Talquetamab Bridging: A Real-World CAR T Strategy in Myeloma

In an interview, Binod Dhakal, MD, MS, provides a detailed breakdown of a clinical study investigating the use of talquetamab (Talvey) as a bridging therapy before CAR T-cell treatment for multiple myeloma. The study included 134 patients who were scheduled to receive standard CAR T-cell therapy. Of these, 119 patients were successfully treated with CAR T, with the majority receiving ciltacabtagene autoleucel (cilta-cel; Carvykti; 98 patients) and a smaller number receiving idecabtagene vicleucel (ide-cel; Abecma; 21 patients).

The study population consisted of heavily pretreated patients, most of whom were triple-class refractory. About half of the patients had high-risk cytogenetics and extramedullary disease, which are often associated with more aggressive cancer. A small percentage (about 10%) had even received prior BCMA-targeted therapies, including CAR T.

A significant finding was that 85% of these patients would not have met the eligibility criteria for the pivotal trials that led to the approval of cilta-cel and ide-cel (CARTITUDE and KarMMa trials). This highlights the real-world nature of this study, as it includes patients who are often excluded from or ineligible for traditional clinical trials.

The median number of talquetamab doses patients received was only 2, with a median bridging time of 23 days between the talquetamab dose and the CAR T infusion. This short duration suggests that talquetamab can quickly control the disease without the need for a full cycle of treatment. The rapid initiation of CAR T was a priority for all patients, which meant researchers didn't wait for a deeper response from the talquetamab.

A small subgroup of 19 patients received talquetamab even before their T cells were collected for manufacturing. This "holding therapy" was necessary because they had rapidly progressing disease and needed immediate treatment to control it while still aiming for CAR T. Of these patients, 16 were successfully manufactured with a CAR T product and received the therapy, suggesting that talquetamab can be used as an effective holding strategy without negatively impacting T-cell collection.

In terms of safety, the talquetamab bridge was well-tolerated. Cytokine release syndrome (CRS) was reported in 73% of patients but was mostly grade 1 or 2. Immune effector cell-associated neurotoxicity syndrome (ICANS) was also primarily grade 1 or 2, with only one patient experiencing grade 3 ICANS. Common talquetamab-related toxicities included skin-related issues (38%), nail changes (17%), and oral toxicities (70%), which were the most significant challenge for patients. However, about 60% of patients had complete resolution of these adverse effects at a median follow-up of 6.9 months, which is encouraging.

After receiving CAR T, most patients experienced grade 1 or 2 CRS and ICANS. One patient had a grade 4 CRS, and one had a grade 3 ICANS. Notably, there was no evidence of delayed neurotoxicity, such as Parkinsonism, peripheral neuropathy, or Guillain-Barre Syndrome, at the 7-month follow-up. This is an important finding, as delayed neurotoxicity has been a concern with CAR T therapies like cilta-cel.

For patients who received talquetamab as a bridge, the overall response rate was 71%, with 19% achieving a complete response or better. After receiving CAR T, the response rate was 88% at 30 days, with over half of the patients achieving a complete response or better. There were no significant differences in response rates between cilta-cel and ide-cel, though cilta-cel had a slightly higher complete response rate.

The median progression-free survival and overall survival had not been reached at the time of the analysis. A key finding from the multivariate analysis was that the presence of extramedullary disease was the only significant factor associated with an inferior outcome.

The researchers also looked at the impact of talquetamab on CAR T expansion. They found that the median peak expansion was consistent with what has been observed in studies of CAR T alone, indicating that prior use of a bispecific antibody like talquetamab does not negatively impact the expansion of CAR T cells. They also observed a sustained decline in soluble BCMA, a marker of disease burden, suggesting that the combination of talquetamab and CAR T leads to a deep and durable response.

Of the 134 patients, 15 were unable to proceed to CAR T. The main reasons included rapid disease progression while waiting for the infusion (7 patients), and manufacturing failure (6 patients). It was noted that four of the six patients with manufacturing failure had prior BCMA-targeted therapy, which may have contributed to the failure. Two patients decided to continue with talquetamab as they were doing well on it. At the last follow-up, 10 of these 15 patients had unfortunately died from disease progression.