From CAR T’s “Wait List Mortality” to “Tethering” Bispecific Antibodies, Oncologists Navigate Time-Sensitive Sequencing in Multiple Myeloma

Janeen Lambert was so healthy during her career as a health care systems administrator that when she retired in 2019, she had accumulated 750 hours of unused sick time. Weeks later, after hurting her back moving a table, the Arizona resident, aged 69 years, went to the hospital and received devastating news: her body was riddled with bone lesions, a sign of the incurable blood cancer multiple myeloma.

“I thought, I am a dead man,” Lambert said in an interview. During the next 4 years, she would receive multiple treatments to keep the cancer in remission: chemotherapy, an autologous transplant, and pomalidomide (Pomalyst; Bristol-Myers Squibb), an immunomodulating agent. In March 2023, her cancer emerged again, and her oncologist, Jeffrey R. Schriber, MD, FRCP, medical director for hematologic malignancies at City of Hope in Phoenix, Arizona, offered a few options: another stem cell transplant, a chimeric antigen receptor (CAR) T-cell therapy, or a new class of medicine called a bispecific antibody.

Lambert was worried about the potential adverse effects that CAR T-cell therapy can induce, such as cytokine release syndrome (CRS), an overreaction of the body’s immune system to the treatment that can cause inflammation and flu-like symptoms in up to 93% of patients.¹ Because her prior stem cell transplant did not work for long, she agreed to try the bispecific antibody, which was teclistamab (Tecvayli; Janssen Biotech).

“I got a call from Dr Schriber when my numbers were going back up—they actually jumped quite rapidly—and he said, ‘Would you be willing to start [teclistamab]?’ And I said, ‘Well, yeah,’ ” Lambert said. She was the center’s second patient to receive a bispecific antibody.

For patients like Lambert, with aggressive disease and concerns around CRS, bispecifics may become a more sought-after option, oncologists say. Although physicians readily praise CAR T treatments as revolutionary for their potential to send stubborn cancers into remission for long periods and even eradicate the disease, they are not without drawbacks and complications.

These medications, which can run up to $1 million when hospital costs are included,² can take weeks, if not months, to reach patients—assuming these individuals can first secure an appointment to collect their blood and separate the white blood cells to send to the manufacturer, a process called leukapheresis. Then the manufacturer, which must also have equipment availability, engineers and expands the patient’s white blood cells into CAR T cells. The customized therapy is sent back to the hospital, where it is administered via infusion to the patient. Post infusion, the patient is monitored closely for potential adverse effects, which can require hospital stays for days while physicians look for signs of a toxic immune response. Finally, negotiating with insurers to pay not only for the therapy but also those hospital stays can delay the start of treatment.

Enter bispecific antibodies. These therapies, which bind to T-cell receptors in the patient and drag them to the cancer cells, are newer to the market than CAR Ts for multiple myeloma but more accessible. Instead of weeks, patients can typically start on the off-the-shelf therapy within days. They are cheaper as well, making them more attractive to budget-conscious hospital systems. However, bispecific antibodies require regular infusions, tying patients to repeated hospital visits for hours at a time, and their long-term effectiveness and durability are unknown.

“This is a great problem for us to have,” said Jason Westin, MD, The University of Texas MD Anderson Cancer Center’s director of the Lymphoma Clinical Research Program and section chief of the aggressive lymphoma research team in the Department of Lymphoma and Myeloma, in an interview. “Having 2 home run therapies and figuring out the right way to sequence them or combine them in the future, this is our great challenge, but we’re very glad to have this problem with multiple great therapies to help people in need.”

The first CAR T to be approved by the FDA was tisagenlecleucel (Kymriah) in August 2017.³ The agency has green-lit 5 additional CAR Ts since, including 2 for multiple myeloma: idecabtagene vicleucel (Abecma) in March 2021 and ciltacabtagene autoleucel (Carvykti) in February 2022.^4-6

On the bispecifics side, the first therapy to win FDA approval was blinatumomab (Blincyto) in 2014 for Philadelphia chromosome–negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia. The agency has signed offonbispecific antibodies in leukemia and lymphoma,⁷ and in the past 14 months has approved 3 in multiple myeloma: teclistamab, elranatamab (Elrexfio; Pfizer) and talquetamab (Talvey; Janssen Biotech).^8-10

This year’s meeting of the American Society of Clinical Oncology featured promising results for using talquetamab in combination with a subcutaneous formulation of the monoclonal antibody daratumumab, as well as combining talquetamab with teclistamab. Bhagirathbhai R. Dholaria, MD, assistant professor of medicine in the Division of Hematology and Oncology at Vanderbilt University Medical Center in Nashville, Tennessee, said talquetamab “appeared to be a good partner” for use in drug combinations.¹¹

How Waiting Affects Treatment Decisions

Although CAR Ts are the preferred option for patients with myeloma and are available as earlier lines of treatment, patients with aggressive disease may not be able to wait the weeks or months it can take for the therapy to be manufactured for them, said Joseph P. McGuirk, DO, director of the Division of Hematologic Malignancies and Cellular Therapeutics at the University of Kansas Cancer Center. McGuirk and colleagues were so concerned about the impact that long wait times for CAR T treatments were having on their patients that they published a paper in August 2023 examining this issue.¹²

