Improving MM outcomes with bispecific antibody combinations Free

In this issue of Blood, Chari et al¹ address a conundrum in relapsed refractory multiple myeloma (RRMM), as to whether adding a routinely used drug to a novel drug has more impact than would be expected from using both drugs as single agents. Put another way, can we develop synergistic combinations to improve outcomes in this poor prognosis group of patients? In the conventional approach to drug development, the aim is to evaluate the safety and efficacy of the drug as a single agent, followed by additional studies evaluating combinations. When building combinations, it is important to incorporate non–cross-reacting agents and to balance clinical effectiveness with safety and tolerability and not to just simply build an alphabet soup of letters into a catchy acronym. A basic rule of thumb for drug combinations is that there should be 1) a biological rationale and mechanism for building the combination and it should overcome resistance based on a synergistic interaction between the agents, 2) an ability to induce high response and survival rates, and 3) a lack of combined toxicity making the combination tolerable and safe to deliver.

The introduction of bispecific antibodies (BsAbs) has revolutionized the treatment of RRMM with unprecedented response rates and long progression-free survivals (PFSs) but relapse has remained a clinical problem. Since their introduction we have learnt a lot about how to manage their toxicities, however, a concern has been that combinations may increase toxicity. The results of TRIMM-2, where talquetamab is combined with daratumumab, negate this fear with excellent response rates pushing the field to exploring further combinations.¹ 

CD38 monoclonal antibodies such as daratumumab are well-established therapies for MM, which combine well with most other myeloma therapies (eg, proteasome inhibitors [PIs], immunomodulatory drugs [IMiDs]) without a significant increase in toxicity.² More recently, talquetamab, a GPRC5D-targeting BsAb has been approved by the US Food and Drug Administration for the treatment of RRMM.³ In the phase 1b TRIMM-2 study, patients with at least 3 prior lines of therapy or double refractory to a PI and an IMiD received talquetamab according to a weekly or biweekly schedule along with daratumumab in a standard approved schedule. The primary end point was safety, with secondary end points being overall response and duration of response, and PFS as an exploratory end point. Sixty-five heavily pretreated patients received therapy. Most patients (n = 51) received talquetamab on a biweekly schedule. Responses occurred in 71.4% to 82.4% of patients depending on the dosing schedule, and were associated with a median PFS of 23.3 and 21.2 months, respectively. Grade 3 to 4 adverse events occurred in 81.5% of patients. From this data, the authors concluded that talquetamab plus daratumumab demonstrated promising efficacy outcomes in heavily pretreated patients, with a safety profile consistent with each agent as monotherapy.

So does this combination meet our 3 rules of an effective drug combination? The rationale for it being a synergistic combination is based on in vitro data suggesting that there is enhanced talquetamab-mediated lysis of MM cells by depleting CD38-expressing T-regulatory cells.⁴ By studying serial samples from patients within the study, the authors provide pharmacodynamic evidence consistent with this. In terms of efficacy, although it is a phase 1b study, the response rates and PFS were impressive. Despite a median of 5 prior lines of therapy, 80% of patients being refractory to anti-CD38 therapy, and 25% refractory to a prior BsAb, response rates of 71% to 82%, with 60% or better in a complete response were seen. The median duration of response was almost 2 years. Whether these outcomes are better than would be expected from single-agent talquetamab is difficult to know especially in RRMM where patient characteristics and previous therapies heavily influence outcomes. In the pivotal MonumenTAL-1 study which used single-agent talquetamab, the response rate and complete response rate were lower (69% and 40%, respectively) and the PFS shorter at 11.2 months.³ In TRIMM-2, more patients had received prior BsAb compared to MonumenTAL-1 (75% and 58%, respectively) and a longer median PFS (15.0 vs 3.9 months, respectively) was seen. However, TRIMM-2 enrolled a lower proportion of patients with high-risk cytogenetics, ISS stage III, and triple-class refractory disease which, although may account for some of the difference, is unlikely to explain all of them.

With respect to safety an ideal combination should have non–cross-reacting toxicities and be well-tolerated. The most common adverse events seen in TRIMM-2 were those broadly associated with BsAbs including CRS (78%, all grade 1-2), infections, oral (89%), skin (80%, grade 3-4, 5%), and nail events (68%). The number of patients having dose delays or reductions were similar to that seen in MonumenTAL-1. Although increased infection rates have been noted with both daratumumab and talquetamab monotherapy, the incidence of grade 3-4 infections with the combination were modest compared to BCMA-targeting BsAbs. No additional safety concerns were noted and the safety profile appeared consistent with each agent alone.

To overcome tumor resistance, it is generally better to use combinations, and consistent with this, MM outcomes have improved with the use of 2, 3, and more recently 4 drug combinations.² Common resistance mechanisms to BsAbs are mediated by either loss or mutation of the target antigens or immune exhaustion.^5-7 The use of the doublet combination of daratumumab with talquetamab could overcome these resistance mechanisms and provides a good biological rationale for enhancing the immune activity against the MM clone. We await the results of the ongoing phase 3 study MonumenTAL-3 looking at this combination to confirm the efficacy results. Other studies exploring decreasing tumor resistance are ongoing. For instance, by combining BsAbs with an IMiD or a PI to decrease T-cell exhaustion, or by combining 2 BsAbs together, or indeed developing trispecific antibodies to decrease the potential for target downregulation. As we look forward to learning about where in the treatment pathway these combinations should be placed and how they should be sequenced, we also look forward to the design of further rationale combinations, which reduce the emergence of resistance and deliver better outcomes to patients.

Conflict-of-interest disclosure: F.E.D. is a member of an advisory board for Bristol Myers Squibb (BMS), GSK, Johnson & Johnson, and Takeda. G.J.M. is a member of an advisory board for BMS, GSK, and Johnson & Johnson.