Cost and Allocation of Scarce CAR-T Therapy for Patients With Multiple Myeloma

What strategies are CAR-T centers using to navigate the limited supply of CAR-T therapies?

Dr Derman: There are a few different ways that CAR-T centers are dealing with the scarcity issue with CAR-T in myeloma. Creating a waitlist is essential, but of course the central question is how to most fairly prioritize patients.⁶ A first come, first served approach “ranks” patients by appointment date, not their disease state. In other words, patients who have delayed time to referral are unjustifiably penalized.

As a physician caring for patients in an underserved community in Chicago, I am keenly aware that many patients in our catchment area don’t get referred as early as they should for CAR-T, and in some cases, they don’t get referred at all or their circumstances prevent them from being evaluated. This is why we recommend that patients should get “credit” for time since they met labeled indications for CAR-T in myeloma. For instance, if a patient progressed on fourth-line therapy in 2020, then their list date should be from that point.

Most CAR-T centers report prioritizing patients who have the greatest need – that is, patients with the most high-risk disease features. However, the patients with the greatest need for CAR-T may very well be the patients who stand to gain the least. Early trial and real-world data suggest that certain disease features – high risk cytogenetic abnormalities, extra medullary disease, high disease burden – are associated with worse outcomes. Even young patients, who should be better able to tolerate the treatment, have been found to benefit less from CAR-T.

We call for a more rigorous and validated risk score to help assess whether a patient stands to benefit from CAR-T, but until then, we do not recommend using any disease features to triage patients.  

One of the most important things we would like to avoid is a patient getting collected for CAR-T but never receiving their cells because they did not survive the “vein-to-vein” time — the waiting time for CAR T-cell manufacturing — which can be as much as 8-10 weeks. It is critical that this time is reduced. 

What are some promising measures that might help to mitigate such issues and increase access to CAR-T therapies?  

Dr Derman: Fortunately, much is underway to alleviate this crisis. The first is that the lentiviral shortage has been somewhat relieved through a variety of actions by industry. The FDA has been allowing CAR-T manufacturers to ramp up production, but it has been slow and will likely remain that way for some time.

This issue may be further exacerbated by the fact that we now have 2 randomized controlled trials, karMMa-3 and CARTITUDE-4 (ClincalTrials.gov Identifiers: NCT03651128 and NCT04181827, respectively), which showed a benefit to CAR-T in myeloma in earlier lines of therapy, which may lead to expanded labeled indications and increased demand.^5,7

I applaud industry for helping with lodging for patients moving forward with CAR-T therapy, so that distance from a CAR-T center is not a limiting factor for as many patients. Still, more could be done by allowing patients to have reliable transportation to and from clinic visits in the time shortly after CAR T-cells are infused. 

The FDA approval of 3 bispecific antibodies for relapsed/refractory MM — teclistamab, elranatamab, and talquetamab — are off-the-shelf therapies that are readily available for patients.⁸ They may not carry the same depth or duration of response for some, but they surely help to relieve some of the demand issues that exist. 

Dr Taxiarchis: Recent improvements in the manufacturing process have improved the supply limitations and will likely continue to improve this issue further. However, the anticipated approval of these therapies at earlier lines of therapies may again increase demand and put pressure on the system. Increasing manufacturing capabilities will likely still be required.

In our paper, the criterion used most frequently across centers to prioritize patients for CAR-T therapies was the availability of alternative therapy options and the likelihood of patients to be able to make it to CAR-T infusion.¹ It is very likely that these issues will be improved when these therapies become available in earlier lines of therapy in MM.

Furthermore, the ability to administer these therapies closer to the patients, such as in larger community cancer centers, would significantly increase access. The development of autologous “off-the-shelf” approaches may also increase availability of these therapies, as will in-house manufacturing by larger academic centers.

Several constructs are in development targeting the existing (BCMA) or novel proteins on the surface of MM cells and with several variations in the mechanism of action/generation of chimeric effector cells that, in theory, will allow for increased efficacy.

Finally, for patients too frail to receive CAR-T or with limited access to larger centers, alternative therapies — specifically bispecific antibodies — will represent an alternative option for T-cell redirecting immunotherapies.⁸

Dr Cliff: In addition to manufacturers investing in increased manufacturing capacity, multiple encouraging approaches are developing:

• Academic CAR T-cells — for example in Spain, India, and Wisconsin.^9-11 This will improve access globally.
• Rapid production of CAR T-cells — for example, by UPenn/Novartis.^12,13 This will improve access for patients with rapid disease kinetics.
• Allogeneic CAR T-cells — for example from Allogene.¹⁴ These will be “off-the-shelf,” again improving access and potentially cost.
• Price negotiation in the United States. However, this will only impact products that have been on the market for 12 years, so it is unclear how this will impact CAR T-cell products.

