Rethinking the “Next Line” in Relapsed/Refractory Multiple Myeloma: Why Using CAR T-Cell Therapy Earlier Matters

An expert Q&A with Rafael Fonseca, MD

The conversation is shifting in the treatment of relapsed/refractory multiple myeloma. In a world of increasing treatment options, the focus is moving toward using effective therapies as early as they are approved. With growing Phase 3 clinical data and real-world insights, CAR T-cell therapies are increasingly being evaluated for use earlier in the treatment paradigm.

In this Q&A, Rafael Fonseca, MD, a leading blood cancer researcher who has authored over 400 publications about innovative treatment approaches in multiple myeloma, discusses why earlier intervention with effective therapies can be critical for optimal care, the risks of delaying treatment, and how clinicians can apply emerging evidence in practice.

Q: Why is earlier intervention with effective therapies important in multiple myeloma, and what is driving the shift towards using CAR T-cell therapies in earlier lines?

Dr. Rafael Fonseca:

Earlier intervention is essential in multiple myeloma because the disease becomes harder to treat with every relapse. As patients move through successive lines of therapy, we see responses become shorter and less complete. That’s largely because the immune system becomes increasingly exhausted, the cancer becomes more genetically complex, and treatment resistance can emerge.¹

In my experience, I’ve seen how the earlier line setting can be a critical turning point for HCPs as they determine the “next line” for their patients. When a patient relapses earlier in their treatment journey, they may still have intact immune function, less treatment-related exhaustion, and disease that is less aggressive or refractory.² CAR T-cell therapies could potentially offer greater feasibility and effectiveness earlier in the treatment journey.

But there’s another, often overlooked reason to act earlier: attrition. Not every patient reaches the next line of therapy.¹

Real world data consistently show that a meaningful proportion of patients never receive third line treatment due to disease progression, declining health, or other barriers.¹ If we hold back effective options for a later line, we may miss the opportunity altogether.

CAR T-cell therapies harness the patient’s own immune system, and data has shown that delivering them when that system is at its strongest can translate into deeper and more durable responses.³

I believe we should aim to use these therapies early in the treatment paradigm, aligned with their labels, because for many patients there truly is no time to wait for the next line of therapy.

Q: How is earlier consideration of CAR T-cell therapy shaping treatment planning in multiple myeloma?

Dr. Fonseca:

Over recent years, there has been growing discussion within the hematology community about the potential role of CAR T-cell therapy earlier in the relapsed/refractory MM treatment paradigm. This conversation has been informed by an increasing body of clinical experience and research activity exploring how timing, disease burden and broader treatment sequencing considerations intersect with the delivery of cell therapy.

Much of the interest stems not only from traditional efficacy endpoints examined in clinical studies, but also from practical considerations observed across treatment settings. In later lines of therapy, a subset of patients may be unable to proceed to cell therapy due to disease progression, clinical instability, or challenges associated with treatment logistics.¹ These real-world factors have led clinicians like me to consider whether earlier integration of this approach could help more patients remain eligible to ultimately receive treatment, while also allowing more time for important considerations in treatment planning, such as specialist referrals and patient counseling, across an evolving treatment landscape.

There has also been attention on biological factors that may differ based on stage of disease and prior therapy exposure. Earlier in the treatment paradigm, some patients may have immune systems that are less impacted by cumulative treatment, which is an important consideration when evaluating cell therapies.² From a translational standpoint, this has contributed to ongoing evaluation of how disease context and immune health may influence the feasibility of treatment, how CAR T-cell therapy is integrated alongside other available options and the patient’s ability to complete the therapeutic process.

Together, the evolving clinical experience suggests that timing is an important consideration when evaluating CAR T-cell therapies. While many questions remain and continued study is needed, earlier use may offer greater opportunity for appropriate patients to be treated without relying on later-line settings, where options can become more limited.

Q: How should clinicians identify patients who may benefit from CAR T-cell therapies earlier in the disease pathway?

Dr. Fonseca:

Identifying the right patients for earlier CAR T-cell therapy begins with a shift in mindset. Even before first relapse, clinicians should be thinking about what options they and their patients would consider in subsequent lines, and from my perspective, CAR T therapies should be part of the discussion. This means that it’s important to not just respond to disease progression, clinicians should be anticipating what comes next.

