Paul Richardson, MD, Calls Mezigdomide “CAR T in a Pill” for Patients With R/R Multiple Myeloma

The opening day of the 2026 meeting of the American Society of Clinical Oncology (ASCO) brought results from the phase 3 SUCCESSOR-2 (NCT05552976) study,¹ featuring mezigdomide, a powerful investigational oral agent in the class of cereblon E3 ligase modulator drugs, or CELMoDs. These agents are seen as successors to the immunomodulatory imide class drugs (IMiDs), such as lenalidomide (Revlimid), which has been among the standard treatments used in combinations to treat multiple myeloma. Among patients with relapsed or refractory disease, SUCCESSOR-2 showed combining mezigdomide with carfilzomib (Kyprolis; Amgen) and dexamethasone yielded a median progression-free survival (PFS) of 18 months, vs 8.3 months for those taking carfilzomib and dexamethasone alone (HR, 0.48; P < .0001).¹

The American Journal of Managed Care® (AJMC®) caught up with lead investigator Paul Richardson, MD, one of the world’s leading myeloma experts, whose excitement about CELMoDs was evident as he discussed their potential as a treatment that will be both highly effective and easily accessible. Richardson is the clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, and the RJ Corman Professor of Medicine, Harvard Medical School.

The discussion opened with Richardson explaining the huge leap in potency of theCELMoD class, when compared with immunomodulatory therapies such as lenalidomide. “The cereblon E3 ligase modulators are different—they’re quite different from the IMiDs,” he said. “They’re true degraders; they have an enantiomer effect where they bind into the cereblon E3 ligase complex, and they plug it completely. They close it down.”

The oral agent is one of a pair of CELMoDs under development by Bristol Myers Squibb; the second, iberdomide, is under review at the FDA with an August 17, 2026, deadline for action.

Understanding the Difference From IMiDs

In myeloma drugs, this “enantiomer effect” refers to how mirrored-image forms of chiral drugs—the R- and S-enantiomers—have different biological effects and differ significantly in their potency, toxicity, and antitumor activity, with the S-enantiomer doing the heavy lifting as it binds tightly to cereblon to trigger cell death.^2,3 Although the IMiDs have this quality, Richardson explained, the CELMoDs take the enantiomer effect to degrees not previously seen.

Among the emerging CELMoD class, another investigational agent, iberdomide (Bristol Myers Squibb), is more potent than the IMiDs, but Richardson said it’s still less powerful than mezigdomide.

Where lenalidomide and pomalidomide might have closed the cereblon E3 ligase complex modestly, iberdomide closes the complex by 50%, he said, “But mezigdomide is amazing. It shuts it down by 100%. So, you close that complex by 100%, and that results in dramatic consequences…. The consequence is that this targeted degradation overcomes relative resistance.”

Richardson briefly explained how the CELMoDs, and mezigdomide in particular, take aim at a pair of transcription factors, IKZF1 and IKZF3—known as Ikaros and Aiolos—through potent modulation of cereblon.³ In a 2024 article, Richardson and coauthors described these factors as “critical to the development and differentiation of hematopoietic cells” because of their ability to control gene expression and support the feedback loop between key oncogenes and an interferon regulatory factor known to have a role in hematological malignancies.³

With mezigdomide, Richardson said, “Ikaros and Aiolos degradation is way beyond anything we would otherwise see.” The result? The scale of the difference in sealing the cereblon E3 ligase complex compared with the IMiDs is stunning.

Compared with lenalidomide and pomalidomide (Pomalyst), he said, “If you scale it, [lenalidomide] closes it by about 15% and [pomalidomide] closes it by about 20%. So, [iberdomide] is 50% and [mezigdomide] is a huge 100%—so much more powerful.

“And what that means is that literally there’s a direct killing of the myeloma because [of] the intense activation of the immune system, be it [natural killer] cells [or] T cells,” Richardson continued. “So, the result is the effects of the drug—in terms of its ability to both enhance immune activation as well as kill myeloma—is a remarkable kind of bonus, frankly. It’s highly synergistic with both [protease inhibitors] and antibodies.”