What research is currently underway in the realm of CAR-T therapies for MM?

Dr Derman: There are several more CAR T-cell therapies under investigation for MM. If these prove to be effective and safe enough to obtain FDA approval, that may help to meet demand. For example, Novartis PHE885 is a BCMA-directed CAR-T therapy under investigation that seeks to significantly shorten the vein-to-vein time for patients, which may help more patients gain access.¹⁵

The wealth of bispecific antibodies under investigation has and will continue to help meet demand for advanced myeloma therapies, though their frequent administration and unique toxicity profiles could stand to be improved.⁸

It is becoming clear that CAR-T therapy provides patients with deep and durable responses, typically on the order of years. Demand will continue to increase as CAR-T therapy moves up earlier in the treatment paradigm for myeloma. CAR-T manufacturers and regulatory agencies need to work diligently and quickly to ensure safe but rapid scaling of CAR-T production.

References

1. Kourelis T, Bansal R, Berdeja J, et al. Ethical challenges with multiple myeloma BCMA chimeric antigen receptor T cell slot allocation: a multi-institution experience. Transplant Cell Ther. 2023;29(4):255-258. doi:10.1016/j.jtct.2023.01.012
2. Chen AJ, Zhang J, Agarwal A, Lakdawalla DN. Value of reducing wait times for chimeric antigen receptor T-cell treatment: evidence from randomized controlled trial data on tisagenlecleucel for diffuse large B-cell lymphoma. Value Health. 2022;25(8):1344-1351. doi:10.1016/j.jval.2022.02.007
3. Derman BA, Parker WF. Fair allocation of scarce CAR T-cell therapies for relapsed/refractory multiple myeloma. JAMA. Published online July 31, 2023. doi:10.1001/jama.2023.11846
4. Cliff ERS, Kelkar AH, Russler-Germain DA, et al. High cost of chimeric antigen receptor T-cells: challenges and solutions. Am Soc Clin Oncol Educ Book. 2023;43:e397912. doi:10.1200/EDBK_397912
5. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335-347. doi:10.1056/NEJMoa2303379
6. Bell J, Jeffries GA, Chen C. Mitigating inequity: ethically prioritizing patients to CAR T-cell therapy. Blood. Published online August 4, 2023. doi:10.1182/blood.2023020703
7. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 2023;388(11):1002-1014. doi:10.1056/NEJMoa2213614
8. 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
9. Sperling AS, Derman BA, Nikiforow S, et al. Updated phase I study results of PHE885, a T-Charge manufactured BCMA-directed CAR-T cell therapy, for patients (pts) with r/r multiple myeloma (RRMM). J Clin Oncol. 2023;41(16_suppl):8004-8004. doi:10.1200/JCO.2023.41.16_suppl.8004
10. Oliver-Caldés A, González-Calle V, Cabañas V, et al. Fractionated initial infusion and booster dose of ARI0002h, a humanised, BCMA-directed CAR T-cell therapy, for patients with relapsed or refractory multiple myeloma (CARTBCMA-HCB-01): a single-arm, multicentre, academic pilot study. Lancet Oncol. 2023;24(8):913-924. doi:10.1016/S1470-2045(23)00222-X
11. Palani HK, Arunachalam AK, Yasar M, et al. Decentralized manufacturing of anti CD19 CAR-T cells using CliniMACS Prodigy®: real-world experience and cost analysis in India. Bone Marrow Transplant. 2023;58(2):160-167. doi:10.1038/s41409-022-01866-5
12. Shah NN, Johnson BD, Schneider D, et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nat Med. 2020;26(10):1569-1575. doi:10.1038/s41591-020-1081-3
13. Ghassemi S, Durgin JS, Nunez-Cruz S, et al. Rapid manufacturing of non-activated potent CAR T cells. Nat Biomed Eng. 2022;6(2):118-128. doi:10.1038/s41551-021-00842-6
14. Dickinson MJ, Barba P, Jäger U, et al. A novel autologous CAR-T therapy, YTB323, with preserved T-cell stemness shows enhanced CAR T-cell efficacy in preclinical and early clinical development. Cancer Discov. 2023;13(9):1982-1997. doi:10.1158/2159-8290.CD-22-1276
15. Mailankody S, Matous JV, Chhabra S, et al. Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results. Nat Med. 2023;29(2):422-429. doi:10.1038/s41591-022-02182-7

This article originally appeared on Hematology Advisor