Modern tools such as sensitive monoclonal protein analysis via mass spectrometry, imaging innovations, and measurable residual disease (MRD) assessments allow us to detect biologic relapse earlier than ever before.⁴ When used thoughtfully, these tools may reveal the trajectory of the disease before the clinical picture deteriorates.

That early warning is not merely informative; it creates a critical window of opportunity. Once disease burden accelerates or bridging therapy becomes unavoidable, the pathway to CAR T-cell therapy can become more complex. By recognizing relapse as it emerges, rather than waiting for symptomatic or biochemical acceleration, clinicians can position their patients to pursue effective therapies while the immune system is still stronger and treatment feasibility is highest.

Early referral also plays an essential role. CAR T-cell therapy requires coordination, education, and planning, especially across community and academic centers. Referral does not commit the patient to treatment; instead, it opens the door to guidance from specialists, comprehensive evaluation, and shared decision making. It ensures that patients understand their options and that care teams can map out a path that aligns with both the disease biology and the patient’s goals. If a patient and their provider decide CAR-T is the right choice for them, the community healthcare professional can remain at the center of their care team, coordinating closely with the other healthcare professionals and teams throughout the treatment process.

Ultimately, the goal is to move from a reactive to a proactive approach. Rather than asking, “What do we do after a relapse?” the more important question becomes, “When is the most optimal moment to use each therapy?” For many patients, that moment comes far earlier in the journey, and recognizing it can make all the difference.

Q: How has adoption of earlier intervention evolved among your peers?

Dr. Fonseca:

Among my colleagues, there’s a clear shift toward considering CAR T-cell therapies earlier in the treatment journey in settings where they are indicated, even if adoption hasn’t been uniform.

Early on, many clinicians assumed these therapies could be deferred and that other regimens could help manage disease in the interim, reserving CAR T for later. But accumulating evidence from clinical studies, along with growing real-world experience in treating patients earlier, is shaping a new decision-making process for the best time to start treatment.¹

What we’re seeing now is a growing recognition that timing matters. The emerging mindset is that these therapies should not just be reserved for late line therapy.

Q: How has the concept of cure in multiple myeloma evolved?

Dr. Fonseca:

I continue to have hope that – one day – we will have a cure for multiple myeloma. For a long time, the focus was on controlling the disease with continuous therapy. That mindset is shifting and there is more optimism around the idea of long-term remission that could ultimately lead to a cure.

In my view, cure isn’t an inherent property of a disease, but we have to collectively align on how to define it so we’re all working together toward the same goal. That’s why it’s important to continue to invest in clinical research, especially research that evaluates the long-term potential of remission with deeper, more durable disease responses and MRD assessment.

There’s been significant innovation in multiple myeloma in recent years, and I’m hopeful that the momentum we’re seeing now will one day help us find a cure.

References

¹ Fonseca, R., Usmani, S. Z., Mehra, M., Slavcev, M., He, J., Cote, S., Lam, A., Ukropec, J., Maiese, E. M., Nair, S., Potluri, R., & Voorhees, P. M. (2025). Frontline treatment patterns and attrition rates by subsequent lines of therapy in patients with newly diagnosed multiple myeloma. PubMed Central. https://pmc.ncbi.nlm.nih.gov/articles/PMC12010075/

² Minnie, S. A., et al. (2023). Immune dysfunction in multiple myeloma and emerging immunotherapies. Frontiers in Immunology. https://pmc.ncbi.nlm.nih.gov/articles/PMC10030780/

³ Dr. Parekh S, et al. Earlier use of ciltacabtagene autoleucel (cilta-cel) is associated with better immune fitness and stronger immune effects as shown by correlative analysis of peripheral blood and the bone marrow tumor microenvironment (TME) from the CARTITUDE-4 study. American Society of Hematology 2025 Annual Meeting. Accessed May 2025.

⁴ Kumar, S., et al. (2016). International Myeloma Working Group consensus criteria for response and measurable residual disease assessment in multiple myeloma. Blood, 127(20), 2459–2466. https://ashpublications.org/blood/article/127/20/2459/35257/