MajesTEC-3 Study: Teclistamab and Daratumumab Combination Dramatically Improves Outcomes in Relapsed Multiple Myeloma
A groundbreaking clinical trial has delivered exceptional results, offering new hope for patients battling relapsed or refractory multiple myeloma. The MajesTEC-3 study demonstrated a remarkable 36-month progression-free survival rate of 83.5% with the combination of teclistamab and daratumumab, significantly surpassing the 29.7% observed in patients receiving standard-of-care treatments.
A Paradigm Shift in Multiple Myeloma Treatment
For years, the sequencing of treatments for multiple myeloma – including CAR T-cell therapy and emerging bispecific antibodies – has been a complex and evolving landscape. Initially, cell therapies were reserved for patients who had exhausted multiple prior lines of treatment. More recently, approval expanded to include use after first relapse. The MajesTEC-3 study was specifically designed to explore the potential of moving these powerful therapies earlier in the treatment sequence, specifically at the time of first relapse.
Researchers focused on the combination of teclistamab, a BCMA-targeted bispecific antibody, and daratumumab, an immunotherapy agent. This approach also addresses a critical need for effective options for patients who may not be ideal candidates for CAR T-cell therapy but could benefit from the safety profile of bispecific antibodies.
Surprising Efficacy and Safety Profile
According to a hematologist/oncologist at Cleveland Clinic, the study findings were “surprising” in their comparability to CAR T-cell therapy. Previously, patients facing first relapse typically had three main options: CAR T-cell therapy, a triplet of standard treatments, or participation in a clinical trial. Now, bolstered by the robust evidence from MajesTEC-3 and supporting guidelines from the National Comprehensive Cancer Network (NCCN), the combination of teclistamab and daratumumab represents a viable and compelling option at first relapse.
Managing Infection Risk and Optimizing Treatment Schedules
The study, conducted during the COVID-19 pandemic, initially revealed a relatively high rate of infections – 54.1% experiencing grade 3 or 4 infections – among patients receiving the combination therapy. However, this risk has been substantially mitigated through the implementation of preventative strategies. These include the use of immunoglobulins and prophylactic antibiotics like sulfamethoxazole-trimethoprim to protect against Pneumocystis jirovecii pneumonia (PJP).
“At our center, we mandate IVIG monthly as well as sulfamethoxazole-trimethoprim, or an alternative if the patient has sulfa allergies,” one physician explained. Furthermore, spacing out the frequency of therapy from weekly to biweekly, and then to monthly, has dramatically reduced infection rates.
Long-term, the study is expected to fuel debate regarding the optimal sequencing of BCMA-targeting drugs. Traditionally, CAR T-cell therapy was favored for initial exposure due to its limited alteration of the BCMA target, while chronic exposure to bispecific antibodies carried a higher risk of modifying the target itself.
The Potential for a Functional Cure?
While cautioning that it’s “a bit premature to say,” experts acknowledge the excitement surrounding the possibility of a functional cure in myeloma, driven by the impressive survival curves observed in the MajesTEC-3 trial. “The survival benefit is one of the highest we’ve seen in a study in a long time,” a leading oncologist noted.
The study protocol involved continuous therapy as long as it remained effective. However, real-world application may see two primary strategies emerge: a fixed-duration approach until patients achieve minimal residual disease (MRD)-negative status, followed by close observation, or an immune-boosting approach with re-dosing every four to six months.
How Teclistamab and Daratumumab Work in Synergy
The combination of teclistamab and daratumumab is believed to be synergistic. Teclistamab specifically targets CD3 on T-cells, while daratumumab modulates T-cell subsets, enhancing the fitness of helper T-cells and increasing the number of CD8 cytotoxic T-cells.
It’s important to note that only a small percentage (approximately 5%) of patients in the MajesTEC-3 study had prior exposure to daratumumab. In the real world, a larger proportion of patients at first relapse have already received daratumumab, and some may be daratumumab refractory. This raises the question of whether daratumumab is always necessary in these cases, with some experts suggesting that teclistamab may be the primary driver of efficacy and could potentially be used as a single agent.
The Benefit of Steroid-Free Treatment
The MajesTEC-3 trial notably excluded steroids after the initial treatment cycle. This is significant, as steroids play a role in myeloma management, particularly for newly diagnosed patients or those with high disease burden, and can provide palliative relief for bone pain. However, physicians are increasingly seeking to minimize steroid use due to their associated side effects. “I’m excited to see us pulling away from using steroids over and over though, as I see more side effects with steroids than I do with any other therapies,” one oncologist stated.
Looking Ahead: MajesTEC-7 and Beyond
Cleveland Clinic is currently participating in the MajesTEC-7 study, which is evaluating combinations of teclistamab, daratumumab, and lenalidomide against talquetamab, daratumumab, and lenalidomide, as well as standard care with daratumumab, lenalidomide, and dexamethasone in patients ineligible for or choosing to defer autologous stem cell transplant. The results of this trial could fundamentally reshape the role of transplant in the future of myeloma treatment.
Expanding Access to Cell Therapies in Community Settings
A key challenge to wider adoption of these therapies lies in ensuring accessibility in community settings. Concerns around managing potential toxicities, particularly cytokine release syndrome (CRS), and limited access to intensive care units (ICUs) in some community hospitals create barriers.
One solution involves establishing partnerships between academic medical centers and community practices, where academic centers manage the initial, acute toxicity phase, and patients then return to their community physicians for ongoing care. Improved preventative strategies, such as upfront administration of tocilizumab, have also significantly reduced CRS rates.
Community oncologists are encouraged to refer patients to academic medical centers early, even before meeting the strict definition of disease progression, as outcomes are generally better with a lower disease burden.
