the hospital for three rounds of another seven-drug regimen. At that point, doctors recommended she undergo an allogeneic and autologous stem cell transplant. She had her own bone marrow cells collected and returned to her and also received cells from a donor. The donor cell transplant sent her into heart failure a month later, and she almost died. Finally, she recovered and was in remission for two years.

Brown tried three other therapies before needing radiation treatments because the cancer wasn’t responding. After a short remission, the cancer returned in her arm. As a result, Brown needed surgery to implant a rod from her elbow to her shoulder.

Through the clinical trial, Brown initially received injections of Tecvayli every week for a year, then every other week. She is now receiving injections every four weeks.

“I have not had a detectable cancer marker since I started,” she says.

Approved Therapies

The FDA approved Tecvayli in 2022 as the first bispecific antibody for use in multiple myeloma.

Elrexfio (elranatamab-bcmm), a BCMA-CD3-directed bispecific antibody immunotherapy, was approved by the FDA in August 2023 to treat adults with relapsed or refractory multiple myeloma who previously received four or more lines of therapy.

The approval was based on findings from the phase 2 MagnetisMM-3 trial. Among patients who had received four or more prior lines of therapy, the overall response rate (ORR, percentage of patients with complete or partial response to therapy) was 58%, with an estimated 82% of patients maintaining that response for at least nine months.

Among patients whose prior treatment included a BCMA-directed therapy, the ORR was 33%, and 84% of these patients maintained their response to treatment for at least nine months, according to the study findings.

Other anti-BCMA therapies being used for multiple myeloma include the following:

• ANTIBODY-DRUG CONJUGATES (ADCs): ADCs contain an antibody that targets BCMA, a chemotherapy agent and a protein that links them together. They work by attaching to cancer cells and delivering chemotherapy directly to those cells. Blenrep (belantamab mafodotin) has been approved by the FDA; it is administered as an intravenous infusion.
• CAR-T CELL THERAPY: With this option, immune system T cells first are removed from a patient’s blood, and then they are genetically engineered in a commercial laboratory to express a receptor that binds to BCMA. Millions of these CAR-T cells are grown in the laboratory and then infused back into the patient, where they populate the marrow and can stay in the circulation long term, seeking out and destroying cancer cells. CAR-T cell therapy is a one-time therapy, whereas the others require treatments every one to three weeks.

Two therapies approved by the FDA for the treatment of multiple myeloma, Abecma (idecabtagene vicleucel) and Carvykti (ciltacabtagene autoleucel), are among the CAR-T cell therapies that the agency has requested come with a warning following reports of T-cell malignancies, including CAR-T positive lymphoma, among patients who had been treated with that class of drug, it was reported in January.

Lasting Responses

Trena Robertson, 51, of Baton Rouge, Louisiana, also has achieved lasting remission with a BCMA- targeted treatment — in her case, CAR-T cell therapy.

Robertson received a diagnosis of multiple myeloma in 2018 after experiencing body pain and having malignant plasma (antibody-producing) cells in more than 90% of her bone marrow.

She first underwent chemotherapy treatments recommended by a local oncologist and then a stem cell transplant at The University of Texas MD Anderson Cancer Center.

She was doing well but started relapsing six months later. By then, Patel, her oncologist, recommended that Robertson enroll in a clinical trial for CAR-T cell therapy as her second line of treatment.

In 2019, Robertson relocated to Houston to start the protocol. She received some injections and had to undergo three rounds of advanced chemotherapy. She made it through the first two rounds but was sick with a fever the first day of the third round. Instead, she ended up in the emergency department in need of a blood transfusion, which meant she had to restart the protocol and chemotherapy a month later.

Later that year, Robertson received treatment with CAR-T cell therapy. She returned home and eventually went back to work as a clinical coordinator for a speech pathology and audiology program at Southern University.