The study looked at the 40 patients who were eligible for idecabtagene vicleucel and on a waiting list to receive the treatment in 2021; the authors found that 60% of the patients were able to secure a production slot but 40% were not. The median time from consult to collection of the patient’s cells for the treatment was 38 days, with a range from 8 days to nearly 2 years—703 days. The median time from cell collection to infusion was 42 days, with a range of 34 to 132 days. For some patients, the wait time proved deadly, resulting in a high mortality rate, according to the study.¹²

“Can you imagine this being one of your family members, and you’ve got a product that can work, but you can’t get it for 2 months, and your brother or sister, your mom, your dad, are going to get too sick and succumb to the disease?” McGuirk said. “We’re giving a lot of bispecifics to our myeloma patients, because we can’t wait 2 months.”

Although “wait list mortality” has improved since the first year the therapy was approved, as manufacturers ramp up production and health care systems and payers have learned to work together efficiently, bottlenecks remain in the system, said Jeremy Larsen, MD, a hematologic oncologist on the hematologic malignancies team at City of Hope in the Phoenix area.

“One of the main limitations for CAR Ts still is the availability,” Larsen said. “Right now, we have a major supply-and-demand mismatch—it’s improving, but that’s a major, major bottleneck.” By contrast, he said he could see a patient on a Friday and have them on a bispecific antibody therapy the following week. Some oncologists who have spoken with Evidence-Based Oncology have described this advantage as reducing the time “from brain to vein,” referring to the number of days from when a decision is made to use a bispecific to when the patient is infused.

Adverse Events and Sequencing

Further complicating matters is the sequence in which patients should receive these treatments: in some cases, their bodies may experience “T-cell exhaustion,” said Michael Tees, MD, a physician at the Colorado Blood Cancer Institute and part of the Lymphoid and Autoimmune Disease Groups, and thus not respond to whichever therapy is given after the first one. Because CAR Ts have been available longer, they are approved for earlier lines of treatment than bispecific antibodies. But patients who have failed 4 or more rounds of therapy could be eligible for either one. “There might be a reasonable sequencing of therapy, where perhaps you don’t use bispecifics before a CAR T,” Tees said.

Bispecifics are not without adverse effects as well. The median CRS rates in early clinical trials testing CAR Ts and bispecific antibodies in multiple myeloma was 66%; however, very few participants in the bispecific trials experienced grade 3 or higher severity, compared with the far higher incidence following CAR T treatment (4% for bispecifics vs 41% for CAR T therapy), according to a study examining the topic published in Cancers inMarch 2023.¹³

Then there is the issue of paying for these treatments. Large cancer centers and academic institutions, with teams of people who can work with insurers, providers, and patients, do not report having difficulty with delays or financing the therapy and associated hospital costs. But for community oncology practices, navigating the process could impact their treatment options.

“I think it’s an underappreciated issue,” Tees said. “There’s a financial risk to take on a treatment for a bispecific or a CAR T product if you don’t have a hospital system supporting you or an academic system.”

Reimbursement Implications

CMS is increasing its base reimbursement for CAR T cases for fiscal year 2024 by 4%, to $257,958, according to a report by Avalere Health.¹⁴ The fixed-loss threshold will increase 10%, to $42,750. As CAR T cases are more likely to qualify for outlier payments than other inpatient stays, hospitals will be required to incur additional financial losses before qualifying for a payment.

“For many of these cases, you’re relying on an outlier reimbursement, meaning that you must incur at least a certain amount of loss before that additional payment kicks in,” said Kolton Gustafson, an associate principal at Avalere Health and an author of the report. “So, if you’re a hospital that can’t even bear that initial loss, then you might be less willing to do this. For some hospitals, the financial decision may be, ‘You know what, this is just a little too risky for us and we don’t really see a way to come out of this in the black.’”

For their part, drugmakers see a big opportunity to expand in multiple myeloma. Sales of Johnson & Johnson’s multiple myeloma drugs jumped 30% over the prior year, thanks in part to recent approvals for its CAR T ciltacabtagene autoleucel and the bispecific antibody therapy teclistamab, the company said during its second-quarter earnings call on July 20.¹⁵ Johnson & Johnson, through Janssen Biotech, is also the maker of daratumumab (Darzalex), a monoclonal antibody that targets the CD38 protein on the surface of myeloma cells.

