Myelodysplastic syndrome (MDS) treatment selection is increasingly being guided by genetic disease features, which are also informing the study of novel agents. These novel agents may soon move the field beyond symptom management toward personalized disease modification, which could improve long-term treatment outcomes, according to Rami Komrokji, MD.

“Patients with deletion 5q [del(5q)] preferentially receive lenalidomide [Revlimid],” Komrokji said in a summary of the lower-risk MDS treatment paradigm during an interview with 

®. “Ring sideroblast [RS]–positive patients preferentially receive luspatercept-aamt [Reblozyl] up front. For the rest, you have a choice between erythropoiesis-stimulating agents [ESAs] and luspatercept as frontline therapy. Then we have imetelstat [Rytelo] for patients after ESA or luspatercept progression, particularly in those who are highly transfusion dependent.”

 for the treatment of anemia in patients with very low– to intermediate-risk, transfusion-dependent MDS based on data from the phase 3 COMMANDS trial (

, in which the rate of red blood cell (RBC) transfusion independence for at least 12 weeks combined with a mean hemoglobin level increase of at least 1.5 g/dL within the first 24 weeks was 58.5% among patients who received luspatercept (n = 86) vs 31.2% among those who received epoetin alfa (n = 48).

 for the treatment of anemia in patients with low- to intermediate-1–risk transfusion-dependent MDS who have lost response to, not responded to, or are not eligible for ESAs.

 This regulatory decision was backed by findings from the phase 3 IMerge trial (NCT02598661), in which patients in the imetelstat arm (n = 118) achieved an 8-week RBC transfusion independence rate of 39.8% (95% CI, 30.9%-49.3%) vs 15% (95% CI, 7.1%-26.6%) in the placebo arm (n = 59; 

In the interview, Komrokji discussed the evolution of treatments for patients with lower-risk MDS that reflect novel classification systems; how major clinical trials like COMMANDS and IMerge have introduced agents that have improved transfusion independence rates in patients with lower-risk disease; ongoing trials that are exploring novel targets and therapies, including oral hypomethylating agents (HMAs) and NLRP3 inhibitors; and future treatment sequencing considerations for incorporating immunotherapy into the MDS armamentarium. 

Komrokji is vice chair of the Malignant Hematology Department and a senior member of the Malignant Hematology and Experimental Therapeutics Program at Moffitt Cancer Center in Tampa, Florida; as well as a professor in medicine & oncologic sciences in the College of Medicine at the University of South Florida.

: How does the current lower-risk MDS landscape reflect recent updates to molecular testing practices and classification systems?

: We've made a lot of progress in better understanding the disease. Now we even talk about a precursor state before MDS. We have patients with clonal hematopoiesis of indeterminate potential [CHIP] and clonal cytopenia of undetermined significance [CCUS]. Patients with CCUS will have low blood counts. They will have somatic mutations or cytogenetic abnormalities, but not enough dysplasia to call it MDS. [In 2024], we published [research looking at data] from Moffitt and the National MDS Study [NCT02775383] showing that high-risk CCUS outcomes and depth of cytopenia are similar to [those of] lower-risk MDS. We are broadening [the population of patients that] we might consider lower risk in the future.

The classification has moved into a molecular definition of certain entities. Classification is a reflection of biology. [We have tried to identify] a group of patients who have a certain biology to explain the underlying ineffective hematopoiesis. In the newer [MDS] classification systems, whether the World Health Organization or the International Consensus Classification, we have entities such as del(5q), which we've known about for many years; 

 mutations; and patients with low and high blast counts. Regarding what we classify as lower risk, it's del(5q), 

Historically, classification [has been] more pathological. However, [the updated classification systems] emphasize important clinical aspects. For patients with del(5q), we have a unique treatment, lenalidomide that we've used for many years. For [patients with] 

 mutations, now luspatercept has emerged as a preferred treatment, even up front. Classification is affecting our choice of therapy.

