Immune Therapies for Myeloma: The CARs Are Here but What's Next?

Ide-cel was approved by the FDA based on the results from the pivotal KARRMA2 trial that were published in late February.¹  This trial enrolled 140 patients with MM with three or more prior regimens and refractory to last-line therapy. Of these, 128 patients (91%) received ide-cel at doses ranging between 150 and 450 million cells. With a median follow-up of 13.4 months, 94 patients (73%) achieved a partial response or better, with 42 patients (33%) achieving a complete response. Minimal residual disease (MRD) negativity was confirmed in 33 patients (26%). The safety profile was consistent with prior reports, with 107 patients (84%) developing cytokine release syndrome (CRS; 5% grade 3 or higher) and 23 patients (18%) developing neurologic toxicities (3% of patients with grade 3 events). Four patients (3%) died from ide-cel–related adverse events within six months of treatment. Cytopenias after treatment were common, with some patients developing persistent cytopenias. The median PFS was 8.8. months (12.1 months for the higher dose of 450 million cells), and updated results show a median OS of 24.8 months.

These results led to the approval of ide-cel for patients with R/R MM with four or more prior lines of treatment. This is the fourth therapy to be approved for this indication in the past two years (selinexor, belantamab mafodotin, and melphalan flufenamide are the other three approved therapies; Table). These treatments have not been evaluated in randomized clinical trials to date and therefore direct comparisons of efficacy and safety are not feasible. However, as shown in the Table, the overall responses, PFS, and OS are numerically higher with ide-cel compared to the other therapies.

The FDA approval of ide-cel provides an important new treatment option for patients with advanced MM. It is also a one-time treatment with no currently recommended maintenance, which allows for a relatively long treatment-free interval for many patients receiving this therapy. However, patients do relapse, and the median PFS is less than one year. The customized nature of CAR-T therapies and the adverse effects associated with it illuminate several challenges. CAR-T therapies are currently available only in select medical centers, and the frequent complications generally require hospitalization. There is typically a three-to six-week delay between apheresis and CAR-T infusion, and many patients require bridging therapies during this time. Some patients are unable to proceed with treatment due to rapid progression of disease despite bridging therapies. CRS and neurologic toxicities are typically seen early after treatment, and the management is specialized. These are typically treated with supportive care, IL-6 antibodies such as tocilizumab, and steroids. Cytopenias and infections are other commonly encountered toxicities and may require growth factor, transfusion support, and infectious prophylaxis. Finally, the costs of ide-cel therapy (list price of $419,500) and associated care including hospitalization may be a significant barrier to access both in the United States and globally.

Ide-cel is the first of the BCMA CAR-T therapies to be approved. At the 2021 American Society of Clinical Oncology Annual Meeting, the results from the pivotal CARTITUDE-1 trial of ciltacabtagene autoleucel (cilta-cel), another BCMA-targeted CAR-T therapy, were presented.²  This trial enrolled 113 patients of whom 97 (86%) received cilta-cel therapy. Ninety-five patients (98%) had a response, with 78 patients (80.4%) achieving a complete response or better. The median PFS was not reached at the time of reporting, with an estimated 18-month PFS and OS of 66 percent and 81 percent, respectively. The adverse event profile was notable for CRS, neurologic toxicities, and cytopenias. Of note, 12 patients (12.4%) had delayed neurologic toxicities including nine (9.3%) with grade 3 or higher events. The patients who developed these events were found to have high disease burden, grade 2 or higher CRS, immune effector cell–associated neurotoxicity syndrome, or high CAR-T expansion. Bispecific antibodies redirect the patients' T cells to the cancer cells by binding to CD3 on the T cells and a specific target protein (BCMA or others) in the malignant cells. These are generally administered intravenously or subcutaneously on a weekly basis (or even less often). CRS and neurologic toxicities are anticipated with the first few doses but afterward, these treatments can generally be administered outpatient. There are currently several BCMA-targeted bispecific antibodies in clinical development, and preliminary results from ongoing phase I/II trials demonstrate promising overall responses. Results from phase II trials with additional patients and longer follow-up are awaited. There are two key questions regarding BCMA-targeted bispecific antibodies and CAR-T therapies: 1) how do the logistics, efficacy, and safety of these therapies differ, and 2) is there a role for sequential administration of bispecific antibodies and CAR-T therapies? Allogeneic CAR-T therapies represent an “off-the-shelf” cellular therapeutic option for the treatment of myeloma. These therapies use donor-derived T cells to manufacture the CAR-Ts and can be administered without need for bridging therapy. At the 2020 ASH Annual Meeting, the results from the first-inhuman allogeneic CAR-T therapy ALLO715 demonstrated the feasibility, safety, and preliminary efficacy of this treatment.³  The logistical advantages of an off-the-shelf CAR-T therapy are significant, but longer follow-up is needed to determine efficacy in comparison to autologous CAR-T therapies such as ide-cel and cilta-cel.

While much of the excitement with immune therapies in MM has focused on BCMA, two other potential treatment targets have emerged recently. G protein–coupled receptor, class C group 5 member D (GPRC5D), is an orphan receptor expressed predominantly in malignant plasma cells. Recent studies from two independent groups have demonstrated the feasibility and preclinical rationale for GPRC5D-targeted CAR-T therapy and bispecific antibodies. At the 2020 ASH Annual Meeting, preliminary results from a phase I trial of talquetamab CD3-GPRC5D bispecific antibody were presented, showing good safety and promising efficacy with an overall response of 69 percent in patients treated at the recommended phase II dose.⁴  There is also an ongoing trial of MCARH109, the first GPRC5D targeted CAR-T therapy; clinical results are awaited. Another target for treatment that has emerged recently is the Fc receptor-homolog 5 (FcRH5) that is expressed in mature B and plasma cells, including myeloma cells. Results from the phase I trial of cevostamab, a CD3-FcRH5 bispecific antibody, were also presented at the 2020 ASH Annual Meeting, showing an overall response of 53 percent in patients treated at the active doses.⁵ 

The FDA approval of ide-cel is a significant first step in the use of immune therapies for MM. While this has an immediate impact for patients with four or more prior therapies, we believe CAR T and other immune therapies will have broader application in MM soon. Ongoing and planned clinical trials will evaluate the role of these therapies in earlier lines of treatment, combinations with other therapies, and improvements in CAR-T manufacturing processes. Additionally, promising preliminary data with allogeneic CAR-T therapy and treatment-targeting novel antigens can potentially translate to new treatments for myeloma. An important consideration for all of us is to ensure timely and cost-effective access to these promising therapies globally.

Dr. Mailankody has received research funding from the National Cancer Institute, Juno/Bristol Myers Squibb, Allogene Therapeutics, Janssen Oncology, Takeda Oncology, and Fate Therapeutics; honoraria from Physician Education Resource and PleXus Communications. Dr. Usmani has received research funding from Amgen, Array Biopharma, BMS, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, and Takeda; consulting fees from Amgen, BMS, Celgene, EdoPharma, GSK, Janssen, Oncopeptides, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, and TeneoBio; and speaker fees from Amgen, BMS, Janssen, and Sanofi.