Potential Therapy Discontinuation For Some Myeloma Patients
- MajesTEC-3 and CARTITUDE-4 signal a major shift in second-line multiple myeloma, showing that BCMA-directed bispecifics and CAR-T therapies can deliver deeper, more durable remissions when used earlier in the disease course.
- As Winship Cancer Institute’s Dr. Sagar Lonial notes, “With the availability of immune-driven therapies, whether CAR T cells or bispecifics, we’re entering an era where we can begin to talk about discontinuation of therapy… if we can potentially eliminate the clone, then maybe we can start talking about cure.”
- Teclistamab + daratumumab significantly improved PFS and OS versus daratumumab-based triplets, with high CR and MRD-negativity rates, offering an off-the-shelf, outpatient immunotherapy option.
- Single-infusion cilta-cel delivered rapid, deep responses and prolonged PFS/OS in lenalidomide-refractory patients, enabling long treatment-free intervals after one intervention.
- CAR-T offers finite therapy with upfront logistics and higher acute toxicity, while bispecifics provide immediate access with lower acute toxicity but require ongoing treatment.
The rapid evolution of immunotherapy in multiple myeloma has moved highly active BCMA-directed strategies into earlier lines of treatment, forcing clinicians to rethink therapy choices in the second-line setting. Two landmark phase III trials, MajesTEC-3 and CARTITUDE-4, provide compelling evidence supporting early use of T-cell redirecting therapies, though they do so through fundamentally different therapeutic approaches.
Integrating these data into routine clinical practice requires careful consideration of efficacy, safety, logistics, and the emerging biology of immune modulation in less heavily treated patients.
As Dr. Sagar Lonial, Professor and Chair of the Department of Hematology and Medical Oncology at Emory University, notes: “With the availability of immune-driven therapies, whether CAR T cells or bispecifics, we’re entering an era where we can begin to talk about discontinuation of therapy, something we couldn’t do with previous generations of treatment. If we can potentially eliminate the clone, then maybe we can start talking about cure.”
MajesTEC-3
MajesTEC-3 evaluated the bispecific T-cell engager teclistamab in combination with subcutaneous daratumumab compared with investigator’s choice of daratumumab-based triplets in patients with one to three prior lines of therapy. The study demonstrated a striking improvement in progression-free survival (PFS), with separation of the curves occurring early that remained durable with extended follow-up.
Depth of response was notable, with a large proportion of patients achieving complete responses and high rates of minimal residual disease (MRD) negativity. Importantly, these benefits translated into an overall survival advantage, an increasingly critical endpoint as therapies move earlier in the disease course. The results position teclistamab plus daratumumab as a highly effective off-the-shelf option capable of producing deep and sustained remissions without the need for cellular manufacturing.
“The combination of teclistamab and daratumumab does in fact have synergy that eliminates some of the cells that may limit the efficacy of a bispecific and it is highly effective in combination … when you look at the curves, what that translates out to is roughly 83% of patients were still in remission at three years compared to only 20-30% in the DPD arm. Probably one of the longer PFS we’ve ever seen in a relapsed myeloma patient population,” Dr. Lonial explains.
“But we also saw an improvement in overall survival. So I think these findings along with much deeper MRD negativity rates and all sorts of other factors that really tell us that this is as close to a home run as you get [and] it’s certainly is potentially practice changing. The label will have to wait on the FDA to weigh in there. Patients need to think through with their doctors is cilta-cel [which] has a pretty good remission in the same space … I think this will push our colleagues in the community to begin this sooner because this is such a great opportunity for patients,” he adds.
CARTITUDE-4
CARTITUDE-4, in contrast, explored a single-infusion BCMA-directed CAR-T strategy using ciltacabtagene autoleucel in lenalidomide-refractory patients after one to three prior lines of therapy. This study confirmed that CAR-T therapy retains its transformative efficacy when deployed earlier in disease course. Responses were rapid and deep, with high rates of MRD negativity, and PFS was significantly prolonged compared with standard pomalidomide- or bortezomib-based regimens. With longer follow-up, an overall survival benefit has also emerged.