We've also refined what we consider lower risk by refining the risk stratification models. We have now the International Prognostic Scoring System—Molecular criteria where we integrate the clinical variables of cytopenias, blasts, and cytogenetics, and we also add the molecular mutations. [From there], we divide patients into 6 groups. The first 3 are considered lower risk. [This system] upstages a subset of patients, but even in the most [updated] risk stratification criteria, approximately 58% of patients [with MDS] are considered lower risk.

[We also need to consider] the natural history of patients with lower-risk MDS. What happens to those patients? [Approximately] 30% of patients, including all-comers, will progress to higher-risk MDS or acute myeloid leukemia [AML], and [approximately] 70% of patients will remain lower risk. The main issue in [the lower-risk] population is the complications from cytopenia. In many of those patients the cause of death, unfortunately, is still attributed to MDS, whether it's a direct result of those cytopenias or an interplay with comorbidity. Cytopenias are not trivial. Historically, the goal of treatment in those patients was to make them transfusion independent, mainly as a palliative [method] to manage symptomatic anemia. However, the field is moving more into [investigating whether we] could alter the natural history [of the disease] if we restore effective hematopoiesis in those patients.

Another [research topic] that's coming up is the causes of mortality among lower-risk patients with MDS. A subset of patients [with MDS] and AML will progress, and that's important, but most patients will not progress. However, what's emerging is that patients [with MDS] are at higher risk of cardiac events. Cardiac mortality is a common cause of mortality.

Historically, we used to think of [this issue] as simplistic: patients become anemic, and they have cardiac stress. However, there is evolving literature on the importance of CHIP, somatic mutations, inflammatory milieu, and accelerated atherosclerosis. The story may not be just cytopenias; the clonal hematopoiesis and inflammatory milieu that's created in MDS could be contributing to [mortality].

What clinical trials have helped define the lower-risk MDS treatment armamentarium?

The past few years have been exciting in MDS. Originally, [research] focused on higher-risk MDS, but breakthroughs and drug approvals have predominantly happened in lower-risk MDS. The 2 major trials that translated to FDA approvals [for patients with lower-risk MDS] investigated luspatercept and imetelstat.

Luspatercept is a fusion trap protein that neutralizes TGF-β ligands and regulates terminal erythroid differentiation. The 

 was based on data from the phase 3 MEDALIST study [NCT02631070] which enrolled patients with RS-positive, or what we now call 

-mutant, MDS after ESA progression. These patients were transfusion dependent and were randomly assigned to receive luspatercept or placebo. [This trial] demonstrated a [38%] transfusion independence rate [of at least 8 weeks] with luspatercept and led to the approval [of the agent] in that setting.

That was followed by a study called COMMANDS, [which moved] luspatercept to the upfront setting. This was the first time we had a randomized clinical trial comparing ESAs with a newer agent [in MDS]. [COMMANDS enrolled] patients with lower-risk, transfusion-dependent MDS—both RS positive and RS negative—and randomly assigned them to receive luspatercept or ESAs. The primary end point was a bit more robust than historical [ones]. [The trial investigated the rate of] patients becoming transfusion independent for [at least] 12 weeks and having an objective [mean] hemoglobin level increase of [at least] 1.5 g/dL [within the first 24 weeks]. Luspatercept outperformed ESAs, particularly in the RS-positive [population, for which] the study was highly enriched.

There were only 48 and 49 RS-negative patients [in the luspatercept and ESA arms], respectively. In the RS-positive [population], we saw a doubling of the response rate and duration of response [with luspatercept vs ESAs]. In the small subset of RS-negative patients, the responses seemed to be similar, but probably more durable. That led to the FDA expanding the label for luspatercept [beyond] post-ESA progression as upfront [therapy]. The National Comprehensive Cancer Network [NCCN] guidelines have been updated to reflect that; in the RS-positive population, it's the preferred choice, and in the RS-negative population, it is an option.

The other pivotal trial has been the IMerge trial. This investigated imetelstat, a telomerase inhibitor. Telomerase activity is increased in MDS cells, as well as in other cancers. The IMerge study enrolled patients after ESA progression and randomly assigned them to receive imetelstat IV infusion once a month or placebo. [This trial] showed that [39.8%] of patients became transfusion independent [for at least 8 weeks], with a median [duration of transfusion independence] of [51.6 weeks]. Hemoglobin levels increased by [a median of] 3.6 g/dL [with imetelstat], so there was robust activity among patients after ESA progression. What's unique in this study was that patients were included if they were heavily transfusion dependent. Historically, we had no agent that was active in that subset of patients with erythropoietin [EPO] levels above 500 mU/mL.

