Need to know:
- There are at least seven bispecific monoclonal antibodies in the race to reach the relapsed or refractory multiple myeloma market.
- Efficacy and safety class effect between assets are expected, and so first-to-market is vital to secure lasting impact among clinicians.
- With assets unlikely to differentiate themselves via efficacy or safety, shift to an earlier line of treatment, administration method, or reduced treatment frequency remain possible avenues.
- Bispecific monoclonal antibodies may take a bite out聽of CAR-T cell therapy market due to the former鈥檚聽off-the-shelf convenience.
The first bispecific monoclonal antibody (mAb) to reach the relapsed or refractory (r/r) multiple myeloma market will likely secure its standard-of-care status for an extended duration despite a bevy of challengers on its tail, experts said. Bispecific mAbs are expected to have an efficacy and safety class effect, which means it will be tough for market latecomers to convince clinicians to switch from what asset they are most used to, they added.
Bispecific mAbs are drawing a lot of buzz in owing to their current efficacy data hinting at a treatment聽paradigm shift, experts said. There are currently several bispecific mAbs under investigation, with ongoing Phase II trials run by聽,听, and聽, as well as Phase I studies supported by聽,听 and聽Roche. These assets鈥� respective ClinicalTrials.gov listings show estimated primary completion dates starting December 2021 through to 2023. Amgen and Germany-based聽Boehringer Ingelheim聽are working together on a Phase II-ready asset.
To persuade clinicians to swap between bispecific mAbs, dramatic efficacy or safety improvement would be needed. But this may be tough to show, given the comparable data between assets so far. Other lines of differentiation such as a shift to an earlier line of treatment, administration method, or treatment frequency are possible but require early strategic decisions from developers.
Not only will the bispecific mAb frontrunner beat out fellow competitors, it may also chip away at the sales of CAR-T cell therapies in the same r/r multiple myeloma market. Bispecific mAbs are more convenient to give and do not have offsite manufacturing requirements, allowing for broader use beyond academic centres, experts noted.
A challenge to break from the pack
The first asset that secures an FDA approval has a time advantage in allowing clinicians to build experience with that specific bispecific mAb, said Perlmutter Cancer Center director of multiple myeloma research Dr Gareth Morgan. It would be hard for competitors to chip away at clinician loyalty, he added. The first-to-market bispecific mAb would be considered a market leader, even if there are other assets yet to reach the market with some efficacy advantage, noted Oslo Myeloma Center head Dr Fredrik Schjesvold.
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By GlobalDataBispecific mAbs鈥� respective efficacy profiles are currently comparable, added Dr Ulf-Henrik Mellqvist, professor, Department of Hematology and Coagulation at Sweden鈥檚 Sahlgrenska University Hospital. Current bispecific mAb overall response rates (ORR) are within the range of 60鈥�80%, Morgan noted.
Dramatic efficacy needed to entice clinicians
While it may be hard to convince clinicians to swap, it is not impossible to do so. If a newcomer bispecific mAb delivers dramatically superior efficacy then it would be a clear reason to switch, Schjesvold noted. He referred to the experience with CAR-T cell therapies like (Cilta-cel) and聽/鈥檚聽Abecma (idecabtagene vicleucel).
In a Phase Ib/II Cilta-cel trial, median progression-free survival (PFS) was not reached in 133 patients although the lower range was 16.8 months in assessable patients. In contrast, Abecma鈥檚 median PFS was 8.8 months in 128 patients in the Phase II KarMMa trial. The nearly doubled PFS benefit would make it hard not to switch, Schjesvold explained.
Abecma garnered FDA approval on 26 March in r/r multiple myeloma, while Cilta-cel has a Prescription Drug User Fee Act date of 29 November. A BMS spokesperson said there have been no head-to-head studies involving Abecma and Cilta-cel and differences in their respective clinical trial designs make comparisons hard.
Differing molecular features may lead to different efficacy
While there is a theorised class effect, bispecific mAbs can have different molecular features that may lead to different efficacy profiles altogether, Schjesvold added. Bispecific mAbs forge a connection between T cells and tumour cells, paving the way for T cells to be cytotoxic against the tumour cell.