Most compelling is the possibility of prolonged treatment-free intervals following a single therapeutic intervention, an outcome that has remained largely unattainable with conventional continuous therapy approaches.
“If you have standard risk myeloma and you get Cilta-cel, your remission is really long and it rivals some of what we talked about, if not better than the MajesTEC3 data. So I think these become the kinds of conversations that we have with patients in first relapse. Do you want to go with a CAR T approach where perhaps the toxicity upfront may be a little bit more, but the down the upside down the road is that you’re on no treatment and that you’re sort of smooth sailing? Or do you want to do something like tec dara where the toxicity is clearly lower but you are on a little bit more longer term therapy? Those are the kinds of discussions we’re going to have with patients,” Dr. Lonial explains.
While both trials demonstrate unprecedented efficacy, their differing modalities introduce practical and biological distinctions with real-world implications. CAR-T therapy requires leukapheresis, manufacturing time, lymphodepleting chemotherapy, and inpatient monitoring, restricting access to specialized centers and necessitating careful patient selection. Bispecific antibody therapy, by contrast, is immediately available and largely outpatient-based, broadening access to highly active immunotherapy across diverse practice settings, albeit with ongoing treatment requirements and frequent early visits.
Potential Side Effects
Toxicity profiles further distinguish these approaches, though both underscore the consequences of engaging the immune system earlier in the disease course. In MajesTEC-3, cytokine release syndrome was common but largely low-grade and manageable, and neurotoxicity was infrequent. However, infectious complications emerged as a major consideration, with high rates of both all-grade and severe infections, reflecting profound immune modulation when teclistamab is combined with daratumumab. These findings have reinforced the importance of immunoglobulin replacement, antimicrobial prophylaxis, and early infection surveillance as integral components of care.
CARTITUDE-4 similarly highlights immune-related risks, though with a toxicity pattern more characteristic of cellular therapy. Cytokine release syndrome and neurotoxicity occurred at expected frequencies and were generally manageable. Of particular relevance is the observation of prolonged cytopenias and delayed immune reconstitution, which contribute to ongoing infection risk well beyond the acute treatment phase. These effects emphasize that while CAR-T therapy is delivered as a one-time intervention, its immunologic consequences can persist for months, requiring structured follow-up and supportive care.
A critical and still evolving question raised by both trials is how earlier exposure to immune-based therapies affects T-cell biology. In less heavily pretreated patients, T cells may be more functional at baseline, potentially enhancing efficacy. At the same time, sustained T-cell engagement, whether through continuous bispecific therapy or CAR-T expansion, may lead to exhaustion, altered immune surveillance, and increased susceptibility to opportunistic infections. Optimal sequencing of bispecific antibodies and CAR-T therapy remains undefined, particularly as prior T-cell engagement may influence subsequent cellular therapy manufacturing and performance. These issues are not yet fully answered by MajesTEC-3 or CARTITUDE-4 but are increasingly relevant as clinicians consider long-term treatment planning rather than isolated lines of therapy.
Both trials also reflect a period of rapid learning. Supportive care strategies, especially infection prophylaxis and immunoglobulin replacement, evolved during trial conduct and continue to be refined in real-world practice. As experience grows, toxicity profiles may shift and outcomes may further improve with better mitigation of immune-related adverse effects. Ongoing studies will be essential to understanding immune recovery, long-term infection risk, and the durability of immune memory following these interventions.
MajesTEC-3 and CARTITUDE-4 represent complementary advances that collectively redefine second-line therapy in multiple myeloma. Bispecific antibody therapy combined with daratumumab offers an immediately available, highly effective option capable of producing deep and durable responses, while CAR-T therapy provides the potential for profound remission with finite treatment in carefully selected patients. Choosing between these strategies requires individualized assessment of patient fitness, access to specialized care, tolerance for short and long term immune toxicity, and broader treatment goals. As immune-based therapies continue to move earlier in the disease course, ongoing vigilance and study will be essential to fully understand their long-term implications and to optimize outcomes for patients with multiple myeloma.
