Novel Agents and Personalized Biomarkers May Propel a New Era of MDS Management

Amer Zeidan, MBBS

The myelodysplastic syndromes (MDS) treatment arsenal is undergoing rapid transformations, including the FDA approvals of luspatercept-aamt (Reblozyl) and imetelstat (Rytelo) supported by landmark trials, a growing focus on early treatment intervention, and a plethora of clinical research that may show the efficacy of combination regimens in this disease, according to Amer Zeidan, MBBS.

“The management of lower-risk MDS has evolved significantly over the past few years,” Zeidan said in an interview with OncLive®. “This is an exciting era with a lot of new changes.”

In the interview, Zeidan discussed evolutions in the MDS treatment paradigm, key data demonstrating transfusion independence with luspatercept and imetelstat, ongoing research seeking to improve treatment efficacy for patients with MDS, and novel agents in early-phase development in this disease.

He highlighted the enduring clinical importance of findings from the phase 3 COMMANDS trial (NCT03682536), which investigated luspatercept for the treatment of anemia in patients with erythropoiesis-stimulating agent (ESA)–naive, lower-risk, transfusion-dependent MDS.1 In this trial, 58.5% of patients who received luspatercept (n = 86) achieved red blood cell (RBC) transfusion independence for at least 12 weeks combined with a mean hemoglobin increase of at least 1.5 g/dL within the first 24 weeks; this rate was 31.2% among patients who received epoetin alfa (n = 48).

Additionally, he spoke to the excitement surrounding the ongoing phase 3 VERONA trial (NCT04401748), which is evaluating azacitidine (Vidaza) plus venetoclax (Venclexta) in patients with relapsed/refractory higher-risk MDS. Previously, a phase 1b trial (NCT02942290) evaluating this combination in this population showed a post-baseline RBC and platelet transfusion independence rate of 36% among 44 evaluable patients who had a median duration of transfusion independence of 4.3 months (range, 2.3-17.8).2

Zeidan is director of Early Therapeutics Research, director of the Leukemia and Myeloid Malignancies Program, assistant medical director of the Clinical Trials Office, and co-leader of the Leukemia and Myeloid Malignancies Clinical Research Team at the Yale Cancer Center in New Haven, Connecticut. He is also chief of the Division of Hematologic Malignancies and a professor of internal medicine (hematology) at the Yale School of Medicine.

OncLive: What does the present lower-risk MDS treatment paradigm look like?

Zeidan: This has been an exciting era where we had 2 drugs specifically approved for patients [who have] anemia with lower-risk MDS. [One is] luspatercept, which was initially approved in the second-line setting in ring sideroblast (RS)–positive [MDS], and then it was subsequently moved to the frontline setting regardless of RS status. [The other approval is] imetelstat, which was approved as a second-line option after ESAs regardless of the presence of RS.

The treatment paradigm is evolving in a way that's similar to what's happening in [the solid tumor realm], where we are interested in the specific molecular alterations that patients have. SF3B1 [expression] has been associated with RS, so that could be a marker for benefit with luspatercept; however, less than 5% of patients with MDS have IDH1 mutations. Ivosidenib [Tibsovo] is approved now in the second-line, higher-risk, [IDH1-mutant] setting, but we also use it in the lower-risk setting. [Additionally], olutasidenib [Rezlidhia] has a National Comprehensive Cancer Network designation [for the treatment of patients with IDH1 mutations]. Both [ivosidenib and olutasidenib] are IDH1 inhibitors. We can still use hypomethylating agents [HMAs], and patients who have deletion 5q can use lenalidomide [Revlimid]. [There is also] ongoing work on second-generation TGF inhibitors, as well as other agents, such as PK agonists and innate immunity system modifiers like IRAK4 and IRAK1 [inhibitors].

What clinical trials have helped refine the lower-risk MDS treatment arsenal?

The most important lower-risk MDS trials in the past 10 years include the [phase 3] MEDALIST trial [NCT02631070], which is the randomized trial that led to the first FDA approval of luspatercept after many years of no [approved agents] in the lower-risk setting. This was a second-line [trial investigating the] agent after ESAs in RS-positive patients who were primarily anemic. Then, the frontline indication [for luspatercept] was based on [data from] the COMMANDS trial, which enrolled patients with frontline, lower-risk MDS who were not previously treated, were anemic, and were transfusion dependent. [These patients] were randomly assigned to receive luspatercept vs ESAs.

Then there was the phase 3 portion of the IMerge trial [NCT02598661], which led to the approval of imetelstat. [That trial] randomly assigned patients in the second-line setting to receive imetelstat vs placebo. This was an international study that accrued 178 patients and showed transfusion independence in a significant number of patients who received imetelstat: 39.8% compared with 15% with placebo. Those 3 trials have changed the management of lower-risk MDS.

What ongoing MDS trials will be important to watch in the near future?

Several studies are ongoing in lower-risk and higher-risk MDS. For higher-risk MDS, the trial all of us are waiting for [results from is] the VERONA trial, which is investigating venetoclax in combination with azacitidine. This is a fully accrued trial of approximately 500 patients that is expected to report in the next few months, and it could [prompt] a major change in the treatment paradigm. Its primary end point is overall survival [OS]. The phase 1b data [with venetoclax plus azacitidine in this population] were promising. There are other [higher-risk MDS] trials, but they are primarily phase 2 and earlier.

