CAR-T Trial Raises Prospect of Preventing Myeloma in High-Risk Group

SAN DIEGO — Ciltacabtagene autoleucel (cilta-cel, Carvykti) as primary therapy induced deep and durable responses in every patient in a small phase II trial of high-risk smoldering multiple myeloma, a precursor to the active form of the malignancy.

At 2 months following a single infusion of the B-cell maturation antigen (BCMA)-targeting CAR T-cell therapy, all 20 patients achieved minimal residual disease (MRD) negativity at the lowest measurable level (10^-6), and this was sustained over a median follow-up of about 15 months, reported Omar Nadeem, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston.

Eighteen of the patients (90%) had a complete or stringent complete response, and MRD-negativity was maintained in the six patients followed for longer than 18 months, according to findings of the CAR-PRISM study presented at the American Association for Cancer Research (AACR) annual meeting and published simultaneously in Nature Medicine.

“This truly has the potential for one-and-done treatment for patients to prevent myeloma in their lifetime,” Nadeem said during a press briefing, noting that the duration of sustained response far exceeds the progression-free survival one would expect with active monitoring.

The efficacy data are “fantastic,” said AACR study discussant Krina Patel, MD, MSc, of the University of Texas MD Anderson Cancer Center in Houston.

“You can’t go above 100%,” she said. “This is just phenomenal data and really important for our field to know that when we go earlier, we can do better for our patients.”

No high-grade cases of cytokine release syndrome (CRS) occurred, but Patel noted several cases of non-immune effector cell-associated neurotoxicity syndrome (NINT), with some patients experiencing mild but persistent motor symptoms.

“If we didn’t have that, I would say this was a complete home run,” said Patel.

‘A Fundamentally Different Strategy’

High-risk smoldering multiple myeloma typically carries about a 50% risk of progression to multiple myeloma within 2 years. It has traditionally been managed with active monitoring until disease progression, where once symptomatic it can lead to irreversible organ damage.

Until last year’s approval of daratumumab-hyaluronidase (Darzalex Faspro), no treatment had been approved for smoldering myeloma. Preliminary data with linvoseltamab (Lynozyfic), a BCMA-targeting bispecific antibody, has also demonstrated excellent efficacy in high-risk patients.

Patients starting anti-myeloma treatment remain on therapy for years, and many do not achieve a deep molecular response, observed press briefing moderator Ecaterina Dumbrava, MD, also from MD Anderson Cancer Center.

With a one-time treatment to intercept the disease early on, the CAR-PRISM study “really explores a fundamentally different strategy” and brings about an important question: “Can we potentially redefine the treatment goals? Can we talk about the word we are always avoiding, which is the ‘cure’ for these selected patients?”

Cilta-cel is approved as a one-time infusion for relapsed or refractory multiple myeloma, but the researchers wanted to see whether its use without induction therapy in smoldering myeloma — a period when the immune system is less altered — could show the potential for even greater benefit.

“The tumor burden is lower in this disease state, and the plasma cells are less genomically complex,” Nadeem explained. “Therefore, we hypothesized that efficacy may be enhanced and toxicities may be reduced. And with the one-and-done approach, there is really a lack of exposure to standard-of-care induction regimens, which can be reserved … if these patients ever progress.”

Study Details

The CAR-PRISM trial enrolled patients with high-risk smoldering multiple myeloma as defined by the 20/2/20 model: plasma cells account for more than 20% of the cells in the bone marrow; blood levels of the M-protein exceed 2 g/dL; and the ratio of involved-to-uninvolved free light-chain proteins in the blood is greater than 20.

Patients were also eligible if plasma cells accounted for more than 10% of their bone marrow and they had additional high-risk biomarkers. As the trial did not involve induction or bridging therapy, patients were excluded if plasma cells comprised more than 40% of their bone marrow, since this group would be more likely to experience toxicities.

Study participants had a median age of 58 years, 70% were men, and 95% were white. The median bone marrow plasma cell infiltration was 20%, and two-thirds had high-risk cytogenetics. Four patients had received prior treatment for their smoldering myeloma.

The two patients who did not achieve a complete or stringent complete response had a short duration of follow-up (median 3.5 months). All 16 patients with at least 6 months of follow-up had a complete or stringent complete response.

Median progression-free and overall survival were not reached in either arm, with all patients alive and free of progression at data cutoff.

Regarding safety, grade 1/2 CRS occurred in all 20 patients. Infections were rare, and those that did occur were grade 1/2 and primarily of the upper respiratory system, Nadeem reported.

There were no cases of immune effector cell-associated neurotoxicity syndrome. However, NINTs — a known complication of cilta-cel — occurred in seven patients. These included facial nerve palsy that resolved in four patients as well as residual mild motor symptoms that did not impact daily activity, according to Nadeem.

While facial nerve palsies are usually reversible, NINTs can be a major concern for patients, said Patel.

“When patients have movement disorders it affects their potential of being normal for the rest of their life,” she pointed out. “That is a big side effect we talk to our patients about.”

Biomarker analyses suggested that NINTs were associated with high absolute lymphocyte count expansion, and Patel wondered whether it would be possible to intervene early in these patients in order to improve these toxicities.