The downside is that imetelstat has a myelosuppressive effect. [It is associated with] grade 3 or 4 thrombocytopenia and neutropenia, which happens in the first cycle or 2 and requires dose holding or adjustment. However, the good news is that [in IMerge], the rates of clinical manifestations, such as febrile neutropenia, were less than 1%, and the rate of bleeding was low.

[The IMerge data] led to the FDA approval of imetelstat in patients post-ESA progression, and the NCCN guidelines also incorporate it [for the treatment of patients with] high transfusion burden. Activity was seen both in RS-positive and RS-negative populations. The NCCN guidelines even position it as a potential option in patients up front if their EPO levels are above 500 mU/mL, they have a high transfusion burden, or even if ESAs and luspatercept don't perform well.

What emerging targets and ongoing research may set investigational MDS agents on the approval path?

Decitabine plus cedazuridine [Inqovi] has been FDA approved

 as an oral [combination]. The label is for intermediate- and higher-risk MDS. The oral formulation of azacitidine is being developed as well. Whether [the benefit of oral HMA formulations is] just ease of use for patients or different preferential activity is yet to be seen. There are ongoing studies with oral HMAs. We usually reserve HMAs for patients who have concomitant neutropenia or thrombocytopenia that limit the use of other agents, or for [patients who have progressed on] several lines of therapy.

Elritercept [KER-050] is similar to luspatercept. [Elritercept] is an activin receptor type IIA fusion trap protein, [whereas] luspatercept is an activin receptor type IIB [fusion trap protein]. Elritercept has been tested in phase 1 and 2 trials and showed promising activity both in RS-positive and RS-negative [patients], even [those with] higher transfusion burden. At least preclinically, it [has also shown the potential for] more trilineage responses. It's [under investigation] in the phase 3 RENEW trial [NCT06499285], where it's going to be used after ESA progression in transfusion-dependent patients who are RS positive or RS negative.

It's exciting that we [may] have 2 agents in the same class. We'll see if [one] retains activity after [progression on the other one]. However, elritercept is the next drug in a phase 3 trial that, if positive, will hopefully lead to FDA approval.

We are also evaluating moving from the point of treating patients only when they become transfusion dependent to treating patients with symptomatic anemia. In practice, most of the time we don't wait for patients to become transfusion dependent [before treating them]. The ELEMENT-MDS trial [NCT05949684] is a randomized phase 3 trial that is similar to COMMANDS. In the ELEMENT-MDS study, patients with lower-risk MDS who are not transfusion dependent, are randomly assigned to receive luspatercept or ESAs. The primary end point is transfusion [dependence rate during any continuous 16-week interval]. This is an exciting trial because it's evaluating changing the dogma of waiting for patients to be transfusion dependent [to see whether there is a] benefit with earlier treatment. It will shape the landscape of when to treat and [show] whether luspatercept is a better option than ESAs in that setting.

There are several other promising drugs that are in earlier-phase studies. A lot of efforts are targeting the inflammatory milieu in the bone marrow, because that seems to be an important aspect [of MDS]. There is the NLRP inflammasome complex. There are NLRP inhibitors in clinical trials. There are the IRAK1 and IRAK4 pathways, and there are IRAK4 and IRAK1 dual inhibitors in clinical trials as well.

There are also drugs trying to target the hepcidin and hemojuvelin pathways. DISC-0974 was tested in myelofibrosis and showed promising anemia response, and it's also been [evaluated] in MDS. Those are several promising pathways being explored actively in clinical trials that are not yet in randomized phase 3 trials.

You coauthored a paper on the management of MDS, which was based on the 2025 inaugural Bridging the Gaps: Leukemia, Lymphoma, and Multiple Myeloma Meeting. What controversies and unanswered questions about the treatment of patients with MDS were discussed at the meeting?

