Best of CAR T at the 2025 Tandem Meetings: Expert Perspectives From Dr. Binod Dhakal and Dr. Olalekan Oluwole

Friday, December 12, 2025

The 2025 Tandem Meetings of ASTCT and CIBMTR showcased a rapidly evolving landscape in cellular therapy, with CAR T-cell therapy for multiple myeloma (MM) continuing to expand in both scientific sophistication and clinical reach. Two insightful presentations came from Dr. Binod Dhakal (Medical College of Wisconsin) and Dr. Olalekan Oluwole (Vanderbilt University), who addressed complementary dimensions of CAR T-cell clinical practice.

Dr. Dhakal focused on therapeutic sequencing, resistance biology, and the growing role of bispecific antibodies, particularly in the peri–CAR-T setting. Dr. Oluwole provided an in-depth look at safety, operational models, infection-related challenges, and the next wave of cellular therapy platforms. Together, their talks offered a nuanced and forward-looking view of how CAR T-cell therapy is reshaping the treatment of relapsed/refractory multiple myeloma (RRMM).

Thank you to Johnson & Johnson and Legend Biotech for their generous support of this webinar.

For more:

Strategic Sequencing: Advancing Novel Immunotherapy in Multiple Myeloma (BCMA-Directed CAR T-Cell Therapies and the Potential of Bispecifics as Bridging Therapy)

Dr. Binod Dhakal

Presentation focus

Dr. Dhakal’s presentation centered on three interlinked questions:

How should BCMA-directed CAR T-cell therapy be optimally used in RRMM?
What is the evidence for moving CAR T-cell therapy into earlier lines of therapy?
What is the role of T-cell engagers (bispecific antibodies) as bridging or subsequent therapy in an era of multiple overlapping immunotherapies?

With the rapid arrival of BCMA- and GPRC5D-directed agents, clinicians must now consider how prior lines of therapy shape subsequent responses, how target antigen expression evolves over time, and how best to prevent disease progression during CAR T-cell manufacturing delays. Sequencing is therefore no longer an academic discussion; it has become a central determinant of survival outcomes in MM.

Historical evidence and current BCMA CAR T landscape

Dr. Dhakal reviewed the pivotal data leading to the approval of the first two BCMA-directed CAR T-cell products:

Cilta-cel (CARTITUDE-1): overall response rate (ORR) 98%, complete response (CR) 83%, median progression-free survival (PFS) 34.9 months.
Ide-cel (KarMMa): ORR 73%, CR 33%, median PFS 8.8 months.

Beyond these, several BCMA-directed CAR T-cell constructs are being investigated in late RRMM, including zevor-cel (LUMMICAR-1), anitocel, and PHE885. The ongoing anitocel trial is particularly notable, with an ORR of 97%, ≥VGPR of 81%, and median PFS not yet reached.

Dr. Dhakal emphasised that treatment selection in MM is inherently multifactorial, shaped by patient-specific and disease-specific factors as well as treatment-related considerations such as age, comorbidities, prior therapies, nature of relapse, and prior toxicities.

Shifting CAR T earlier in the treatment paradigm

A key message was the growing evidence supporting earlier use of CAR T-cell therapy. Phase 3 trials CARTITUDE-4 and KarMMa-3 compared BCMA CAR T-cell therapy against standard-of-care (SOC) regimens and demonstrated substantial PFS gains:

CARTITUDE-4 (cilta-cel): PFS rate 76% vs. 49% with SOC.
KarMMa-3 (ide-cel): PFS rate 41% vs. 19% with SOC.

In both trials, serious adverse events (SAEs) were lower with CAR T-cell therapy than with SOC, and cytokine release syndrome (CRS) rates were manageable. Overall survival and PFS were significantly higher with cilta-cel in CARTITUDE-4. Importantly, these benefits were maintained in clinically challenging subgroups, including high-risk cytogenetics, early relapse, prior BCMA-directed therapy, and extramedullary disease.

Earlier placement of CAR T therefore creates new opportunities for durable control in patients who previously had very limited options. However, it also introduces a more complicated interplay with other immunotherapies, particularly BCMA and GPRC5D bispecific antibodies, delivered before or after CAR T.

The challenge of prior BCMA exposure

A major theme of Dr. Dhakal’s analysis was the adverse impact of prior BCMA-directed therapy, especially BCMA bispecific antibodies (BsAbs), on subsequent CAR T outcomes. Across multiple datasets, patients exposed to BCMA BsAbs before receiving BCMA CAR T experience:

Shorter median PFS after CAR T
Lower CR and deep response rates
Higher rates of early progression or failure to reach infusion
Biologically, a higher likelihood of BCMA antigen downregulation or loss

Target antigen loss appears to be more frequent for GPRC5D than for BCMA, but BCMA antigen loss following prolonged BCMA BsAb therapy is increasingly recognised and may occur in up to ~40% of patients after extended exposure. In addition, T-cell exhaustion induced by chronic bispecific therapy can compromise the quality of T cells collected for manufacturing.

