Relapsed multiple myeloma treatment is rapidly evolving with the emergence of CAR T-cell therapy and bispecific antibodies. In this expert discussion, Dr. Ghulam Rehman Mohyuddin reviews key clinical trial data, safety considerations, and practical strategies for selecting and sequencing modern immunotherapies at first relapse.

Dr. Ghulam Rehman Mohyuddin is a hematologist-oncologist specializing in multiple myeloma at the University of Utah Health. At the Best of Hematology and Breast Cancer conference, Dr. Mohyuddin presented a comprehensive overview of treatment approaches for relapsed multiple myeloma, with particular focus on first relapse.

His presentation highlighted the evolving treatment landscape, comparing traditional triplet therapies with newer immunotherapy options, including CAR T-cell therapy and bispecific antibodies. Drawing on recent data from ASH 2025 and pivotal clinical trials, Dr. Mohyuddin offered practical guidance on treatment selection and sequencing in the modern era of myeloma therapy.

The transcript below has not been reviewed by the speaker and may contain errors.

The Spectrum of Relapsed Multiple Myeloma

Time constraints necessitate focusing predominantly on the first relapse of multiple myeloma. The intention is not to overwhelm with extensive data, but rather to provide a framework showing where treatment approaches were previously and where they stand now. The patient population spans a wide spectrum. Some patients don't require immediate treatment, while others need rather intense intervention. Understanding this entire spectrum is essential for optimal patient management.

Patient Heterogeneity in Relapsed Multiple Myeloma

When considering relapsed myeloma treatment, numerous patient-specific factors require consideration. Some patients experience indolent relapse occurring many years after initial therapy, while others face very aggressive disease, relapsing even while on quadruplet therapy. Geographic proximity to academic centers varies significantly. Some patients live close to specialized centers, while others do not. Additionally, tolerance to previous treatments differs substantially, with some patients struggling considerably while others tolerate therapy well. All these factors are critically important when making treatment decisions.

The Role of Observation in Select Relapsed Patients

No discussion of relapsed myeloma is complete without highlighting that some relapses—though representing a minority of patients—can be observed rather than immediately treated. Occasionally, patients relapse very slowly, purely biochemically, many years after stem cell transplant or other induction therapy. Identifying these patients is important.

This approach requires the right patient selection. Suitable candidates are typically amenable to observation and don't particularly favor jumping into treatment immediately. Close monitoring is essential, incorporating frequent advanced imaging such as MRI or PET scans, along with regular laboratory testing. The goal is to ensure that if relapse worsens, intervention occurs before any CRAB features (hypercalcemia, renal insufficiency, anemia, bone lesions) develop. There remains a role for observing some patients after the first relapse.

Historical Treatment Principles: The Triplet Era

Treatment decision-making has evolved substantially from historical approaches. General principles previously dictated using three drugs rather than two drugs, with triplets requiring two novel agents plus dexamethasone as the third component. Much has changed since then, rendering this approach somewhat outdated.

Past evidence demonstrated that triplets were consistently superior to doublets. However, triplets were never compared against other triplets, creating a conundrum about which specific triplet to use, how to optimally treat myeloma, and how to sequence therapies. Newer trials have begun addressing these sequencing questions.

Stem Cell Transplantation in Relapsed Disease

Regarding stem cell transplantation in the relapsed setting, the guidance is straightforward. Patients who already received a stem cell transplant should not undergo another transplant. For patients who haven't received a transplant, other treatments will likely provide better outcomes. In the relapsed setting, at least in the United States, stem cell transplantation has a minimal role.

Incorporating CAR T-Cell Therapy and Bispecific Antibodies

Having addressed historical triplet therapy and transplantation, the critical question becomes how to incorporate CAR T-cell therapy and bispecific antibodies into treatment algorithms. This represents the core of modern relapsed myeloma management, requiring discussion of both CAR T-cell data and bispecific antibody data before outlining practical treatment approaches.

CARTITUDE-4: Ciltacabtagene Autoleucel in Early Relapse

Many are already familiar with the CARTITUDE-4 study, a randomized trial in patients with one to three prior lines of therapy. Patients were randomized to receive either ciltacabtagene autoleucel (cilta-cel) or standard-of-care therapy, which was predominantly daratumumab-based triplets.

The patient population was notable: the majority of patients were not triple-class refractory (only about 15% were triple-class refractory). Approximately 35% of patients had high-risk cytogenetics. Importantly, patients had to be refractory to lenalidomide—a point that warrants emphasis and will be revisited.