There are many controversies [and questions] that need more answers and more clinical trials. One is how we treat patients with high-risk CCUS, because although the drug approvals [we've had for MDS are] not for patients with high-risk CCUS, in practice, we see those patients who are cytopenic and need treatment, and we have [increasingly] convincing evidence that those patients probably have lower-risk MDS.

Another controversy is when to start therapy. Do we wait, as we've done historically, for patients to become transfusion dependent [to align with current drug approval indications], or is there an advantage of earlier treatment for those patients?

Also, how do we sequence therapies? Do we move luspatercept up front in all-comers? Is there still some role for ESAs? What would the responses be if we used luspatercept first then ESAs, or the other way around? Could there be an advantage of combining those therapies? We've had early results showing that sometimes after luspatercept progression, adding an ESA can salvage patients. There is no 100% consensus though. People are moving luspatercept up front, but there's a bit of controversy [about that] in the RS-negative population. People are moving to start treatment earlier, but most of those data are based on responder/nonresponder analyses, so [that answer is] not conclusive.

Regarding higher-risk MDS, [there is also] a lot of controversy [about whether patients] need to have a response before transplant. At what last cutoff can you take patients to transplant? We presented data from the VALIDATE consortium showing that HMA use before transplant did not affect the transplant outcome. The consensus was that if patients did not have a response to HMAs, that lack of response should not preclude them from receiving allogeneic stem cell transplant [allo-SCT].

In the higher-risk setting, the challenge had been how to improve the current standard, because for almost 2 decades we have used HMAs. Those [agents] have led to complete response rates of approximately 15% to 20% and median survival durations of approximately 1 and a half years. Several trials adding agents to HMAs have unfortunately failed to show an advantage, and part of it is probably not just the agents, but the designs of the trials and the heterogeneity of the populations that were included in the trials.

Another part of the discussion is that we have to have more homogeneous patient groups. For example, many of those trials were enriched with patients with 

-mutant disease, which is a subset of MDS and AML that unfortunately does not do well [with current treatments], and that may have affected the trial outcomes. Some of those studies were not powered enough to detect a stepwise improvement in survival, etc.

 are not functional. That's the worst subset of MDS. This group of patients with MDS and AML does poorly [with treatment]. Unfortunately, most trials have not shown improvement in that subset. Even in the AML literature, where venetoclax [Venclexta] had been an advancement and [patients receive] azacitidine [Vidaza] plus venetoclax, there was no survival advantage in patients with 

The major controversy in the [MDS] field is: Do you transplant those patients? Patients with 

-mutated disease who are going to transplant have an approximately 80% chance of recurrence, so the cure rates [with transplant in this population] are only approximately 20% compared with other subtypes, where [the rates are approximately] 40% to 50%. The transplant [supporters] will say that a 20% cure rate is better than 0%, because in those patients, unfortunately, survival durations are less than 1 year. In younger patients, that's still the go-to [treatment]. The people against transplant will [ask whether an] 80% chance of recurrence is ethically worth putting the patient through a transplant.

I think [this decision is] not that simple; it's complex and depends on many variables. Patients [can make] individual decisions, but [transplant is] a huge area. There are institutions that will immediately transplant every patient with 

 mutations and institutions that will not transplant patients with 

 mutations. [This is] an area of unmet need that needs more data and more consensus.

Another area that has been discussed is what to do at the time of progression on standard therapies, particularly HMAs, in higher-risk patients not going to transplant. What's emerging as an important point is to reassess the disease and look for targeted abnormalities. We always have to advocate to repeat the evaluation of the disease and check the molecular profile. In approximately one-third of patients a target may be identified.

 mutations are not the most common in MDS [and are present in approximately] 5% to 10% of patients. We see the emergence of 

 mutations in approximately 5% [of patients and] 

 [mutations can also occur]. Collectively, approximately 20% to 30% of patients are [eligible for] targeted therapy.

