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L. Rasche et al.
different agents of the same class will be confirmed in larger trials. However, most patients will favor subcuta- neous administration, especially if lower rates of side effects will allow for outpatient use.
Regarding CAR T-cell approaches, the only available data relate to constructs that target BCMA. While phase III results are awaited, the numbers of patients in report- ed trials are higher and clinical development is more advanced when compared to those for TCE.
For the two most advanced constructs, ide-cel and cilta- cel, grade 3/4 CRS and ICANS are relatively uncommon and less of a concern when compared to the side effects of CD19-directed CAR T-cell therapies. Nonetheless, there seem to be differences in the timing of onset of these toxicities. Ide-cel-associated CRS and ICANS emerge within the first 10 and 30 days, respectively, whereas the median times to onset of CRS and ICANS following cilta-cel treatment are 7 and 8 days after infu- sion, respectively. Moreover, delayed neurotoxicities associated with cilta-cel treatment, not attributable to ICANS, have been reported to occur even several months after infusion. This has implications for the logistics and timing of the required observation period after CAR T- cell therapy.
As it is highly unlikely that we will ever have random- ized trials comparing different members of the same class of agents, we will have to wait for larger clinical trials and ultimately real-world post-approval data to tease out the specific characteristics of individual members of the immunotherapeutic armamentarium.
Despite the unprecedented responses to both CAR T cells and TCE, all patients eventually seem to relapse. It is therefore very important to understand mechanisms of
resistance to the different immunological therapies,58 including lack of CAR T-cell persistence in MM patients, MM cell target antigen loss,38 and functional inactivation of T cells by an immunosuppressive microenvironment.59 Based on translational data, promising strategies to improve the duration of response to MM immunothera- py include: (i) generation of CAR T cells with a higher potential for persistence in vivo (e.g., by in vitro generation of less exhausted effector-type and more functionally fit naive cells);60,61 (ii) targeting more than one MM tumor antigen simultaneously by dual CAR T-cell approach- es;60,61 and (iii) concurrently inhibiting endogenous tumor escape mechanisms, such as T-cell-expressed immune checkpoint molecules or myeloid cell arginase-mediated arginine deprivation.59
Positioning in the treatment landscape
With increasing treatment options, there needs to be a focus on the timing and sequencing of compounds and strategies. For the time being and likely for the next few years, this issue will be answered (or dictated) by which of these different immunotherapies have been approved for clinical use. However, there is strong interest in using these agents at earlier lines of treatment with less exhausted T cells present in the bone marrow to be exploited by TCE or available to be transduced into CAR T cells. In this regard, results from CAR T-cell trials involving less heavily pretreated patients, although still RRMM patients, do not appear to show greater efficacy, notwithstanding all the limitations of inter-trial compar- isons and small numbers of patients.
Another important aspect relates to how to use cellular or antibody-based immunotherapy best in hard-to-treat
Figure 2. Our view on potential patient selection as a basis for further discussion. CAR T: chimeric antigen receptor T cells; TCE: T-cell-engaging antibodies; ADC: antibody- drug conjugate; CRS: cytokine release syndrome; GFR: glomerular filtration rate; MM: multiple myeloma; ECOG: Eastern Cooperative Oncology Group performance status; CNS: central nervous system; PCL: plasma cell leukemia; EMD: extramedullary disease.
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