Essentially, this study examined cilta-cel at first relapse and showed quite clearly that cilta-cel was substantially superior. At 30 months, progression-free survival approached 60% for cilta-cel compared to only about 25% for standard care. Generally, patients receiving cilta-cel with only one prior treatment performed better than those receiving cilta-cel after more extensive treatment—an unsurprising finding, as therapies typically work better when used earlier.

Standard Risk Disease Outcomes: Potential for Cure?

New data presented at ASH 2025 examined standard-risk disease outcomes after cilta-cel treatment. This represents a fairly impressive benchmark: at 30 months, standard-risk disease patients achieved 80% progression-free survival. Whether this constitutes a cure remains uncertain and requires longer follow-up. However, the suspicion is that at least some people will maintain very long remissions. Eventually, some may develop something else while still being MRD-negative (minimal residual disease-negative)—which arguably represents a cure. This is very exciting.

Comparative Effectiveness: Ciltacabtagene Versus Idecabtagene

Idecabtagene vicleucel (ide-cel) is no longer favored in practice, though this assessment aims not to offend the manufacturer. The data is quite clear. Beyond problematic cross-trial comparisons—complicated because the ide-cel trial enrolled slightly more relapsed patients than the cilta-cel trial—examining the entirety of available data reveals accumulating real-world evidence from across the globe demonstrating that cilta-cel is more effective than ide-cel.

Safety Concerns with Ciltacabtagene Autoleucel

Cilta-cel is not without significant risks, and highlighting these side effects is critically important. For many patients, the side effects simply aren't worth the potential benefit, especially for indolent relapses occurring many years after treatment. Subjecting such patients to these risks may not be justified.

Neurological and Systemic Toxicities

Parkinsonism rates vary across studies. Thankfully, in the CARTITUDE-4 trial, Parkinsonism was quite low at less than 2%. However, other datasets report rates up to 6%. Cranial neuropathy occurred in approximately 9% of patients (one in every nine patients) in the CARTITUDE-4 study.

Colitis is under-recognized. Without specifically looking for it, severe diarrhea would likely be attributed to other causes. Multiple cases over the past year involved patients with severe diarrhea and malnutrition, requiring long-term proton pump inhibitors and intense immunosuppressants, with some patients dying. Biopsies revealed evidence of CAR T-cells migrating to the gut and causing substantial damage.

Treatment-Related Mortality

One meta-analysis combining real-world data and clinical trial data (mostly for patients with three to four prior lines of therapy) found treatment-related mortality with cilta-cel at a staggering 15%—approaching allogeneic transplant levels. While this likely doesn't represent the non-relapse mortality rate at first relapse, and some mortality is probably driven by myeloma-related factors, these figures demonstrate that these treatments are far from benign.

Improved MRD Negativity Rates with Novel Therapies

As treatment has evolved from older conventional triplets to newer therapies, MRD negativity rates have improved substantially. There is considerable excitement about imitamab [unclear: possibly "imide-cel" or another agent], which may occupy a happy medium—much more effective than ide-cel but also much safer than cilta-cel based on available data.

To current knowledge, close to 200 patients have received this therapy, with available data, and none appear to have developed cranial neuropathy, colitis, or Parkinsonism. This represents a genuinely exciting option for practice.

Personally, accepting—through shared decision-making with patients—a loss of efficacy perhaps in the 20-30% range would be worthwhile for the peace of mind of avoiding those severe side effects.

Sequencing CAR T-Cell Therapy and Bispecific Antibodies

There is considerable discussion about always giving CAR T-cell therapy first and bispecific antibodies later. This approach has never been personally endorsed, as it relies on very flawed reasoning. Several important points warrant consideration.

Selection Bias in Clinical Trials

The patient populations receiving CAR T-cell therapy in studies differ fundamentally from those receiving bispecific antibodies. When disease is rapidly progressing and patients may not survive the approximately three-month lead time required for CAR T-cell therapy, selection bias inevitably makes CAR T-cell therapy appear superior to bispecific antibodies in retrospective comparisons.

Additionally, all comparative data assumes bispecific antibodies will be administered indefinitely—week after week or month after month until T-cells are exhausted—before attempting CAR T-cell therapy. However, this isn't the only approach. Bispecific antibodies can be given for finite duration, fundamentally changing the risk-benefit calculation and sequencing considerations.

MAJESTIC-3: Practice-Changing Data for Teclistamab

MAJESTIC-3 represents truly practice-changing and impressive data, warranting the suspense built toward this discussion. The critical context is that this patient population was not daratumumab-refractory, and daratumumab exposure occurred in only 5% of patients. These are not the typical patients seen at first relapse in the United States today, where many are daratumumab-refractory and most have received daratumumab previously.

