Pros and cons of emerging therapeutic targets in multiple myeloma

Dr Rutger Callens, a haematologist at AZ Delta in Roeselare, delved into the intricacies of emerging therapeutic targets in multiple myeloma (MM), weighing the pros and cons associated with these advancements.

Within the BCMA-directed therapeutic domain, notable modalities include CAR T cells, T-cell engagers (TCE) and antibody-drug conjugates (ADC).

A pivotal advantage of CAR T therapy lies in its singular administration, leading to a protracted treatment-free remission, a distinctive feature within the relapsed/refractory paradigm of MM. However, the non-off-the-shelf nature of CAR T cells poses a drawback, necessitating bespoke fabrication and potentially mandating a bridging treatment. Despite encountering CRS, ICANS and infections post-therapy, the observed degrees of CRS and ICANS are generally milder and more manageable than those witnessed in CD19-directed CAR T therapies.

BCMA-directed TCE offer the notable advantage of being readily available off the shelf and are amenable to combination with other therapeutic molecules. Reflecting on historical developments with proteasome inhibitors, IMIDs, and anti-CD38 antibodies, monotherapy yielded an overall response rate of approximately 30%. However, combining these agents demonstrated a remarkable extension. In the case of BCMA TCE, the overall response rate stands at around 60-70%, providing a promising foundation for future combinatorial approaches that may further enhance patient survival. A distinctive characteristic of TCE is their potential to induce CRS. To mitigate these associated risks, a common strategy involves a step-up dosing regimen. Additionally, infections represent a prevalent side effect of CAR-T and BCMA-directed therapy. A recent study from a French group presented at ASH indicated that approximately half of patients undergoing TCE treatment experienced a grade 3 or higher infection. Notably, these infections were predominantly pulmonary or systemic, encompassing bacterial and viral origins. Consequently, it remains imperative to administer appropriate anti-infectious prophylaxis following TCE and BCMA-directed CAR T therapy to optimize patient outcomes and safety.

The third modality within the BCMA-directed therapeutic landscape involves ADC, exemplified by belantamab mafodotin. Belantamab is notably linked to ocular toxicity, a factor that has impeded its routine utilization. However, recent findings in a second-line therapy context demonstrated that the combination of belantamab with bortezomib and dexamethasone exhibited superior PFS compared to the VRd regimen. This development raises intriguing prospects for a potential resurgence in the use of belantamab.

A secondary therapeutic target in focus is GPRC5D, with talquetamab serving as a representative TCE extensively examined in the MonumenTAL study. This intervention yielded an overall response rate of approximately 70%. Distinctive to GPRC5D-directed therapies is the occurrence of less common side effects, including taste aberrations, as well as nail and skin alterations. While these effects are generally non-life-threatening, they significantly impact patients’ quality of life and frequently evoke concerns. In the phase 1b MonumenTAL study, patients who achieved a partial response or better were afforded the option of dose de-escalation. Notably, this approach revealed that a significant majority of these patients demonstrated a deepening of responses. Moreover, some individuals experienced improvements in side effects. Furthermore, in the realm of GPRC5D-directed therapies, a recently presented CAR T therapy demonstrated promise, boasting an impressive overall response rate of 87% within a heavily pretreated patient cohort, all of whom had undergone prior BCMA-directed therapies.

In a distinct category of molecules, iberdomide and mezigdomide represent two Cereblon E3 ligase modulators (CeLMoDs). CeLMoDs are recognized for their cerebral modulation properties, and both iberdomide and mezigdomide have demonstrated promising results, particularly in heavily pretreated patient populations. These agents primarily manifest haematological toxicities, which, thus far, appear to be manageable.

Lastly, in the context of translocation involving chromosome 14, BCL2 inhibitors have emerged as promising therapeutic candidates. While the BELLINI trial did not achieve its intended endpoint of overall survival benefits, noteworthy outcomes were observed in the combination of venetoclax with daratumumab and dexamethasone. This regimen exhibited robust responses, a high rate of MRD negativity and an extended PFS. These findings underscore the potential efficacy of BCL2 inhibition in the treatment of MM. A novel agent, sonrotoclax, appears to boast a more favourable toxicity profile compared to venetoclax. The anticipation is that this improved safety profile could pave the way for broader utilization of BCL2 inhibitors in the MM treatment landscape.

With the educational support of: