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Novel immunotherapies in MM
populations of patients, such as those with high-risk MM, early clinical relapse, or extramedullary disease. While reported TCE trials have been too small to allow any con- clusion to be drawn, for ide-cel an initial subgroup analy- sis found that high-risk markers, such as a revised International Staging System score of 3, even in late-stage refractory disease, are still associated with lower response rates and a shorter median PFS.49 For the time being, cellular therapies will be an attractive option for otherwise hard-to-treat, high-risk patients. However, it is possible that cellular immunotherapy might be best used in good-risk patients to induce deep and durable, sus- tained minimal residual disease negativity in an attempt to cure the disease rather than chasing high-risk disease that is inherently biologically capable of adapting quickly to and thereby prevailing the attack of modified T cells. Preliminary indications can be expected from ongoing studies that address the efficacy of CAR T-cell therapy in patients with early relapse or insufficient response after first-line therapy (e.g., KarMMa-2, CARTITUDE-2) as well as from subgroup analyses of the phase III trials KarMMa-3 and CARTITUDE-4 in relapsed patients after two to four and one to three lines of therapy, respective- ly.
Other questions regarding the best use of cellular or antibody-based immunotherapies include their place rel- ative to autologous stem cell transplantation, their role in post-transplant consolidation, in the treatment of persist- ent minimal residual disease positivity, and their potential to replace or shorten maintenance therapy. One funda- mental difference between these two immune-based approaches is how quickly they can be provided to a given patient. CAR T cells need to be manufactured, requiring several weeks of planning, scheduling, and pos- sibly bridging treatment, at least with current technology and constructs. This setting appears to be best integrated into an established treatment algorithm, similar to that for autologous stem cell transplantation, or in a setting of consolidation or minimal residual disease. TCE, converse- ly, are readily available and represent an outpatient com- munity-based option, although uncertainties relating to repeated dosing and treatment-free intervals need to be explored. However, TCE are suitable candidates for inte- gration into combination regimens, a strategy that has previously been proven to result in superior outcomes for patients.
Selecting the right patient
Last but not least, the most frequently asked question relates to patient selection. As the first ADC was approved in Europe and the USA in 2020, and as the first CAR T-cell construct is expected to be approved early in 2021, this is a clinically pressing concern (Figure 2).
Cellular immunotherapy should not be limited to cer- tain age groups, but should rather be considered for use in
fit patients, without significant comorbidities, who would tolerate intensive care treatment if CRS or ICANS occurs. Patients would need to be able to travel to the designated cell-therapy centers and close collaboration between these centers and community-based hematolo- gists is required.
T-cell engagers, such as TCE or modified BiTE®, are associated with a lower risk of immune-mediated toxici- ties such as high-grade CRS or ICANS, as a result of which less-fit patients can be considered as treatment candidates. In addition, patients with high disease dynamics requiring urgent treatment might benefit from the immediate availability of TCE.
Finally, ADC may be potentially suitable for frail patients if the patients are closely monitored for ker- atopathy or other ophthalmological side effects. However, these toxicities may impact and limit activities of daily life. The relatively long intervals of 3 weeks between therapy administration may more easily allow for treatment of patients with limited mobility. (Figure 2)
Despite all remaining open questions and issues that still need to be addressed, and hopefully answered and resolved within the next years, we are now, without any doubt, at the dawn of a new era that will significantly improve patients’ outcome. There is a light at the horizon towards curing MM.
Disclosures
LR has received a grant from Skyline Dx and personal fees from BMS, Janssen, GSK, Sanofi and Oncopeptides. RW has received grants from Janssen and Sanofi and personal fees from Janssen, Novartis, BMS/Celgene, Amgen, Gilead, Pfizer, Sanofi and Takeda. MM has received a grant from Incyte, per- sonal fees from Janssen, Amgen, BMS, Abbvie, Sanofi, GSK and Takeda, and non-financial support from Janssen, Amgen and BMS. HG has received grants from: Amgen, BMS, Celgene, Chugai, Janssen, Sanofi and Takeda, personal fees from: Amgen, BMS, Celgene, Chugai, Janssen, Sanofi, Takeda, Novartis, Adaptive Biotechnologies and Glaxo Smith Kline (GSK), non-financial-support from Amgen, BMS, Celgene, Janssen, Sanofi and Takeda, and research support from Amgen, BMS, Celgene, Chugai, Janssen, Sanofi, Incyte, Molecular Partners, Merck Sharp and Dohme (MSD), Mundipharma, Takeda and Novartis. MSR has received grants from BMS, Novartis, Amgen and Sanofi, and personal fees from BMS, Novartis, Amgen, Janssen and Sanofi.
Contributions
LR and MSR wrote the manuscript, RW and MM contributed topic-specific sections. All authors read, revised, and approved the submitted manuscript.
Acknowledgments
The authors thank Patrick J. Hayden for helpful discussions and excellent native-speaker language editing of the manuscript.
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