This shift is clinically meaningful. As BCMA BsAbs move earlier in the treatment sequence and become more widely used, CAR T performance risks being eroded unless sequencing strategies deliberately preserve the CAR T option. Dhakal’s conclusion was explicit: when feasible, CAR T first, followed by BCMA BsAb, remains the most biologically coherent and clinically effective order.

Bridging therapy and attrition before infusion

Another critical aspect is disease control during the 6–8-week interval required for CAR T-cell manufacturing. High disease burden at infusion negatively affects both safety and efficacy, making bridging therapy essential rather than optional.

Dr. Dhakal highlighted one of the least appreciated threats to CAR T success: patient attrition between apheresis and infusion. In real-world series, 10–15% of patients never reach infusion due to rapid progression, particularly those with high tumour burden, extramedullary disease, plasmacytomas, or high-risk cytogenetics.

This reality elevates the importance of bridging regimens that:

Provide rapid cytoreduction
Do not irreversibly exhaust T cells or eliminate target antigen
Preserve the ability to successfully manufacture and expand CAR T cells

Successful bridging is now a central component of CAR T care, not merely a stopgap.

GPRC5D-directed agents as bridge or alternative

Both BCMA and GPRC5D-directed CAR T and BsAbs remain active in many patients with prior BCMA exposure. Dr. Dhakal highlighted the growing utility of talquetamab, a GPRC5D-directed bispecific antibody, as both a bridging agent and a post-CAR T option.

Key advantages of talquetamab in this context include:

Rapid cytoreduction, allowing disease control while awaiting manufacturing
Maintenance of response rates even when used shortly before BCMA CAR T
Lower propensity to induce BCMA antigen downregulation
Minimal negative impact on T-cell fitness for apheresis

Talquetamab therefore stands out as a strategically important and relatively safe agent in the peri–CAR T timeline. When long manufacturing times or scheduling constraints prevent prompt infusion, GPRC5D-directed agents may provide a more biologically favourable bridge than BCMA BsAbs.

Resistance mechanisms: antigen loss and T-cell exhaustion

Dr. Dhakal concluded by examining resistance mechanisms that reinforce the importance of thoughtful sequencing. Prolonged exposure to single-antigen targeted therapies can promote antigen escape (particularly GPRC5D loss) and accelerate T-cell exhaustion, both of which reduce responsiveness to subsequent cellular and T-cell–engaging therapies.

Overall, these mechanistic insights argue for:

Minimising prolonged continuous bispecific therapy in patients who may later receive CAR T
Preserving antigen heterogeneity where possible
Planning treatment sequences prospectively rather than reactively

Safety, Operational Realities, and the Next Generation of CAR T Therapies

Dr. Olalekan Oluwole

While Dr. Dhakal focused on biologic optimisation and sequencing, Dr. Olalekan Oluwole turned to the pragmatic dimensions of delivering CAR T safely and efficiently. His talk covered the evidence supporting earlier use of CAR T, the feasibility of outpatient administration, the evolving toxicity profile dominated by infections, and the potential of next-generation CAR T platforms.

Reinforcing the case for early CAR T

Dr. Oluwole revisited CARTITUDE-4 and KarMMa-3, underscoring how CAR T dramatically outperforms SOC when used earlier in the disease course. Both cilta-cel and ide-cel achieved substantial PFS advantages, deep MRD negativity, and durable responses in lenalidomide-refractory early relapse.

These trials also allowed bridging therapy, acknowledging that even earlier-line patients may require interim disease control. Importantly, the superiority of CAR T was preserved despite this, signalling that manufacturing time, when managed appropriately, does not negate the benefits of early CAR T.

Real-world feasibility and prognostic signals

To complement trial data, Dr. Oluwole presented findings from a multicentre US cohort of 255 patients undergoing apheresis for cilta-cel manufacturing. This real-world experience confirmed that CAR T delivery is feasible across diverse centres, but outcomes were strongly influenced by pre-treatment risk factors:

Prior BCMA-directed therapy
Early relapse
Extramedullary disease

These factors correlated with decreased response rates and shorter PFS, mirroring Dr. Dhakal’s observations from a sequencing standpoint. Despite variation in product conformance and local practice, most patients received standard fludarabine/cyclophosphamide lymphodepletion and maintained high response rates, reinforcing that CAR T is manageable beyond the confines of clinical trials when risk is recognised and mitigated.