闯&补尘辫;闯鈥檚 , Pfizer鈥檚 PF-06863135 (elranatamab), and Regeneron鈥檚 REGN5458 bind to B-cell maturation antigen (BCMA) on multiple myeloma cells and CD3 receptors on T-cells. Meanwhile, 闯&补尘辫;闯鈥檚 talquetamab targets GPRC5D on the myeloma cell, while Roche鈥檚 cevostamab targets FcRH5.
But showing dramatic efficacy superiority over individual bispecific mAbs may be challenging, which will allow the first-to-market asset to maintain its market territory. Certain bispecific mAbs may be used in patients that progress from an earlier bispecific mAb, but this would be a much smaller market, Mellqvist said.
This underscores the importance of being first-in-class with this approach, noted University of California San Francisco Medical Center clinical professor of medicine Dr Thomas Martin. Even when it comes to subpopulations, it is currently tough to say if certain bispecific mAbs would be better than others, Schjesvold added.
Safety edge also challenging to tease between competitors
Overall, there are no concerning side-effects among the bispecific mAbs, Schjesvold said. But some assets may have neuropathy issues while others won鈥檛, he noted. Pfizer owing to three cases of peripheral neuropathy in an ongoing Phase I study. But more information is needed to tease differences between assets as current data involves a small number of patients with a short follow-up, Schjesvold added.
There is also the issue of cytokine release syndrome (CRS), Martin said. But this is present in all bispecific mAbs so far, he added. CRS may only occur in a small number of patients, but it can be difficult to manage, Morgan noted. However, with experience, incidence rates can go down and help uptake across the board, he added. CRS is a known risk associated with immunotherapies that activate the body鈥檚 own immune system, but the cause is still not fully understood, a Roche spokesperson noted.
There could be nuances in the safety profiles of different bispecific mAb assets depending on their individual targets, Mellqvist said. But even then, perhaps only those clinical trial sites that have experience with multiple bispecific mAbs can recognise any differences, he added.
Starting at a lower dose can ease side-effect risk
These safety risks could be alleviated by starting with the lowest dose first and observing patients during a hospital stay, Martin said. Once the ideal dose is identified, the chronic treatment can evolve as a weekly or twice-weekly outpatient procedure, he added. CAR-T cell therapy Abecma has a black box warning on neurologic toxicities and CRS, and patients need to be monitored at least daily for seven days following infusion.
A much clearer way for any asset to edge competition would be via the administration method. REGN5458 is intravenously (IV) administered, while elranatamab and talquetamab have both IV and subcutaneous versions. A more convenient subcutaneously administered bispecific mAb or one that requires less frequent dosing would have a valuable advantage, Schjesvold said. Bispecific mAbs regimens are weekly, fortnightly or, in the case with cevostamab in its Phase I trial, every three weeks, the Roche spokesperson said.
Clear bispecific mAb advantage over CAR-T
That said, bispecific mAbs have a clear advantage over CAR-T cell therapy in r/r multiple myeloma in terms of convenience, experts agreed. While CAR-T therapies require T cells to be sent to an offsite manufacturing center, bispecific mAbs are 鈥榦ff-the-self鈥� products. The limited number of manufacturing facilities makes securing CAR-T cell therapy slots an issue, Morgan said. The complicated process draws pause on how often they would be used, Mellqvist added.
It is possible that, due to the convenience of bispecific mAbs, they would be used broadly in the community setting while CAR-T cell therapies are used in academic centres with more experience, Morgan said. Still, bispecific mAbs do require a significant degree of experience in monitoring side effects, which could limit how often they are used in the community, Martin added.
A J&J spokesperson noted that bispecific mAbs and CAR-T cell therapies may be complementary of each other depending on the patient鈥檚 condition, profile, and preferences. Bispecific mAbs may be for patients who require immediate treatment or have comorbidities that preclude them from CAR-T cell therapies, she added. Other bispecific mAb developers did not respond to a comment request.
So far, both approaches have almost comparable ORR efficacy profiles but more PFS data with bispecific mAbs is needed, Schjesvold said. Nevertheless, there is a strong correlation that positive ORR data will lead to positive PFS in r/r multiple myeloma, he noted. Also, these assets may have better PFS as patients are treated more often versus CAR-T cell therapies, which are one-and-done, he added.
