CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: July 17, 2023
Expiration: July 16, 2024
Immunotherapy Includes More Than Just CAR
There are also now several alternatives to autologous CAR T-cell therapy, and immunotherapy has become prominent in the treatment of MM. BCMA-targeting agents such as the CAR T-cell therapies we have discussed are the most fully developed, but other identified antigens have also shown therapeutic promise.
Belantamab Mafodotin: Anti-BCMA Antibody–Drug Conjugate
Belantamab mafodotin (BCMA-directed antibody and microtubule inhibitor conjugate) had received accelerated approval based on the phase II DREAMM-2 trial, with an ORR of approximately 30% as a single agent in patients with R/R MM who had received at least 3 previous lines of therapy.26 Unfortunately, belantamab mafodotin did not meet its primary endpoint of improved PFS in the phase III DREAMM-3 trial when compared with pomalidomide and dexamethasone in patients with R/R MM. Consequently, that therapeutic has been taken off the market.
However, there are multiple phase III trials looking at belantamab mafodotin in combination with other standard MM agents in patients who have received at least 1 prior line of therapy (DREAMM-7, NCT04246047; DREAMM-8, NCT04484623) and a phase I trial in patients with newly diagnosed MM (DREAMM-9, NCT04091126).
MajesTEC-1: Phase II Study of Teclistamab BCMA T-Cell–Redirecting Bispecific Antibody
Another immunotherapy option for patients in the heavily pretreated setting is the bispecific BCMA-directed CD3 T-cell engager teclistamab.27 Teclistamab anchors itself by binding to BCMA on the MM cell and then activates CD3 on T-cells through its other binding domain.
Teclistamab was approved based on the results of the phase I/II MajesTEC-1 trial, which showed an ORR of 63% and CR or better of 39%. The label indication is for the treatment of adult patients with R/R MM who have received ≥4 prior lines of therapy, including a proteasome inhibitor, an IMiD, and an anti-CD38 monoclonal antibody.28
Given as a weekly subcutaneous injection, teclistamab has reduced the demand for CAR T-cell therapy, especially for patients with aggressive disease or those who have trouble collecting adequate lymphocytes for CAR T-cell generation.
Overview of Bispecific Antibodies for MM
Bispecific antibodies have generally had better-than-expected results. These antibodies differ by the way they bind to the tumor antigen, via single or double binding domains. Some bind to CD3 with less affinity and therefore may produce less T cell activation (and potentially less CRS), whereas others might have a stronger affinity on binding to CD3 (and perhaps greater T-cell activation), causing more toxicity. Thus, each of these antibodies have the potential for distinct safety and efficacy profiles.
That said, when we look at the big picture, we see some good responses among the BCMA-directed bispecifics.
I mentioned teclistamab-cqyv previously, which showed an ORR of 63% in the phase I/II MajesTEC-1 trial, leading to its FDA approval.27
The phase I MagnetisMM-1 trial looked at elranatamab in patients with triple-refractory R/R MM (N = 55), showing an ORR of 64%.29This result has been confirmed by cohort A (n = 123; naive to BCMA-targeted therapy) of the phase II MagnetisMM-3 trial, which had an ORR of 61%.30
In a phase I dose escalation and expansion trial in patients with R/R MM who had received ≥3 prior lines of therapy, the ORR for those who received ≥40 mg ABBV 383 (n = 79) was 68%.31
Phase I data from the phase I/II LINKER-MM1 trial in patients with R/R MM who had progressed on ≥3 prior lines of therapy showed an ORR of 68% for those receiving linvoseltamab 200 mg (n = 117).32
Considering agents that have targets other than BCMA, the phase I/II MonumenTAL-1 trial looked at talquetamab (GPRC5D-directed) in patients with R/R MM (N = 288), showing an ORR of 74% for patients treated at either recommended phase 2 dosing schedule.33,34
Finally, in the phase I GO39775 study, patients with R/R MM who received cevostamab (FcRH5 directed) at the active dose (3.6/20 mg) or above in the single step-up dosing cohort (n = 161) showed an ORR of 57%.35
These agents are very exciting and will be potential alternatives to use instead of CAR T-cell therapy, especially for patients who cannot manufacture a CAR T-cell product or otherwise lack the logistical support needed for them to do CAR T-cell therapy.
