Bloodlines Series: CAR T-cell Therapy Shows Promise for Smoldering Myeloma

An immunotherapy typically used in advanced stages of multiple myeloma may be effective against an early form of the disease known as smoldering myeloma—offering a potential new option for a disease that, until recently, had no approved treatments.

The treatment, ciltacabtagene autoleucel (Carvykti), is a chimeric antigen receptor (CAR) T-cell therapy, a type of immunotherapy in which a patient’s own immune cells are isolated from their blood, engineered to recognize their cancer cells, and infused back into the patient.

In a phase II clinical trial of patients with high-risk smoldering myeloma, a single infusion of the treatment led to responses in all patients, and most had no remaining traces of their disease, according to results reported at the AACR Annual Meeting 2026 by Omar Nadeem, MD, a medical oncologist at Dana-Farber Cancer Institute and an assistant professor at Harvard Medical School.

“Our hope is that these responses continue to be durable in the long term to the point where we can say that patients are cured,” Nadeem said.

What is High-risk Smoldering Myeloma?

Smoldering myeloma is a precursor to the more advanced, symptomatic form of multiple myeloma known as active multiple myeloma. Patients with smoldering myeloma have an accumulation of abnormal plasma cells (a type of immune cell that produces antibodies) in their bone marrow but do not experience any of the symptoms characteristic of active disease. As a result, smoldering myeloma is often diagnosed incidentally through routine blood work or tests for other health conditions or through close monitoring of patients known to be at risk of smoldering myeloma.

A subset of patients with smoldering myeloma have a particularly high risk of progressing to active multiple myeloma, based on the greater accumulation of plasma cells in their bone marrow and higher levels of certain proteins produced by the plasma cells.

“Almost half of patients with high-risk [smoldering myeloma] will experience progression to active multiple myeloma within two years, developing bone lesions and debilitating symptoms such as kidney failure, anemia, pain, and frailty,” said Nadeem.

(Learn more about how smoldering myeloma develops, how it’s diagnosed, and how often it progresses in an earlier blog post.)

How Is High-risk Smoldering Myeloma Typically Treated?

Until recently, the only option available to patients with high-risk smoldering myeloma was active monitoring through regular lab tests, imaging, and/or bone marrow assessments to check for signs of progression.

“Typically, patients with [smoldering myeloma] would begin therapy only after they had already developed organ damage or other symptoms of active multiple myeloma,” Nadeem said, adding that while some patients could receive investigational treatments by enrolling in a clinical trial, such trials are less accessible to the majority of patients treated outside of a major cancer center.

In November 2025, the U.S. Food and Drug Administration (FDA) approved daratumumab and hyaluronidase (Darzalex Faspro), a CD38-targeted monoclonal antibody, for the treatment of high-risk smoldering myeloma, marking the first approved therapeutic for this disease. The treatment reduced progression to active multiple myeloma by 51% in a clinical trial, but Nadeem noted that the trial did not evaluate whether patients had any trace levels of disease remaining, known as minimal residual disease (MRD), which can increase a patient’s long-term risk of disease progression.

Why Did Researchers Explore CAR T-cell Therapy for Smoldering Myeloma?

Unlike many other systemic treatments, CAR T-cell therapy is given as a one-time infusion. This means it “has the potential to truly be a ‘one-and-done’ treatment for these patients to prevent myeloma in their lifetime,” said Nadeem.

In 2022, the FDA approved ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. This CAR T-cell therapy targets the BCMA protein that is found on the surface of abnormal plasma cells, such as those that comprise smoldering and active forms of multiple myeloma.

“Due to its efficacy in relapsed multiple myeloma, and the fact that it is given as a single infusion, we reasoned that ciltacabtagene autoleucel could be a practical and effective approach for patients with high-risk [smoldering myeloma] to intercept the disease before the patient develops any symptoms,” said Nadeem.

“The other rationale was that the T cells are fitter during this early disease state, and so the efficacy of CAR T-cell therapy may be even greater when administered during [smoldering myeloma], when the immune system is more robust.”