Comparing Outcomes With CAR T-Cell Therapy

What animates Richardson most is talking about the survival data for SUCCESSOR-2, when compared to the options patients have today. “What’s so exciting is that we got that median PFS of 18 months, which is great, with a hazard ratio of 0.48,” he said.¹ “But most importantly, that’s very similar to what we saw in other settings.”

Richardson offered the caveat of being careful to compare data across trials, but he noted the results from KarMMa-3 (NCT03651128) of idecabtagene vicleucel (ide-cel), which reported a PFS of 13.3 months for triple-class–exposed patients in December 2024.⁴ And in CARTITUDE-4 (NCT04181827), he said, a look at the cohort for patients refractory to lenalidomide and anti-CD38 therapy shows a PFS of 19.4 months.⁵

“Mezigdomide achieves more than ide-cel, and it’s pretty close at 18 months to 19 [months],” Richardson said. “The point is, this is why we say mezigdomide is CAR T in a pill. And we also call it the CELMoD for all seasons, because essentially you can use it everywhere, so 1 to 9 prior [therapies], and the median number is about 2—isn’t that great?”

Richardson pointed out that administration of mezigdomide could occur without the complications—and costs—seen in chimeric antigen receptor (CAR) T-cell therapy: the leukapheresis, the manufacturing process, the shipments of precious customized cells, the refrigeration. “There’s none of that—none of the problems that you normally have.”

A Viable Option for Older Patients, Those With EMD

Do these factors make mezigdomide a good option for patients 75 years or older, as was seen in the trial? “Our oldest patients were octogenarians, ages 85 and 86,” he said, noting that the study design allowed for a patient population close to that of the “real world,” in that 30% had extramedullary disease (EMD), which has a poor prognosis.

“This was a hard-to-treat population, and the control arm reflected that,” Richardson said, comparing the 8.3-month PFS in SUCCESSOR-2 to much longer PFS results seen in another trial with more classical limitations on enrollment. The control arm PFS was close to the control in MajesTEC-9 (NCT05572515), also presented at ASCO, he said, as study investigators look to include more patients who reflect real-world populations.

Richardson said CAR T-cell therapy has moved the field forward and saved many lives but noted that it’s not suitable for about 20% of the patients who have relapsed with myeloma.

The SUCCESSOR-2 results, he said, reflect the calls for therapies that will serve patients who are older, frailer, and cannot travel long distances for treatment. “A prescriber can say, ‘Well, I’ve got a patient with EMD, they’ve got high-risk cytogenetics, and they’re an older patient. What on Earth am I going to do?’ And sure enough, you’ve got a mezigdomide-based approach. Today, if you have an 85-year-old patient who comes in, CAR T is really not on the table.”

References

1. Richardson PG, Schjesvold F, Fu C, et al. Mezigdomide, carfilzomib, and dexamethasone (MeziKd) vs carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM): results from the phase 3 SUCCESSOR-2 trial. J Clin Oncol. 2026;44(suppl 17):LBA7506. doi:10.1200/JCO.2026.44.17_suppl.LBA7506
2. Wu L, Aslanian AM, Liu JF, Hogan J, Tung R. CTP-221, a deuterated S-enantiomer of lenalidomide, possesses significantly enhanced immunomodulatory and anti-proliferative properties relative to the R-enantiomer and to racemic lenalidomide. Blood. 2012;120(21): 2463. doi:10.1182/blood.V120.21.2463.2463
3. Liu Y, Mo CC, Hartley-Brown MA, et al. Targeting Ikaros and Aiolos: reviewing novel protein degraders for the treatment of multiple myeloma, with a focus on iberdomide and mezigdomide. Expert Rev Hematol. 2024;17(8):445-465. doi:10.1080/17474086.2024.2382897
4. Ailawadhi S, Arnulf B, Patel K, et al. Ide-cel vs standard regimens in triple-class-exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses. Blood. 2024;144(23):2389-2401. doi:10.1182/blood.2024024582
5. Puig N, Diels J, van Sanden S, et al. Comparative efficacy of ciltacabtagene autoleucel vs standard-of-care treatments for patients with previously treated relapsed or refractory multiple myeloma: a matching-adjusted indirect comparison. Adv Ther. 2025;42(7):3223-3239. doi:10.1007/s12325-025-03205-8