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Sagar Lonial, MD, FACP, FASCO, discusses findings from the CC-220-MM-001 trial of iberdomide plus daratumumab and dexamethasone in newly diagnosed myeloma.
The CELMoD iberdomide (CC-220) displayed promising efficacy and a tolerable safety profile in combination with daratumumab (Darzalex) and dexamethasone for the treatment of patients with transplant-ineligible/deferred newly diagnosed multiple myeloma, according to Sagar Lonial, MD, FACP, FASCO.
During the
“CELMoDs are oral, so they’re easy to administer,” Lonial explained in an interview with OncLive®. “The toxicities are predominantly hematologic, something that those of us who take care of patients with myeloma are relatively comfortable... Having agents that are better tolerated than the immunomodulatory drug [IMiD] class is a huge step forward for patients. Perhaps [they will not require] the continuous maintenance approach that we’ve needed with IMiDs because they’re not as potent as CELMoDs. [With CELMoDs], we may be able to give limited duration therapy, get more efficacy, better safety, and, ultimately, talk about discontinuation.”
In the interview, Lonial discussed the mechanism of actions of CELMoDs, key data from CC-220-MM-001, and the potential future roles for this drug class in multiple myeloma.
Lonial is a professor and chair of the Department of Hematology and Medical Oncology at Emory University School of Medicine, as well as chief medical officer at Winship Cancer Institute of Emory University in Atlanta, Georgia.
Lonial: From my perspective, what we are most excited about with CELMoDs is that they are engineered to be more potent than the previous immunomodulatory drugs [IMiDs]. Both lenalidomide [Revlimid] and pomalidomide [Pomalyst] bind cereblon, but they do so with different binding affinities. Iberdomide and mezigdomide, which are the 2 CELMoDs being evaluated in myeloma, bind cereblon with much higher affinity and downregulate the transcription factors Ikaros and Aiolos more rapidly. That means they kill the cell, rather than simply slowing or halting cell division, which is more commonly seen with lenalidomide and pomalidomide. This concept of cytotoxicity is very important.
Furthermore, as part of the engineering process, these molecules are also more potent immune stimulators. [With CELMoDs], we not only enhance immune-mediated activity, but also achieve a stronger direct anti–cereblon-binding effect that leads to greater myeloma cell death.
When we look at cohort K, which evaluated iberdomide plus dexamethasone in transplant-ineligible patients, there were several key take-home messages. The first relates to depth of response. The CR rate was [approximately] double what we saw in the [phase 3] MAIA trial [NCT02252172], suggesting that replacing lenalidomide with iberdomide results in deeper responses.2
In addition, the MRD-negativity rate was also approximately double what was observed in MAIA, indicating that the higher CR rate is translating into deeper and more durable responses.
Finally, in this transplant-ineligible and frail patient population, the adverse effect profile was more favorable than what we typically see with lenalidomide. Many of the [toxicities associated with IMiDs, [such as] fatigue, diarrhea, confusion, or “swimmy-headedness”, were much less frequent, if present at all, with CELMoDs. Overall, efficacy was improved, safety was improved, and MRD outcomes were better.
From a safety standpoint, the first question is always combinability. What happens when you combine iberdomide or mezigdomide with other agents? Early phase 1 data combining these drugs with proteasome inhibitors such as bortezomib [Velcade] or carfilzomib [Kyprolis] have shown that both CELMoDs are highly active in combination, similar to what we have seen with IMiDs.
What really distinguishes iberdomide and mezigdomide is their activity when combined with bispecific antibodies or monoclonal antibodies. That is why we are particularly excited about the [phase 3] EXCALIBER-RRMM study [NCT04975997], which combines daratumumab [Darzalex] with iberdomide. At ASH, we [also] saw data with elranatamab-bcmm [Elrexfio] plus mezigdomide and elranatamab plus iberdomide, as well as early signals with cevostamab [BFCR4350A] combined with CELMoDs. This represents a major and exciting step forward.
CELMoDs will likely have a role across every line of therapy, in the sense that they enhance the activity of more traditional partners such as CD38 antibodies and proteasome inhibitors. They may also improve T-cell fitness prior to CAR T-cell collection and serve as a distinct option for short-duration maintenance following CAR T-cell therapy.
Additionally, when combined with bispecific antibodies, CELMoDs may deepen responses. We already know that patients who progress on BCMA- or GPRC5D-directed CAR T-cell therapies can have responses reactivated with pomalidomide. Using a CELMoD earlier may deepen responses upfront and potentially eliminate the need to add it later by priming the immune system while simultaneously killing myeloma cells.
For iberdomide, we are hopeful that EXCALIBER-RRMM will ultimately lead to FDA approval. We have seen a press release indicating that the study met its primary end point, although we are still awaiting full data.3 EXCALIBER-RRMM maintenance [
NCT05827016], which is a [phase 3], head-to-head comparison [of iberdomide] with lenalidomide in the maintenance setting, is especially important. It will help address whether the scientific promise of CELMoDs translates into meaningful clinical benefit for patients.
For mezigdomide, combinations with carfilzomib are particularly interesting. Mezigdomide also appears to have unique properties, including increased potency compared with iberdomide and activity in extramedullary disease. For patients with high-risk extramedullary myeloma, this could represent an important therapeutic niche.
