Immunotherapies ‘offer incredible hope’ in journey toward multiple myeloma cure
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Although multiple myeloma remains incurable, treatment advances during the past several years have dramatically improved clinicians’ ability to slow progression of the disease.
Most recently, novel T-cell-directed immunotherapies, such as chimeric antigen receptor T cells and bispecific antibodies, have extended survival and improved quality of life for many patients.
Image: Samer Al Hadidi, MD, MS, FACP
For those with advanced multiple myeloma, the impact of these treatments has been profound, according to Samer Al Hadidi, MD, MS, FACP, assistant professor of medicine at University of Arkansas for Medical Sciences and associate member of the myeloma center at Winthrop P. Rockefeller Cancer Institute.
“The recent approval of two CAR-Ts and one bispecific antibody means more options for patients in need, many of whom have no treatment options left,” he told Healio | HemOnc Today. “These immune-based therapies have changed what is possible and allowed many more patients with relapsed or refractory disease to experience longer remissions.”
Healio | HemOnc Today spoke with experts about how recent FDA approvals of B-cell maturation antigen (BCMA)-targeted immunotherapies have changed the treatment paradigm for multiple myeloma and whether these advances have shifted the goal to treating the disease as a chronic condition or perhaps have opened the door to a potential cure.
Outcomes of BCMA-directed immunotherapy
The number of available therapies for patients with advanced multiple myeloma has increased substantially within the past 2 years.
In March of 2021, FDA approved idecabtagene vicleucel (Abecma; Bristol Myers Squibb, 2seventy bio) as the first CAR T-cell therapy for treatment of relapsed or refractory multiple myeloma. Approval of a second CAR-T, ciltacabtagene autoleucel (Carvykti; Janssen, Legend Biotech), followed in March of 2022. And in October, teclistamab-cqyv (Tecvayli, Janssen Biotech) became the first bispecific T-cell engaging antibody to receive FDA approval for patients with advanced multiple myeloma.
All three agents target BCMA, and all are indicated for adults who received four or more previous lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.
Beyond opening up “a new avenue of treatment options,” BCMA-directed immunotherapies have produced markedly higher response rates compared with previously approved agents for treatment of multiple myeloma, Al Hadidi said.
A single infusion of idecabtagene vicleucel — also known as ide-cel — conferred a 71% overall response rate among patients with relapsed or refractory disease compared with 42% among those who received one of five standard regimens, according to results of the pivotal randomized phase 3 KarMMa trial published in The New England Journal of Medicine. Patients who received ide-cel also had superior PFS vs. the standard regimens (13.3 months vs. 4.4 months; HR = 0.49; 95% CI, 0.38-0.65), albeit with a higher rate of grade 3 or grade 4 adverse events (93% vs. 75%).
Earlier this year, Janssen announced that the randomized phase 3 CARTITUDE-4 trial — which is evaluating the safety and efficacy of ciltacabtagene autoleucel, also known as cilta-cel — met its primary endpoint of significantly improved PFS vs. standard-of-care treatments for patients with relapsed and lenalidomide-refractory multiple myeloma.
Teclistamab also showed encouraging efficacy among patients with relapsed or refractory disease in the single-arm, multicenter phase 1 MajesTEC-1 study, which served as the basis for the agent’s approval. Researchers reported an ORR of 61.8% (95% CI, 52.1-70.9).
“It is an almost doubling of what we used to see with newly approved agents,” Al Hadidi said. “That is what is most exciting about all these newer immunotherapies.”
Newly approved BCMA-directed immunotherapies have also conferred high rates of minimal residual disease negativity among responders in this heavily pretreated patient population, according to Faith E. Davies, MD, director of the clinical myeloma program and Center for Blood Cancers at NYU Langone’s Perlmutter Cancer Center.
“Some responses are lasting anywhere between 1 to 3 years, which is quite unusual in the relapsed and refractory setting,” she told Healio | HemOnc Today. “For patients treated with these agents in clinical trials and now commercially, they really do offer incredible hope, as well as an additional treatment option.”