Study Population and Design

Patients had received a median of two prior treatment regimens, similar high-risk cytogenetics compared to the cilta-cel trial, but clearly a less pretreated population overall. The comparison was teclistamab plus daratumumab versus daratumumab-containing regimens (daratumumab-pomalidomide or daratumumab-lenalidomide).

Efficacy Results

The progression-free survival curves are very impressive—a designation not often applied, but genuinely practice-changing in this case. The study demonstrated 83% three-year progression-free survival with teclistamab-daratumumab compared to less than 30% with control regimens.

Infection Management

Infections represent a significant concern with bispecific antibodies. Since mandatory intravenous immunoglobulin (IVIG) use was implemented, infection rates became manageable and actually decreased over time. Even better outcomes might be achievable by stopping bispecific antibody treatment at some point—a strategy requiring prospective data generation.

Comparative Analysis: Teclistamab, Ciltacabtagene, and Belantamab

Comparing studies reveals important distinctions. The lenalidomide-refractory population in MAJESTIC-3 was 80% compared to 100% in CARTITUDE-4. Combined with lower CD38 exposure, this represents a less pretreated population in MAJESTIC-3. Direct progression-free survival comparisons are therefore somewhat unfair, though teclistamab's results remain quite impressive.

Belantamab mafodotin plus pomalidomide and dexamethasone will likely struggle in comparison, as ocular side effects prove quite frustrating—complications not encountered with bispecific antibody therapy.

Emerging Treatment Options Beyond BCMA

Numerous other options and drug classes are emerging beyond BCMA-targeted therapies. GPRC5D-targeted agents are FDA-approved or approaching approval, providing additional treatment possibilities for the future.

Current First Relapse Treatment Algorithm

Current approaches to first relapse will likely change soon, given readouts from additional trials, but current strategies can be outlined based on patient characteristics.

Daratumumab-Sensitive, Lenalidomide-Refractory Disease

For patients who are daratumumab-sensitive and lenalidomide-refractory, teclistamab-daratumumab is honestly preferred over cilta-cel. This preference reflects achieving amazing results with less risk—a lower chance of severe side effects. Ideally, treatment could be stopped, though the optimal duration remains uncertain. Perhaps one year won't suffice for everyone, possibly requiring two years, but a finite treatment duration is the goal for patients starting this regimen.

Lenalidomide-Sensitive Disease

For lenalidomide-sensitive patients—not the population enrolled in MAJESTIC-3 but occasionally encountered in clinical practice—historically, daratumumab maintenance provided excellent outcomes with predictable safety profiles. However, the prospect of teclistamab-daratumumab is very tantalizing, potentially achieving MRD negativity, possibly curing some patients with a finite treatment duration.

Daratumumab-Refractory Disease

For daratumumab-refractory patients, current preference leans toward cilta-cel. However, following results from the recent MAJESTIC-7 study, teclistamab-daratumumab may prove appropriate for some patients in this category as well.

Special Populations

Some patients can be observed without immediate treatment. Treatment approaches will continue to differ based on individual circumstances. Autologous transplantation in the relapsed setting is not routinely recommended.

Future Outlook: Evolving Treatment Paradigms

The future is exciting, though admittedly provocative. Cilta-cel should hopefully be phased out in favor of better, safer therapies. Bispecific antibodies will increasingly be used earlier in the disease course.

Numerous duplicated trials are anticipated because multiple bispecific antibodies will be studied against the same non-bispecific control arms, resulting in many "me-too" drugs demonstrating similar efficacy. Despite this redundancy, the overall trajectory is quite exciting for patients with relapsed multiple myeloma.

Summary: Personalized Approaches in Relapsed Myeloma

Treatment of relapsed multiple myeloma has been transformed by CAR T-cell therapies and bispecific antibodies, offering unprecedented efficacy with distinct safety profiles. Optimal treatment selection requires careful consideration of prior therapies, disease biology, patient factors, and treatment goals. While cilta-cel demonstrates impressive efficacy, particularly in standard-risk disease, significant toxicity concerns warrant careful patient selection. Bispecific antibodies, particularly teclistamab-daratumumab, offer compelling efficacy with more manageable safety profiles and potential for finite treatment duration. As the field continues evolving with emerging agents and accumulating long-term data, personalized treatment approaches balancing efficacy and safety will remain paramount in optimizing outcomes for patients with relapsed multiple myeloma.