Sequencing CELMoDs With BsAbs and CAR T as a 'Sandwich Strategy' in Multiple Myeloma

Muhamed Baljevic, MD, FACP, and Paul Richardson, MD, address how cereblon E3 ligase modulators (CELMoDs) such as mezigdomide and iberdomide could be used as a "sandwich strategy" between T-cell–redirecting therapies like CAR T-cell therapy and bispecific antibodies. They reference data from the phase 3 SUCCESSOR-2 trial (NCT05552976), the phase 2 SELECT trial (NCT04191616) of carfilzomib (Kyprolis), pomalidomide (Pomalide), and dexamethasone (KPd), the phase 1 MagnetisMM-30 trial (NCT06215118) combining elranatamab-bcmm (Elrekfio) and iberdomide, and the phase 1/2 STOMP trial (NCT02343042) combining mezigdomide with selinexor (Xpovio), as well as a developing combination strategy with belantamab mafodotin-blmf (Blenrep).^1-4

Baljevic is the associate professor of medicine and director of Plasma Cell Disorders Research at Vanderbilt-Ingram Cancer Center, and Richardson is director of Clinical Research and Clinical Program Leader at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute.

Transcript:

Baljevic: I’d say there’s a role for both approaches. CELMoDs, particularly in savvy combinations like with [carfilzomib], look quite good. [The SUCCESSOR-2 data looks] competitive with KPd, which we use a lot in our clinics. I’ll also call out the MagnetisMM-30 data: at ASH last year, the combination of elranatamab with iberdomide showed overall response rates of 89% to 100%, incredible potency, although dosing of iberdomide is still being worked out to mitigate the neutropenia signal. The field is at a point where anti-BCMA bispecific or CAR T-cell therapies are firmly entrenched, at least in the second line, and we’re awaiting data on how CAR T-cell therapy may perform in the frontline setting.

Several frontline trials are also incorporating bispecifics targeting BCMA and GPRC5D. It’s going to be important to have powerful companion drugs we can use in the second line as we figure out the best sequencing between these therapies. Sequencing one bispecific after another is challenging, because so much depends on the T-cell fitness and innate immune capacity the patient has left. A colleague and I are studying exactly this approach right now: incorporating a CELMoD-based combination for 4 cycles after either CAR T-cell or bispecific therapy, and then sequencing into T-cell–redirecting therapy as we normally would, but prefaced by those 4 cycles of CELMoD therapy. We’re hoping to achieve some T-cell recovery and rejuvenation, giving the immune system a more potent T-cell and NK-cell population to lead tumor killing directly.

Richardson: I like those strategies, though we have to be careful about toxicity, since these are very potent platforms. It’s going to be important to think thoughtfully and rationally about sequencing, because combining these agents can be very active, but we still need to work out other effects, like endothelial toxicity. [Baljevic] touched on something important: in the SUCCESSOR-2 trial, median progression-free survival [PFS] across all lines came out to about 18 months, and it hadn’t yet been reached in the first-line subgroup. You mentioned KPd, and the comparison is telling. In the phase 2 SELECT trial, KPd in the SELCT trial achieved a median PFS of around 11 months and missed its primary end point of a 60% or higher response rate, coming in at 58%. At least in prospective phase 2 data, KPd isn’t going to be able to compete with carfilzomib- or mezigdomide-based regimens.

To another point you made… as we think about positioning mezigdomide in various immunotherapy settings, this idea of restoring immune activity during immune exhaustion means we need to think carefully about combination partners. My colleague Clifton Mo, MD, leads a study within the STOMP trial combining mezigdomide with selinexor (Xpovio), where we’re seeing amazing effects, reversal of T-cell exhaustion on multiple markers, but also, interestingly, a reduction in inflammation, which matters because inflammation feeds the myeloma. T-cell reactivation and regeneration take that on directly, so these rational combinations are going to have real legs. There’s one more drug class mezigdomide will likely enhance: antibody-drug conjugates, which are appealing because they don’t require hospitalization, carry low infection rates, and have low rates of IVIG use. Ocular toxicity is something to manage, but we’ve learned to make that much easier than it used to be. With all that in mind, we’re waiting with great interest on combination strategies of mezigdomide with belantamab mafodotin.

Baljevic: [Richardson], I want to echo that. We’re genuinely excited about that STOMP combination; I wish I could have opened that arm at my own institution. We intend to use mezigdomide with selinexor, since XPO1 inhibitors have an analogous immune effect, and we think it’s a great pairing, although we’re adjusting the dosing since you can’t use these agents at the highest doses studied in other regimens. Another point that’s been important to me over the years is the inflammation signal. It’s reflected in the venous thromboembolism, or VTE, signal, and CELMoD therapy appears quite favorable on that front compared with IMiDs. Data we’ve analyzed from the MAIA trial, for example, which should be published soon, shows an 18% VTE incidence, with events occurring mostly 2-plus years into treatment, and pulmonary embolism incidence increasing relative to deep vein thrombosis over time.

Looking at relapsed/refractory and even newly diagnosed data with mezigdomide and iberdomide, the VTE rates have been impressively low, single digits, not 0, but meaningfully lower than what I’ve seen with other IMiD-containing combinations. Thrombosis risk in newly diagnosed myeloma, where tumor bulk is often higher, is closely tied to use of IMiD-containing regimens. We’ve seen this in the phase 3 ALCYONE trial [NCT02195479] and phase 2 LYRA trial [NCT02951819], for example, where VTE rates were under 5% in a regimen without an IMiD backbone.^5,6 This has remained, and remains, largely an IMiD-related issue. I’m excited about the possibility that CELMoD-containing therapy could produce a more favorable signal on this front. People often forget that pulmonary embolism can be more deadly than a heart attack, and while arterial events like stroke or [myocardial infarctions] are about 2% or less, any of these can range from fatal to severely debilitating to threatening function and quality of life. That’s another angle I’m excited about.

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(17):LBA7506. doi:10.1200/JCO.2026.44.17_suppl.LBA7506
2. Perrot A, Delimpasi S, Spanoudakis E, et al. An open-label phase 2 study treating patients with first or second relapse of multiple myeloma with carfilzomib, pomalidomide, and dexamethasone (KPd): SELECT study. Leuk Lymphoma. 2024;65(6):833-842. doi:10.1080/10428194.2024.2322030
3. Suvannasankha A, Kaufman J, Badros A, et al. Safety and efficacy of elranatamab in combination with iberdomide in patients with relapsed or refractory multiple myeloma: Results from the phase 1b MagnetisMM-30 trial. Blood. 2025;146(1):100. doi:10.1182/blood-2025-100
4. Kang Y, Neff J, Ellero A et al. Selinexor-based treatments are associated with increased expression of T-cell activation markers in multiple myeloma. Blood Immunology & Cellular Therapy. 2025;1(3):100009. doi:10.1016/j.bict.2025.100009
5. A study of combination of daratumumab and Velcade (bortezomib) melphalan-prednisone (DVMP) compared to Velcade melphalan-prednisone (VMP) in participants with previously untreated multiple myeloma. ClinicalTrials.gov. Updated August 22, 2025. Accessed June 30, 2026. https://tinyurl.com/3nhd7thm
6. A study to evaluate Dara-CyBorD in previously untreated and relapsed subjects with multiple myeloma. ClinicalTrials.gov. Updated October 8, 2026. Accessed June 30, 2026. https://tinyurl.com/nherpu8f