Regarding lower-risk MDS, the phase 3 RENEW trial [NCT04419649] has just started with the second-in-class, TGF-β ligand trap elritercept [KER-050]. This agent is similar to luspatercept, but it's supposed to be a bit [more effective] in RS-negative patients, based on phase 2 data. The [design of the RENEW trial is] similar to that of MEDALIST, where patients in the second-line setting received the [investigational] drug vs placebo. However, the main difference from MEDALIST is that RENEW is allowing patients who are RS negative. There are also many early-phase trials [in the lower-risk setting].

How might luspatercept be repurposed for patient populations beyond those with anemia from MDS?

This is an interesting area because many of us feel that treating patients at an earlier stage of their disease course—rather than waiting until they are transfusion dependent—might be the better strategy. It can potentially lead to delays in becoming transfusion dependent. Additionally, many of us feel that anemia and its complications are a major contributor to morbidity in patients with MDS, and earlier intervention might help with that.

Building on the COMMANDS trial, we have designed the phase 3 ELEMENT-MDS trial [NCT05949684]. This is an ongoing trial in patients with lower-risk MDS who are receiving [luspatercept] vs ESAs who are anemic with a hemoglobin level no higher than 9.5 g/dL and transfusion independent. This is an important trial, and if it's positive, it could change the paradigm [to allow for luspatercept use in] patients before they become transfusion dependent.

You coauthored a paper based on the 2025 Bridging the Gaps: Leukemia, Lymphoma, and Multiple Myeloma Meeting. What current controversies or unanswered questions in the treatment of patients with MDS were discussed in the paper?

Several of us [hematologists attended] that meeting and debated areas of controversy in MDS. Unfortunately, many of [these controversies] need further agreement and consensus establishment. However, the focus [of our conversation] in lower-risk MDS was: What do we use in the frontline setting for patients with lower-risk MDS who are RS negative? There is ongoing debate about using luspatercept vs ESAs. We discussed combination-based approaches and moving therapies to earlier lines, such as what's happening with the ELEMENT-MDS trial. [We also asked]: How can we look for end points beyond transfusion independence? How can we aim higher and be more ambitious [to try to achieve] disease modification in lower-risk MDS?

For higher-risk MDS, the debate primarily focused on: How can we finally move on from HMA monotherapy, which has been the standard of care for approximately 20 years? We are waiting on [data from the] VERONA trial, but there are many issues related to that trial design. How can we optimize trial designs in the future to minimize the therapeutic failures of phase 3 studies, of which there have been many in MDS? There was also a lot of discussion about what to do after HMA progression, which is a difficult treatment setting for patients with MDS. It was a good meeting. The paper is useful for hematologists who are interested in the disease to understand the current paradigm.

How have previously reported data with the use of immunotherapy in MDS spurred future study directions with novel agents or strategies?

I've been active in the field of MDS in clinical trials [that have] focused on several immune checkpoint inhibitors [ICIs]. One study was a randomized phase 2 clinical trial [NCT02775903] with durvalumab [Imfinzi], which is an anti–PD-L1 inhibitor, [in combination with azacitidine]. This trial was done in patients with MDS, and unfortunately, it was clinically negative.

[I have also investigated] other ICIs. One of them is sabatolimab [MBG453], which is an anti–TIM-3 agent. We conducted the randomized phase 2 [STIMULUS-MDS1] trial [NCT03946670] that we published in Lancet Hematology. There were encouraging signals regarding the durability of response [with sabatolimab plus HMAs in patients with previously untreated higher-risk MDS], but there was no clear extension of progression-free survival or complete response rate [vs placebo plus HMAs]. The phase 3 [STIMULUS-MDS2] trial (NCT04266301) of sabatolimab plus azacitidine vs azacitidine plus placebo [was conducted] in 530 patients [with first-line, higher-risk MDS]. We presented [findings from] this trial at the 2024 EHA Congress, and although the OS trended in favor of the combination—approximately 22.31 months compared with approximately 18.83 months—that OS benefit was not statistically significant.

I am also involved in the VERONA trial, and we are excited for those results, as well as [those from] the ELEMENT-MDS trial. In addition to these phase 3 trials, we have many ongoing phase 1 and 2 trials with what I would say are promising agents. For example, tebapivat [AG-946], which is a PK agonist for patients with lower-risk MDS with anemia, is an interesting agent [under investigation in a phase 2b trial (NCT05490446)] that we are enrolling right now. We also have a couple of trials examining ICIs, [as well as a phase 2 trial (NCT06196203) investigating] the anti–CD47 agent ligufalimab [AK117] in combination with azacitidine in patients with higher-risk MDS. [Additionally, the phase 2 BEXMAB trial (NCT05428969) trial is evaluating] the anti–clever-1 [inhibitor] bexmarilimab in combination with azacitidine [in patients with high-risk MDS]. I'm excited about several of those agents; hopefully, we get to report on the results of these trials in the near future.

References

1. US FDA approves Bristol Myers Squibb's Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes who may require transfusions. News release. Bristol Myers Squibb. August 28, 2023. Accessed May 9, 2025. https://news.bms.com/news/details/2023/U.S.-FDA-Approves-Bristol-Myers-Squibbs-Reblozyl-luspatercept-aamt-as-First-Line-Treatment-of-Anemia-in-Adults-with-Lower-Risk-Myelodysplastic-Syndromes-MDS-Who-May-Require-Transfusions/default.aspx
2. Zeidan AM, Borate U, Pollyea DA, et al. A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes. Am J Hematol. 2023;98(2):272-281. doi:10.1002/ajh.26771