“Our aspiration in myeloma is that…we would be in a position to have 3 out of every 4 patients starting in Janssen containing regimen by the end of this decade,” Joaquin Duato, the CEO of Johnson & Johnson, said during the earnings call, according to a transcript.¹⁵

Bristol Myers Squibb (BMS), the maker of idecabtagene vicleucel, reported that sales of the drug have spiked nearly 50% this year, to $132 million, fueled by growing demand and an expanded capacity to make the medicine, according to a transcript of the company’s second-quarter earnings call on July 27.¹⁶

“We’re very confident in our ability to compete in myeloma with this important product, Abecma [idecabtagene vicleucel],” said Adam Lenkowsky, BMS’ chief commercialization officer, during the earnings call. “I think most importantly, we continue to see and hear from physicians about favorable perceptions for Abecma based on our durable responses in a real-world setting, as well as high manufacturing success rates, now that are north of 90%. So, taken together, we do remain very confident about Abecma’s outlook in the second half of 2023 and beyond.”¹⁶ Johnson & Johnson and BMS are actively expanding their manufacturing footprints around the world to meet growing demand for their therapies.

Larsen, the City of Hope oncologist, says the success of bispecific antibodies in the relapse/refractory setting is leading to trials testing the treatment in patients with new diagnoses who are not headed for stem cell transplants. “We’re definitely in a revolution for the therapy of multiple myeloma,” he said.

The downside of bispecifics, compared with CAR T-cell therapy, is the need for continued infusions. For Lambert, the City of Hope patient with multiple myeloma who started on a bispecific antibody in March, the initial 8-day step-up period was “miserable,” even as she passed the time getting her daily steps in at the facility and playing online games. The drug protocol also requires Lambert to visit the medical center once a week for an infusion, indefinitely. This means a 25-minute drive each way, plus a wait time of 2 to 5 hours for her blood to be drawn and analyzed, and then for the infusion to be ordered and set up.

“In the beginning, I never thought a weekly shot would be so tethering,” said Lambert, who enjoys visiting national parks with her husband for hiking and fishing trips. “We’re retired, but we can only go for 6 days if we’re going to go somewhere. So, that is one thing to consider.” 

REFERENCES

1. Li Y, Ming Y, Fu R, et al. The pathogenesis, diagnosis, prevention, and treatment of CAR-T cell therapy–related adverse reactions. Front Pharmacol. 2022;13:950923. doi:10.3389/fphar.2022.950923
2. Real-world CAR-T treatment costs can range from $700,000 to $1 million. News release. Prime Therapeutics. April 1, 2021. Accessed September 25, 2023. https://bit.ly/48kHQQS.
3. FDA approval brings first gene therapy to the United States. News release. FDA. August 30, 2017. Updated March 26, 2018. Accessed September 14, 2023. http://bit.ly/3sQi32N
4. CAR T cells: engineering patients’ immune cells to treat their cancers. National Cancer Institute. Updated March 10, 2022. Accessed September 11, 2023. https://bit.ly/3ZpVQEX
5. FDA approves first cell-based gene therapy for adult patients with multiple myeloma. News release. FDA. March 27, 2021. Accessed November 2, 2023. https://bit.ly/47h3kgk
6. U.S. FDA approves Carvykti (ciltacabtagene autoleucel), Janssen’s first cell therapy, a BCMA-directed CAR-T immunotherapy for the treatment of patients with relapsed or refractory multiple myeloma. News release. Johnson & Johnson. February 28, 2022. Accessed November 2, 2023. https://bit.ly/45Wyc4K
7. Bispecific antibodies: an area of research and clinical applications. FDA. August 2, 2023. Accessed September 14, 2023. https://bit.ly/3Pm8PTB
8. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. FDA. October 25, 2022. Accessed November 5, 2023. https://bit.ly/3FI8IgK
9. FDA grants accelerated approval to elranatamab-bcmm for multiple myeloma. FDA. August 14, 2023. Accessed November 5, 2023. https://bit.ly/40pmcr3
10. FDA grants accelerated approval to talquetamab-tgvs for relapsed or refractory multiple myeloma. FDA. August 10, 2023. Accessed November 5, 2023. https://bit.ly/3srnN31
11. Caffrey M, Inman S, Sava J. ASCO 2023: multiple myeloma. Am J Manag Care. 2023;29(6):SP500-SP503.
12. Ahmed N, Wesson W, Mushtaq MU, et al. “Waitlist mortality” is high for myeloma patients with limited access to BCMA therapy. Front Oncol. 2023;13:1206715. doi:10.3389/fonc.2023.1206715
13. Swan D, Murphy P, Glavey S, Quinn J. Bispecific antibodies in multiple myeloma: opportunities to enhance efficacy and improve safety. Cancers (Basel). 2023;15(6):1819. doi:10.3390/cancers15061819
14. Gustafson K, Shvets E, Neal JC, West M. CAR-T reimbursement updated in FY 2024 IPPS Final Rule. Avalere Health. August 16, 2023. Accessed November 5, 2023. https://bit.ly/3rGjTTz
15. Johnson & Johnson (JNJ) 2023 Q2 earnings call transcript. CapEdge. July 20, 2023. Accessed November 5, 2023. https://bit.ly/3ZAwHYc
16. Bristol Myers Squibb (BMY) Q2 2023 earnings call transcript. The Motley Fool. July 27, 2023. Accessed November 5, 2023. https://bit.ly/3ZknG5w