Delayed impact
Although the efficacy results have been impressive, the impact of these BCMA-directed immunotherapies on patient care has yet to reach its full potential because of accessibility issues, according to experts with whom Healio | HemOnc Today spoke.
”At the moment, the decision-making process about which CAR-T agent to use is dictated by the availability of whatever physicians can get their hands on,” Davies said. “We have just the one BCMA-targeted bispecific available now, but we are expecting others to be approved shortly.”
Therapeutic choices are likely to increase as CAR-T manufacturers begin to work out their initial ramp-up issues and additional bispecifics make their way through late-stage testing.
Davies anticipates the availability issues will be resolved in the next 6 months to a year, “so that physicians and their patients can come to a joint decision about which CAR-T is best for the situation or if a bispecific is preferable based on weighing the potential benefits versus the side-effect profile.”
Al Hadidi said his center is still experiencing problems with availability of commercial CAR-T, despite the additional approval of cilta-cel in 2022.
“We have better options now, but there are more patients who need the product than we are able to provide for,” he said. “For that reason, bispecifics tend to be more available and ready to use for patients in need.”
FDA approval of the bispecific teclistamab has come just in time to help ease the CAR-T manufacturing bottleneck for patients with high-risk or advanced disease, according to Saad Z. Usmani, MD, MBA, FACP, chief of myeloma service at Memorial Sloan Kettering Cancer Center and HemOnc Today Editorial Board Member.
“We have many patients who would qualify for CAR-T and would like it as an option, but we can't offer it to them,” he told Healio | HemOnc Today.
A logistical issue has been the availability of CAR-T manufacturing slots allotted to each cellular therapy center, which is limited to one or two per month per manufacturer, he noted.
Available slots may not always match up with a patient’s disease course, which makes options for an off-the-shelf immunotherapy attractive in today's environment, Usmani said.
“Having teclistamab approved helps in getting a BCMA-directed option to our patients,” he said, adding that many clinicians are likely not yet aware of its availability.
Centers like his have already started treating patietns with teclistamab — which has a similar yet distinct safety profile from CAR-T that requires some hospitalization after initial infusion.
“Once we have more clarity on the safety profile then we should be able to treat patients in the outpatient setting, and that will make things easier,” Usmani added.
Navigating more options
Physicians welcome the availability of novel BCMA-targeted therapies, which are of high value when treating a disease that typically requires an individualized approach, according to Paul G. Richardson, MD, director of clinical research at Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, and a HemOnc Today Editorial Board Member.
“Multiple myeloma is 100 diseases under one tent,” he told Healio | HemOnc Today.
To combat this heterogeneity, Richardson said it is important to consider the patients' characteristics and their treatment goals, in addition to the overall activity of any particular therapeutic modality.
“I think it’s important to have a strategic view,” he said. “With multiple options available, a tactical, throw-everything-at-once approach is perhaps not the wisest. Sometimes a more staggered approach is appropriate, particularly with a keen eye on quality of life and side-effect management.”
A strategic view about the use of BCMA-directed immunotherapy is especially important among older, more frail patients and also in certain younger patients who will spend the duration of their lives receiving some type of treatment, Richardson noted.
“I think [they have] been highly impactful in terms of promise and potential,” he said. “The reality of what that means in community practice and to the majority of patients with relapsed and refractory disease remains to be confirmed, not least because these approaches can be operationally and clinically complex to deliver.”
Richardson said he hopes future research will show these new immunotherapies have provided “a broad-brush benefit” across the patient population with relapsed and refractory disease, and not just for a select group who have access to specialized centers.
Researchers are still trying to determine which should come first — the CAR-T or the bispecific.
“It is a very important question that is being explored now, especially with more large data sets available on how these therapies have been used in real-world practice,” Al Hadidi said.
Data thus far suggest bispecifics can be effectively used even after a patient progresses following CAR-T, according to Al Hadidi. However, the choice between CAR-T and bispecifics depends on many variables, the most important of which is whether a patient’s disease course will allow enough time for the CAR-T manufacturing process.