“They told me before the treatment that it was supposed to last anywhere from 18 to 24 months,” she says. “This month makes 47 months that I’ve been in remission. ... I’ve been doing very well.”

Side Effects

Selecting the appropriate treatment for each patient depends partly on availability and access, according to oncologists. Because CAR-T treatment regimens are made specifically for each patient and only two therapies are approved for multiple myeloma, there are limited slots available, and the products take several weeks to manufacture. Patients who are frail or can’t tolerate some of the side effects of bispecifics may be better candidates for ADCs, Patel says.

The side effects of CAR-T cell therapy and bispecifics include cytokine release syndrome (signs of systemic inflammation such as fever, chills and drops in oxygen or blood pressure), which is likely associated with the activation of T cells, says Dr. David Avigan, director of the Beth Israel Deaconess Medical Center Cancer Center and a professor of medicine at Harvard Medical School in Boston.

Other reactions include neurotoxicity, which can cause seizures but usually responds to steroids, or a temporary suppression of blood counts, which can increase the risk of infection. Blenrep, the ADC, can cause ocular side effects such as blurred vision or dry eyes.

Some patients have expressed fear over the ocular side effects, Joseph says, but they shouldn’t. Studies have shown that with treatment these side effects completely resolve in nearly all patients. Symptoms vary and can be mild.

“Patients can tolerate this drug and have quality of life. That’s important because sometimes I feel like I have to convince someone to take it, where the other option is hospice care,” Joseph says.

When Brown started the trial, she spent just under two weeks in the hospital with cytokine release syndrome and says she had increased pain in the areas of her body that had active myeloma at the time.

“But after probably four treatments, I didn’t get that anymore,” she says. “Occasionally at the injection site, I get a little rash that itches for a couple of days. But that’s sort of sporadic. It’s very well tolerated. ... I get the shot and I leave.”

She receives monthly infusions of intravenous immunoglobulin proteins to help fight infections, has laboratory tests every two weeks and has a PET scan every three months. She has some mild symptoms akin to an upper respiratory infection and says she feels a little tired but overall is doing well.

Robertson experienced a fever within the first 24 hours of receiving her CAR-T cell therapy. “They said that was good because it meant the treatment was doing what it was supposed to be doing,” she says.

She has since been monitored with blood and urine testing, as well as periodic PET scans and bone marrow biopsies.

Questions to Answer

Some questions remain about the use of anti-BCMA therapies. Could the therapies be used earlier on? Can these therapies be administered one after the other if needed, such as giving a bispecific after CAR-T cell therapy? The predominant thought is that T cells could be exhausted after their first round of therapy, but data published by Richter’s group demonstrated that may not be the case. Some patients who received CAR-T cell therapy or a bispecific, and then received another T-cell engager as their next line of therapy, did better than patients who received other types of therapies as the next line.

“It turns out you can reinvigorate and reactivate those T cells sequentially,” Richter says.

Other concerns are whether myeloma cells will adapt and shut off the expression of BCMA to evade therapy, as well as how best to manage infections and alert doctors regarding symptoms to watch.

Much of the science is focused on trying to understand the mechanisms of resistance and how to get around them, Avigan says, as well as how to prevent cells such as CAR-T cells from being rejected. Similar to how oncologists initially used chemotherapy to simultaneously give different drugs that work in different ways, combination immunotherapies may emerge to help avoid pathways of resistance by targeting different pieces of the immune system, Avigan says.

And so, research continues. Other promising agents in the pipeline include the bispecific antibodies linvoseltamab, which is being developed by Regeneron, and ABBV- 383, which is being developed by AbbVie, Patel says.

For now, oncologists are focusing on BCMA as the primary target, but there are others being studied, such as G-protein coupled receptor family
C group 5 member D (GPRC5D) and Fc receptor-like protein 5 (FcRH5).

“[With] the more knowledge we accrue, is there a magic combination we can use to start curing [patients] on a regular basis? I’m hopeful we can,” Richter says.