To evaluate the safety and efficacy of ciltacabtagene autoleucel, Nadeem and colleagues conducted the phase II CAR-PRISM trial, which enrolled 20 patients with high-risk smoldering myeloma.

How Effective Was the CAR T-cell Therapy?

Within two months of treatment, all patients who received ciltacabtagene autoleucel were negative for MRD, as measured by genetic sequencing for disease-specific markers. In addition, 18 of these patients also had complete responses, meaning they had no signs of the disease-associated myeloma protein in their blood, and their plasma cells accounted for less than 5% of their bone marrow.

“In this pilot study, a one-time infusion of ciltacabtagene autoleucel … led to universal MRD negativity,” said Nadeem, highlighting that MRD negativity occurred without the need for any prior treatments to reduce the patient’s cancer burden.

“No instances of disease progression have been observed after a median follow-up of 15.3 months, far exceeding the progression-free survival we would expect with active monitoring,” he said. Six patients who were followed for longer than 18 months continued to be disease-free.

“These results support our hypothesis that administering CAR T-cell therapy earlier—before the onset of active multiple myeloma—can lead to deep responses,” Nadeem added. 

What Were the Side Effects of the Treatment?

CAR T-cell therapy can sometimes elicit severe and life-threatening side effects that lead to discontinuation or dose modification of the treatment. In this trial, however, no dose-limiting toxicities occurred, and most adverse events were either low-grade or transient, according to Nadeem. The most common adverse events were transient hematologic toxicities, including reduced immune-cell levels.

All patients experienced low-grade cytokine release syndrome. Certain neurologic toxicities occurred in seven patients: facial nerve palsy in four patients that resolved completely, and residual, but improved, mild motor symptoms in three patients.

After Nadeem’s presentation, discussant Krina Patel, MD, MSc, an associate professor at The University of Texas MD Anderson Cancer Center, praised the trial’s efficacy results. “You can’t go above 100%,” she said, referring to the overall response and MRD-negativity rates observed in the trial.

Patel, who was not involved in the study, noted that patients with smoldering myeloma may have a different definition of acceptable toxicity than patients with active myeloma. She explained that even though the motor symptoms observed in the trial were mild, the patients, who were asymptomatic before treatment, may have to live with those motor symptoms for the rest of their lives. If the treatment is ultimately approved for smoldering myeloma, patients and clinicians should carefully weigh the risks and benefits associated with ciltacabtagene autoleucel when making treatment decisions, Patel said.

One Patient’s Experience

After Angelo Chrysoulakis was diagnosed with high-risk smoldering myeloma, he had a couple of options.

“The time surrounding diagnosis was somewhat overwhelming, but as I recall, I was given the option of doing nothing (i.e., ‘wait and see’) or pursuing a treatment regimen” as part of a clinical trial, he said. “My primary oncologist at Yale strongly suggested I get a second opinion and also explore clinical trials due to the high-risk nature and burden of my specific disease.”

He was referred to Nadeem, and together, they considered the pros and cons of various clinical trials. Ultimately, Chrysoulakis decided to enroll in the CAR-PRISM study.

“Being diagnosed with a potentially life-ending disease was akin to a punch in the gut,” Chrysoulakis said. “I am a relatively young person who enjoys all sorts of activities and living life to the fullest. But most of all, I relish every moment I can spend with my family. My primary motivation for enrolling in the CAR-PRISM trial was to extend both my life and the related quality therein.”

During treatment with ciltacabtagene autoleucel, he experienced a mild form of cytokine release syndrome, and he continues to have a weakened immune system after treatment, for which he is receiving monthly treatment to help his immune system recover.

“Overall, I was expecting more severe side effects than I actually experienced,” he said.

Like the other 19 patients on the trial, Chrysoulakis’ smoldering myeloma responded well to treatment.

“I’m not sure anyone who’s received a similar diagnosis will ever not be concerned about possible disease progression,” Chrysoulakis remarked. “That said, I am much less worried about progression than I was prior to receiving treatment. I am beyond grateful to currently be in remission.”