Al Hadidi maintained that offering CAR-T first is typically the best approach to allow patients a treatment-free interval after therapy if possible. In cases where high-risk disease requires a more immediate treatment option, the use of a bispecific first is an entirely reasonable strategy, he added.
Davies agreed and said disease pace is an important factor in choosing among available therapies, especially when CAR-T is a consideration due to the manufacturing turnaround required.
“However, having an off-the-shelf therapeutic — such as a bispecific — is beneficial in cases where patients have explosive relapse,” she said. “This can be delivered the next day and will be a better option.”
The most appropriate therapeutic strategy will become more evident over time as researchers learn about more about the agents biologically, Davies said.
“Patient choice may also dictate which of these therapies is used, as some may opt for a shorter hospital stay of bispecifics while others will prefer the one-and-done approach of a CAR-T,” she added.
Moving toward a cure
BCMA-directed immunotherapies ultimately may not be the cure for multiple myeloma, but their unprecedented efficacy appears to be shifting expectations about whether they can help turn the disease into a chronic condition.
The true test will be determined after longer follow-up, especially if higher-risk patients survive long enough that — on average — they achieve their average life expectancy and die of other causes, according to Al Hadidi.
“I am looking to see how these agents will work for patients with high-risk disease, where our treatment options work but only for a short period of time,” he told Healio | HemOnc Today. “I think this is where BCMA-directed immunotherapies may play a bigger role in getting those patients to achieve better and longer responses compared with what we previously had to offer.”
Richardson advocates for a multifaceted approach rather than a monotheistic one to multiple myeloma care, but nonetheless sees the benefit of these newer immunotherapies for patients.
“Immune therapy broadly in multiple myeloma is a pillar for improved outcomes and ultimately — God willing — in years to come will achieve functional disease control that translates into a functional cure,” he told Healio | HemOnc Today.
Physicians who treat patients with multiple myeloma will need to manage expectations about the effectiveness of novel immunotherapies, Richardson added. He noted a perception among patients and families that CAR-T, for example, is a one-time treatment that can lead to a long-term cure, as has been seen with CD19-based therapies for B-cell lymphoma.
“We need to be careful about this perception because there is real value to these immunotherapy platforms,” he said. “And I am very impressed by the data so far, but I am also clear with my patients about the possible limitations and encourage them to think about their use strategically within the tapestry of available management options.”
A string of newly developed treatments over the past several years has enabled many patients to achieve disease control and survive for years or even decades with multiple myeloma, Usmani said. He is also bullish on T-cell directed immunotherapies and their ability to improve outcomes.
“We're thinking about potentially curative strategies for multiple myeloma knowing that we have so many effective treatments,” he told Healio | HemOnc Today. “I think the field is heading in the direction of a functional cure and we will probably get there within the next 10 years.”
To read a related story, “A new immunotherapy target emerges in advanced multiple myeloma,” click here.
References:
- Abecma (idecabtagene vicleucel) [prescribing information]. Summit, New Jersey: Bristol Myers Squibb; 2021.
- Johnson & Johnson. Janssen announces unblinding of phase 3 CARTITUDE-4 study of Carvykti (cilta-cel) as primary endpoint met in treatment of patients with relapsed and refractory multiple myeloma. Available at: www.jnj.com/janssen-announces-unblinding-of-phase-3-cartitude-4-study-of-carvykti-cilta-cel-as-primary-endpoint-met-in-treatment-of-patients-with-relapsed-and-refractory-multiple-myeloma. Published Jan. 27, 2023. Accessed March 6, 2023.
- Rodríguez-Otero P, et al. N Engl J Med. 2023;doi;10.1056/NEJMoa2213614.
- Tecvayli (teclistamab-cqyv) [prescribing information]. Horsham, Pennsylvania: Janssen Biotech Inc.; 2022.
For more information:
Samer Al Hadidi, MD, MS, FACP, can be reached at salhadidi@uams.edu.
Faith E. Davies, MD, can be reached at faith.davies@nyulangone.org.
Paul G. Richardson, MD, can be reached at paul_richardson@dfci.harvard.edu.
Saad Z. Usmani, MD, MBA, FACP, can be reached at usmanis@mskcc.org.
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