Autologous vs Allogeneic CAR T-Cell Therapy
Allogeneic CAR T-cells have many advantages over the autologous CAR T-cells.36 The possibility of bulk manufacturing from normal, healthy donors means that cell quality might be better and that the products can be used for repeat dosing either in the same or in multiple patients. Because these are “off-the-shelf” therapeutics stored at treatment centers, there may be no need for bridging therapy in patients undergoing an allogeneic CAR T-cell therapy, as they can receive the treatment quickly. Typically, eligible patients with good performance status and the necessary logistical and social support can receive allogeneic CAR T-cells within 1-2 weeks.
There are, however, potential problems with allogeneic CAR T-cells. One is the risk of graft-vs-host disease. There are various strategies to address this, including using CRISPR to knock out T-cell receptor from individual cells. In addition, there is a risk of host versus graft disease, which we have tried to address using more intensive LD and monoclonal antibodies against CD52. Furthermore, CRISPR technology and gene knockout technology are also being used to knock out genes that might be associated with host versus graft disease, such as β2-microglobulin.
UNIVERSAL: First Allogeneic BCMA-Targeted CAR T-Cell Therapy
The initial report has been published from the phase I UNIVERSAL study on ALLO-715, which is the first allogeneic BCMA-directed CAR T-cell therapy in MM.37 Like the other CAR T-cell products discussed, it targets BCMA through an scFv. One special feature is the use of TALEN mediated knockout of the T-cell receptor alpha chain to limit graft vs host disease. TALEN mediated knockout of CD52 can also prevent cross-reactivity when the patient receives anti CD52 antibody (ALLO-647) for LD chemotherapy.
The first-in-human phase I UNIVERSAL trial looked at ALLO-715 in patients with R/R MM.37 All study participants had received ≥3 prior lines of therapy including an IMiD, proteasome inhibitor, and CD38 antibodies and were refractory to their last line of therapy. This was a dose-escalation study with 43 patients in the safety and efficacy population, starting from a small dose of 40 million and moving up to 480 million CAR T-cells given in 1 dose (320 million was the most efficacious and least toxic dose). Various LD chemotherapy strategies were tested, based on fludarabine, cyclophosphamide, and ALLO-647. Primary endpoints included the safety and tolerability of the CAR T-cell therapy and LD regimen. Secondary endpoints included ORR, pharmacokinetics, and DoR.
UNIVERSAL: ALLO-715 Outcomes
In total, 24 patients received 320 million CAR T-cells, with an ORR of 71%, very good partial response or better rate of 46%, and CR or better rate of 25%.37 The median DoR was 8.3 months, although the median follow-up was only 3.8 months, so the patients will need to be followed further. Some patients in this study did have responses close to 1 year, but we might expect less durable responses because of loss of the allogeneic CAR T-cells.
Safety was encouraging, with CRS and neurotoxicity possibly somewhat lower than with autologous CAR T-cells.
Cereblon E3 Ligase Modulators: Next-Generation Immunomodulatory Agents
The 2 approved immunomodulatory agents, lenalidomide and pomalidomide, work directly by modulating the CEL, enhancing degradation of the Ikaros and Aiolos proteins, which are transcription factors that promote survival and proliferation of MM cells.38 These drugs also enhance immunostimulatory activity of T-cells, natural killer cells, and other immune cells in the environment.
