Fair Allocation of Scarce CAR T-Cell Therapies for Relapsed/Refractory Multiple Myeloma

The treatment landscape for relapsed/refractory multiple myeloma has undergone an immunotherapeutic breakthrough with the introduction of 2 commercial B-cell maturation antigen (BCMA)–directed chimeric antigen receptor (CAR) T-cell therapies for patients with heavily pretreated relapsed/refractory multiple myeloma: idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti).^1,2 These therapies have led to durable responses and significantly reduced the risk of progression or death compared with alternative chemotherapies.

Unfortunately, access to these groundbreaking therapies has been severely limited. First, patients with heavily pretreated relapsed/refractory multiple myeloma may not live the amount of time currently required to harvest their T cells, modify them to express a transgene encoding a tumor-specific CAR, and infuse the modified CAR T cells; this “vein-to-vein” time spans at least 6 weeks. Second, the number of leukapheresis slots offered by manufacturers has been limited by lentiviral vector shortage and the challenge of increasing scale while maintaining quality. Although the number of available leukapheresis slots will expand, the vein-to-vein delay cannot be reduced with current technology.

Although the total supply of CAR T cells is difficult to quantify, it is undoubtedly insufficient for the more than 170 000 individuals in the US with multiple myeloma. A 2023 study of centers offering CAR T-cell therapy for multiple myeloma found that for every allocated slot per month per center, there were 20 patients on the waitlist; patients were waiting a median of 6 months prior to leukapheresis.³ Despite ongoing efforts to increase supply through expanding manufacturing capabilities, this severe shortage will likely increase as CAR T-cell therapy demonstrates superior efficacy over alternatives earlier in the course of multiple myeloma.^1,2 Even if new therapies such as off-the-shelf bispecific antibodies reduce demand, there will not be enough CAR T-cell therapy slots for all eligible patients.

Current CAR T-Cell Therapy Allocation Practices Are Unfair

In a 2023 survey, 71% of academic centers used the initial appointment date at the referral center to construct waitlists for CAR T-cell therapy.³ This “first come, first served” allocation system is problematic because the US health care system prioritizes wealthy and well-connected patients for advanced treatments such as CAR T-cell therapy. In the clinical trial setting, there have been socioeconomic and racial disparities in enrollment for CAR T-cell therapy in multiple myeloma, with low representation of Black individuals.¹ Historically marginalized populations have delays in gaining access to stem cell transplant; the same may occur with CAR T-cell therapy. Recognizing these baseline injustices in the US health care system, we propose a practical approach to CAR T-cell therapy allocation built on the principles of scarce health care resource allocation designed to be easily implemented by CAR T-cell therapy centers.⁴

Count Waiting Time From Disease State, Not Appointment Date

Patients with myeloma may have met the labeled indications for CAR T-cell therapy long before they gained access to a CAR T-cell center. In deceased donor kidney allocation, racial disparities in kidney transplant were narrowed considerably when candidates were given waiting time credit for time spent receiving dialysis prior to being put on a waitlist.⁵ The analogous approach with CAR T-cell therapy is to start counting waiting time from the date when the patient met regulatory agency indications for CAR T-cell treatment. Centers should identify and document this disease progression date and order their waitlist accordingly. This approach treats people equally and avoids constructing a waitlist that is heavily dependent on socioeconomic status and access to health care. Instead, patients should be considered based on the time when their disease relapsed on the requisite number of therapies. This strategy should still apply even if the patient temporarily responded to an alternative therapy while waiting because such responses are unlikely to be long lasting.⁶

Avoid Arbitrarily Prioritizing Subcategories of Eligible Patients

Commercial CAR T-cell therapy should be administered to patients who meet the labeled indications for therapy, which currently is for patients with 3 to 4 prior lines of therapy, prior requisite therapy exposures, and meeting standardized criteria for progression. As new data emerge on the benefit of CAR T-cell therapy administered earlier in the disease paradigm compared with standard care, we propose prioritizing patients with at least 3 to 4 prior lines of therapy given the availability of suitable alternatives for patients with less pretreated disease.

However, within the group of eligible patients, it is truly unknown which subgroups benefit most from CAR T-cell therapy. Most surveyed academic centers offering CAR T-cell therapy endorsed prioritizing patients with the highest disease burden and aggressiveness,³ but this approach may not maximize benefits overall. The least-efficient outcome is for a patient to die during the vein-to-vein delay. Both clinical trial and real-world data suggest that 10% of patients will never receive their CAR T-cell therapy,^1,2,7 implying that a “sickest first” strategy will lead to unacceptable levels of wasted patient-specific therapies. Furthermore, there is mounting evidence that patients with disease characteristics that portend the highest risk of death without CAR T-cell therapy—those with higher disease stage, high-risk cytogenetic abnormalities, extramedullary disease, and prior BCMA-directed therapies—are the ones who also appear to benefit less from BCMA-directed CAR T-cell therapy even if they do not die during the vein-to-vein delay.^1,2,7

Conversely, patients with a high probability of surviving to CAR T-cell infusion and tolerating its complications may not have the highest survival benefit from treatment either. In a real-world analysis of patients with multiple myeloma receiving idecabtagene vicleucel, younger age was associated with worse progression-free survival.⁷ In contrast to organ allocation policy, which is based on empirical analysis of hundreds of thousands of recipients, we lack sufficient information to make a rigorous survival benefit–based score for CAR T-cell therapy allocation. With more data, an accurate model of survival benefit from CAR T-cell therapy should be possible, but using an arbitrary score that has not been rigorously externally validated may lead to lower benefits than random allocation while unfairly deprioritizing large classes of patients.

Mitigate Health Inequities by Reserving Appointments for Patients From Socially Disadvantaged Neighborhoods

Black individuals are at a higher risk for multiple myeloma and comprise approximately 20% of newly diagnosed multiple myeloma cases in the US; yet, only 4.5% of participants in trials included in new drug application submissions for multiple myeloma indications between 2003 and 2017 were Black.⁸ This underrepresentation of Black individuals extends to CAR T-cell therapy trials in multiple myeloma.^1,2 This will likely apply to the clinical distribution of CAR T-cell therapy due to (1) lack of or delayed referral, (2) unconscious physician bias, (3) lack of social support and/or transportation, and (4) institutionalized barriers from under- or uninsurance. Patients from rural communities with high area deprivation are also at a disadvantage for many of the same structural factors.

Providing transportation and temporary lodging proximal to the medical center is one way to help alleviate issues of social support and transportation. CAR T-cell therapy centers and manufacturers can also actively counter these structural inequities byreserving slots for patients from socially disadvantaged neighborhoods in their primary service area proportional to their local expected multiple myeloma burden. Alternatively, centers could use a weighted lottery that gives patients with longer eligibility times and who live in disadvantaged neighborhoods more chances to “win” an allocated CAR T-cell therapy slot.⁹ Although many barriers exist, CAR T-cell therapy would ideally be allocated nationally analogous to the organ allocation system with restrictions in place to prevent CAR T-cell therapy “shopping” from affluent patients.

CAR T-cell allocation protocols should (1) rank-order patients by disease state, not listing date, (2) avoid arbitrary subclassifications of eligible patients, and (3) prioritize patients from socially disadvantaged neighborhoods. Actively and practically incorporating established ethical principles can lead to more efficient and fairer CAR T-cell therapy allocation.