The LINKER-4 study that we are presenting at ASH looked at linvoseltamab, which is a B-cell maturation antigen targeted T-cell engager, as an initial therapy for newly diagnosed patients with symptomatic myeloma. Right now the standard of care in this setting is usually either a four-drug regimen for patients who are transplant eligible or transplant ineligible but robust, or if you’re transplant ineligible and older or frail a three-drug regimen. But T-cell engagers like linvoseltamab have shown some of the highest single-agent response rates and minimal residual disease negative rates that we’ve ever seen in the relapsed/refractory setting. Linvoseltamab just recently got FDA approval in that setting so we were interested in seeing if giving the same drug earlier could be of benefit to patients with the thought that, first of all, in newly diagnosed patients T-cells could be healthier and also the myeloma cells should be less drug resistant because they haven’t survived multiple prior therapies.
What were the key results?
This was a phase I/II study, the goal being to first identify a safe and tolerable and effective dose for linvoseltamab and then later on a dose expansion to obtain additional experience. With T-cell engagers there’s usually an initial period of step-up dosing to try to minimise the risk of what’s called cytokine release syndrome and also ICANS, or immune effector cell associated neurotoxicity syndrome, and then several different doses were evaluated for the full dose. The conclusion of the study was that the 200mg full dose, which is actually the same dose that’s approved for relapsed/refractory disease, it appeared that that dose gave very good safety and also very good efficacy data. So that’s the dose that is being recommended for additional study.
What do you think could be the clinical significance of these results?
The overall response rate that was seen in the study, especially if we focus just at the 200mg dose, was 86% with 43% of patients having a complete response or better. It’s quite possible, by the way, that those numbers will improve further because many of the patients are still undergoing additional therapy. Across the whole study minimal residual disease negativity was at 85.7% and at the 200mg dose essentially 100%, or nine out nine who were evaluable, were MRD negative at 10-5 and also at 10-6. So these are the highest levels of complete response and MRD negativity that have been seen for any single agent in the newly diagnosed setting and certainly support further study both of linvoseltamab alone and potentially in combinations to try to maximise the benefit of induction therapy, which is really important because myeloma is most sensitive when it’s newly diagnosed and that’s when you want to try to get the maximum reduction. The other benefit of using fewer drugs is that there is generally less toxicity to patients if you use fewer drugs, including potentially less financial toxicity, and you preserve more options for later if the patients do suffer disease relapse down the road.