Among the novel therapeutics under investigation are next-generation CEL modulators (iberdomide and mezigdomide), which potentially have 10-20 times greater affinity compared with lenalidomide and pomalidomide. Both novel agents are proimmunostimulatory agents that have been shown in in vitro models to increase secretion of interleukin 2 by treated peripheral blood mononuclear cells, suggesting that they in fact will provide a more potent immunostimulatory effect.
We are excited about integrating these drugs along with immunotherapy into the MM treatment paradigm, both in the early- and late-line settings.
CEL Modulators: Clinical Trials
Iberdomide was tested in the phase I/II CC-220-MM-001 trial in patients with R/R MM.39 The combination of iberdomide plus dexamethasone was effective and well tolerated, with an ORR of 26% in the dose-expansion phase (n = 107).40 We have also seen data from other arms of the trial that suggest potent synergy between iberdomide and other agents. Cohorts of patients receiving iberdomide plus dexamethasone and daratumumab (n = 19) or bortezomib (n = 21) showed ORRs of 35% and 50%, respectively, across all dosing groups.41 Some of these combinations are now being tested in additional phase III clinical trials (EXCALIBUR-RRMM, NCT04975997, recruiting; GEM21menos65, NCT05558319, not yet recruiting).
Mezigdomide was tested in the phase I/II CC-92480-MM-001 trial in patients with R/R MM.42 Patients receiving the recommended phase II dose of mezigdomide plus dexamethasone (n = 101) showed an ORR of 39.6%. Patients with extramedullary disease (n = 39) also showed good responses (ORR: 31%), which is very exciting, since these patients have more difficulty achieving CR and durable responses. There are also phase III trials currently recruiting that are studying mezigdomide in combination with dexamethasone and bortezomib (SUCCESSOR-1, NCT05519085) or carfilzomib (SUCCESSOR-2, NCT05552976).
Strategies for the Use of CEL Modulators in MM
There are potentially great advantages for the use of these novel CEL modulators during CAR T-cell therapy. Before apheresis, they could augment the activity of T-cells, allowing us to collect better (less exhausted) T cells during apheresis for autologous CAR T-cell production. As a bridging therapy, these agents would augment anti MM effects and provide a platform with more proimmune effects going into CAR T-cell infusion. There are other immune cells in the microenvironment other than CAR T-cells that are providing a direct anti MM effect, and the use of CEL modulators as bridging therapy may enhance the microenvironment effects in the post–CAR T-cell time frame.
These drugs might also be useful during the CAR T-cell therapy itself, by modulating cytokines to ameliorate CRS and ICANS while enhancing the anti MM effects. They could be used as maintenance therapy after CAR T-cell infusion not only to increase the persistence of CAR T-cells, but also to enhance the immune microenvironment’s function as a support network for the CAR T-cell therapy.
Finally, CEL modulators also will be combined with other immunotherapies, such as bispecific antibodies, where they can enhance the anti MM effect and provide a better microenvironment to enhance T-cell activities while decreasing T-cell exhaustion. They may also help to provide immune recovery as maintenance therapy after the immunosuppression caused by bispecific T-cell engager therapy.
Conclusions and Future Directions
In conclusion, currently available BCMA-directed CAR T-cell therapy can achieve impressive outcomes for patients with R/R MM, especially with more recent data demonstrating its use in earlier lines of treatment. We have a good understanding of the most frequently seen adverse events and how to manage them, including those that are potentially more serious, such as neurotoxicity and CRS. The major barriers to good real-world patient outcomes are those of timely access to the CAR infusion product. Availability of allogeneic CARs in the future might provide more widespread and quicker access, but as these seem to produce less durable responses and introduce the potential for graft-vs-host disease, I expect them to be reserved for later lines of treatment. Effective bridging strategies, therefore, will continue to be necessary to allow patients to experience the maximum benefit from CAR T-cell therapy. Novel agents always will be welcome into this treatment space as additional tools for our repertoire. The availability of more treatment choices ultimately means greater access to therapeutic benefit for more of our patients.
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