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Novel immunotherapies in MM
response of 4.2 months. CRS grade 3/4 was seen in 32% and ICANS grade 3/4 in 12% of patients.37
Idecabtagene vicleucel
More advanced data have been reported on idecabta- gene vicleucel (ide-cel, bb2121) and ciltacabtagene autoleucel. In the phase I study of ide-cel, a BCMA-CD28 construct, 62 RRMM patients were treated with escalat- ing doses from 50 to 800x106 cells. The ORR was 76% with a 39% complete response rate and a median PFS of 8.8 months with a follow-up of 18.1 months. Toxicity was comparatively low with grade 3/4 CRS occurring in 7% and ICANS in 2% of patients.46,47
In the phase II KarMMa trial of ide-cel, 128 RRMM patients were treated. The ORR was 73% with a com- plete response rate of 33% and a median PFS of 8.8 months. The rate of grade 3/4 CRS was 5% and that of ICANS was 3%.48,49 In the ongoing KarMMa-2 study ide- cel is being evaluated in patients who have relapsed early following first-line therapy and in patients who achieved less than a very good partial response after autologous stem cell transplantation. The phase III study, KarMMa-3, is comparing ide-cel with standard-of-care regimens in RRMM.
Ciltacabtagene autoleucel
Ciltacabtagene autoleucel (cilta-cel, LCAR-B38M or JNJ-4528), a BCMA-4-1BB construct with two BCMA binding domains, was first developed in China. The phase I trial, LEGEND-2, enrolled 57 patients. The ORR was 88% with 74% of patients achieving a complete response. The median PFS was 19.9 months. With regard to adverse events, the rate of grade 3/4 CRS was 7% and no grade 3/4 episodes of ICANS occurred.50-52 Cilta-cel was then evaluated in the phase I/II CARTITUDE-1 trial with 97 patients treated so far. The ORR was 97% and the complete response rate was 67%. At a follow-up of 12.4 months the median PFS had not been reached and the 12 months PFS rate was 76.6%. The rate of grade 3/4 CRS was 5% while that of grade 3/4 ICANS was only 2%; however, there were also other delayed episodes of neurotoxicity reported in 9% of the patients in the latest follow-up.53-55
In the ongoing CARTITUDE-2 study, cilta-cel is being evaluated following first-line therapy in patients who have not achieved a complete response after autologous stem cell transplantation or in those with prior exposure to a BCMA-targeting drug. Cilta-cel is also being evaluat- ed in the phase III CARTITUDE-4 study comparing CAR T cells versus pomalidomide-based triplets in lenalido- mide-refractory patients.
Allogeneic chimeric antigen receptor T cells
The disadvantages of currently available autologous CAR T-cell therapy include the long time needed for pro- duction and the reduced fitness of T cells due to the heavy pretreatment of the patients in current clinical tri- als. This may be overcome in part by preemptive T-cell collection early during the course of the disease. Off-the- shelf allogeneic CAR T cells may be an alternative. Mailankody et al. presented preliminary data on the first allogeneic BCMA CAR T-cell study for RRMM at the ASH meeting in 2020. In these allogeneic CAR T cells the T-cell receptor is knocked out to avoid graft-versus-host disease and CD52 is knocked out to permit the use of an
anti-CD52 antibody for selective and prolonged lym- phodepletion to improve engraftment. Gene editing is performed with transcription activator-like effector nucle- ase (TALEN) technology. The ORR in the group given a dose of 320x106 cells was 60% (6/9 patients) with no grade 3/4 CRS or ICANS or graft-versus-host disease.56 CAR-transduced natural killer cord blood cells may be another potential source of future off-the-shelf cellular products.57
Discussion
With the plethora of novel immunotherapy approaches and treatment strategies that are currently in all stages of clinical development, including some recently approved by regulatory authorities, the treatment landscape in MM is likely to evolve rapidly over the next 5 years, as it did with the introduction of high-dose therapy and autolo- gous blood stem cell transplantation about 30 years ago or with the development of proteasome inhibitors and immunomodulatory drugs in the first decade of this cen- tury, followed by monoclonal antibodies in recent years. These novel agents display unprecedented single-agent activity with ORR exceeding 80% in RRMM patients, translating into response durations of more than 1 year, even in patients with no other treatment options. However, there are, as yet, no phase III clinical datasets available. Therefore, there are still many unanswered questions as to when and how to utilize these different immunotherapeutic agents in our daily clinical practice.
Differences and similarities
Given the many therapeutic agents that are being developed within each immunotherapeutic class - ADC, TCE, and CAR T cells-much work will be required to assess their relative merits. Most data are available for ADC, for which a range of ocular toxicities have been observed, especially those affecting visual acuity. While belantamab mafodotin induces a clinically significant, reversible keratopathy in about a third of patients, other ADC are associated with lower rates of keratopathy (AMG224) or as yet unexplained photophobia (MEDI2228). However, as the latter two ADC have only been given to limited numbers of patients so far, it is too early to assess potential differences in side effects or even in efficacy.
The same considerations apply to TCE, despite their seemingly similar side-effect profiles, mainly CRS and cytopenias. However, based on early phase clinical trial data, some agents seem to cause CRS less frequently, e.g., TNB-3838, whereas others cause CRS in the majority of patients, yet mostly of minor grade. CC-93269 and tal- quetamab seem to induce grade 3/4 CRS in some patients. While TNB-3838 was specifically designed to induce less CRS by having a lower affinity for CD3, the reason for the higher CRS rates with other agents remains to be better understood. Of note, the route of administra- tion appears to have an impact on side effects in general and on the rate of CRS specifically, as the rates of both were lower when teclistamab and talquetamab were given subcutaneously rather than intravenously. Interestingly, so far, the specific target of individual TCE does not appear to affect the side-effect profile. Again, it remains to be seen whether these distinctions between
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