Patients relapsing after lenalidomide maintenance now face a different playbook. Ralph V. Boccia, MD, FACP, who leads The Center for Cancer and Blood Disorders and teaches at MedStar Georgetown, has started to upend the old order. He weighs scientific logic against each patient’s situation, refusing to default to a single protocol.
His method: start with CAR T-cell therapy after lenalidomide-based maintenance fails, then move to bispecific antibodies. The reason is practical. Using bispecifics first can drain T-cell reserves, leaving CAR T less effective. Sequence matters. If relapse hits six months or more after CAR T, Boccia turns to teclistamab-cqyv (Tecvayli). If relapse comes sooner, or if teclistamab has already been used, talquetamab (Talvey) steps in.
In July 2025, the FDA approved linvoseltamab for adults with relapsed or refractory multiple myeloma after several prior lines of therapy, based on results from the LINKER-MM1 study.
Fixed-duration therapy is gaining ground for those who hit deep, lasting responses—often tracked by minimal residual disease (MRD) negativity. Boccia points to the MajesTEC-3 phase 3 trial, which tested teclistamab plus daratumumab and hyaluronidase-fihj (Darzalex Faspro), and the TRIMM-2 phase 1b trial, which paired talquetamab with daratumumab. Both combinations worked at similar rates, but their side effect profiles split, forcing doctors to tailor plans for each patient.
Regulators have sped up bispecific antibody approvals in relapsed or refractory myeloma. The FDA gave talquetamab (Talvey) the green light in August 2023 for adults who had already cycled through at least four prior therapies, including a proteasome inhibitor and an anti-CD38 antibody, as detailed in an OncLive clinical report. This pace reflects a growing pile of evidence for bispecifics in patients with few options left.
MRD negativity is now forcing a rethink of what counts as long-term disease-free survival, and even the idea of cure, in standard-risk myeloma. This isn’t just a theoretical shift. It’s changing how doctors decide when to stop therapy and what success looks like.
The MonumenTAL-3 study put talquetamab, daratumumab, and pomalidomide up against daratumumab–pomalidomide–dexamethasone. The new combo cut the risk of progression or death by 72%, with a hazard ratio of 0.28 (95% CI, 0.20–0.40) and an overall response rate of 88.2%. These numbers show bispecific-based regimens can deliver deep, lasting responses for relapsed patients.
By 2025, three BCMA-targeted bispecific antibodies—teclistamab (approved in 2022), elranatamab (2023), and linvoseltamab (2025)—had received regulatory approval for heavily pretreated multiple myeloma, each initially indicated for patients after at least four prior lines of therapy.
In AL amyloidosis, daratumumab-based regimens have moved the needle but still fall short of a cure. Boccia sees BCMA-targeted bispecific antibodies as the next wave, with CAR T-cell therapy possibly following. Trials like MajesTEC-7 are now testing BCMA-targeted bispecifics in newly diagnosed patients, putting them head-to-head with established regimens and hinting at a shake-up in first-line treatment.
These shifts echo broader moves in blood cancer immunotherapy, as seen in recent efforts to widen trial access and break old boundaries.
As sequencing of CAR T and bispecifics grows more precise, the definition of best care keeps changing. Boccia’s strategy—rooted in MRD data, side effect profiles, and patient specifics—marks a clear break from one-size-fits-all regimens. Fixed-duration plans and new bispecifics are now setting the pace for durable response and patient quality of life.