Infection as the dominant cause of non-relapse mortality

Perhaps the most striking message from Dr. Oluwole’s presentation was the changing toxicity landscape. A meta-analysis of over 7,600 patients treated with CAR T for lymphoma or myeloma showed that:

51% of non-relapse deaths were infection-related
CAR T–specific toxicities such as CRS, ICANS, and HLH accounted for only a small minority

These findings suggest that CAR T-specific toxicities, while still critical to manage, are no longer the predominant driver of non-relapse mortality in contemporary practice. Instead, the focus must shift to infection control, prolonged surveillance, and early recognition of immune impairment.

Fungal infections, historically considered rare, accounted for nearly one-fifth of infection-related deaths in pooled analyses. Dr. Oluwole noted that the initially reported low rates may largely reflect short follow-up in early trials. As patients live longer after CAR T, opportunistic bacterial, viral, and fungal infections are emerging as a major long-term concern.

Operationalising outpatient CAR T therapy

Driven by cost pressures, patient preference, and bed capacity constraints, many centres are moving towards outpatient CAR T infusion. Dr. Oluwole outlined the typical outpatient journey: apheresis, bridging therapy, lymphodepletion, infusion, and intensive early monitoring.

Successful outpatient programmes require:

Clear monitoring pathways and toxicity algorithms
Structured patient and caregiver education
24-hour emergency access and rapid escalation procedures
Reserved inpatient beds for patients requiring admission
Multidisciplinary coordination across physicians, nurse practitioners, coordinators, pharmacists, home-care teams, and family caregivers

Delayed recognition of CRS or ICANS is the key safety concern in outpatient settings. Although most events occur within the first week, rare but serious toxicities can arise slightly later, underscoring the need for careful patient selection and robust communication channels. Neutropenia and subsequent infections frequently emerge when patients are at home, further highlighting the importance of education and surveillance.

Dr. Oluwole emphasised that outpatient CAR T is safe only in the context of this systematic infrastructure; it cannot simply be a change of location without a corresponding change in process.

Variability in CRS and ICANS across products

An additional point was product-specific variability in the timing and severity of CRS and ICANS. While all approved CAR T products carry known risks, new-onset CRS or ICANS after day 14 is exceedingly rare, supporting the strategy of intensive early monitoring followed by a step-down in visit frequency. This temporal profile aligns well with many centres’ outpatient models.

Next-generation CAR T constructs

Dr. Oluwole concluded by surveying next-generation constructs designed to address key limitations of current therapies:

Anitocabtagene autoleucel (anito-cel) — an autologous BCMA-directed CAR T using a novel D-domain binder, with high ORR, deep sCR/CR rates, and a favourable safety profile.
GC012F dual-target CAR T — simultaneously targeting BCMA and CD19, built on a “FasT” platform with 22–36-hour manufacturing and encouraging durability.
GPRC5D-targeted CAR T products — offering powerful options for patients progressing after BCMA-directed therapy and contributing to antigen-diverse strategies.

These platforms aim to reduce manufacturing delays, broaden antigen coverage, and enhance both safety and durability, ultimately allowing clinicians to deploy CAR T earlier, faster, and more reliably.

Where CAR T Is Heading in 2025 and Beyond

Taken together, the perspectives of Drs. Dhakal and Oluwole highlight both the scientific advances and practical challenges that define contemporary myeloma immunotherapy.

Several unifying themes emerge:

CAR T is moving into earlier lines of therapy. Consistent trial and real-world data support earlier use in relapse, with clear benefits in PFS, depth of response, and potentially overall survival. This trend is likely to continue as manufacturing times shorten and eligibility broadens.
Sequencing now determines long-term success. BCMA BsAbs can compromise later CAR T efficacy through antigen loss and T-cell exhaustion, while GPRC5D-directed agents may offer more favourable bridging options. Anticipating the need for CAR T and structuring sequences accordingly will be critical to maximising benefit over the course of disease.
The main threats are progression before infusion and infection afterwards. Dhakal’s focus on bridging and attrition dovetails with Oluwole’s emphasis on infection prevention and multidisciplinary outpatient models. A holistic approach that integrates disease control, safe manufacturing windows, and long-term infectious risk management is essential.
Next-generation CAR T platforms are poised to address current limitations. Faster manufacturing, dual-target strategies, and novel binders are all converging to expand access, increase durability, and potentially reduce toxicity.

In summary, the field is moving toward a more personalised, strategically sequenced, and operationally sophisticated approach to CAR T in MM. Drs. Dhakal and Oluwole jointly underscore that the success of CAR T in 2025 and beyond will depend not only on the biologic potency of new constructs, but also on coordinated clinical pathways that integrate sequencing, bridging therapy, patient selection, outpatient infrastructure, and vigilant long-term care.

References

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