Now we have an IDH1 inhibitor, ivosidenib [Tibsovo], 

-mutant] MDS, so that could be an option. Historically, the duration of survival for patients post-HMA progression has been approximately 4 to 6 months. In the subset of patients [with 

-mutant disease] who receive an IDH1 inhibitor, [the survival rate increases to approximately] 36%. Those are effective treatments in the subset of patients [with 

How do we move those agents [to earlier lines of therapy] in those small subsets? There have been trials by a French group trying to move IDH1 and IDH2 inhibitors more upfront and more in the lower-risk population. There are even trials investigating them in CCUS. We should shy away from lumping patients with targetable mutations [into 1] group [and thinking that] HMAs are always the standard-of-care therapy for those patients.

What lessons have been learned from previous research investigating immunotherapy in MDS?

Unfortunately, [the phase 1 study (NCT02117219) evaluating durvalumab [Imfinzi] alone or in combination with tremelimumab [Imjudo] and azacitidine in patients with MDS was] terminated, and I don't think we are moving forward [with that research]. We published the results [in 

 in March 2025]. A challenging area in MDS has been taking advantage of the immune therapies that have been breakthroughs in solid tumors, lymphomas, and myelomas. We've done numerous studies. Other groups were involved with other agents like nivolumab [Opdivo] and ipilimumab [Yervoy]. Recently, there were big, randomized phase 3 trials investigating sabatolimab [MBG453] and magrolimab. All of those are immune therapies that unfortunately failed to show an advantage [in patients with MDS].

The main issue with those trials is that the immune system in patients with MDS is exhausted; there's clear evidence that these patients' T cells are exhausted. [Immunotherapies are] trying to harness an immune system that's not functional, and recruiting T cells that are not functional is not going to be effective. We know for sure that immune therapy is effective in MDS, because allogeneic transplant is the main treatment. Allo-SCT is an immune therapy, as it replaces the immune system for the patient. We are starting to move into considering off-the-shelf treatments and donor T cells. If we are going to move to CAR T-cell therapies, [we want to consider] off-the-shelf [T-cell therapy] approaches or maybe try to start positioning those patients [for CAR T-cell therapy] after transplant to prevent relapse when the immune system is still intact.

There are other trials investigating new agents. There is a pathway called Clever-1 that seems to be important that relies on macrophages. There are promising early data in leukemia and MDS, and [Clever-1 inhibitors are] going into trials now. However, immune therapies cannot rely on the patient's immune system [in MDS], because it's not intact, and immune deregulation is part of the disease. Therefore, we have to [use] off-the-shelf or allogeneic donor T cells or move [immunotherapies to] after transplant where we've replaced the patient's immune system.

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 13, 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

FDA approves imetelstat for low- to intermediate-1 risk myelodysplastic syndromes with transfusion-dependent anemia. FDA. June 6, 2024. Accessed May 13, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-imetelstat-low-intermediate-1-risk-myelodysplastic-syndromes-transfusion-dependent

Articles

Rami Komrokji, MD, discusses the evolution of lower-risk MDS treatments that reflect novel classification systems and trials exploring novel therapies.

Genetic Insights and Novel Trial Designs Contribute to an Era of Individualized MDS Management

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 

®. “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 (

, which investigated luspatercept for the treatment of anemia in patients with erythropoiesis-stimulating agent (ESA)–naive, lower-risk, transfusion-dependent MDS.

 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).

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.

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

: 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, 

 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, 

 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. 

 [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 

-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 

 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 in Hematologic Malignancies 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 

. 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 

, 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.

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

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. 

. 2023;98(2):272-281. doi:10.1002/ajh.26771

Amer Zeidan, MBBS, discusses evolutions in the myelodysplastic syndrome treatment paradigm and ongoing research seeking to improve treatment efficacy.  

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

Dr Zeidan on the Evaluation of Immunotherapy and Other Novel Therapies in MDS

“I’m quite excited about several of these agents, and hopefully we get to report on the results from the trials [evaluating them] in the near future.”

Amer Zeidan, MBBS, 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 Yale Cancer Center; as well as chief of the Division of Hematologic Malignancies and a professor of internal medicine (hematology) at Yale School of Medicine, discussed ongoing and recently completed clinical trials evaluating immunotherapy and other novel agents in patients with myelodysplastic syndromes (MDS).

A phase 1 clinical trial (NCT02117219) evaluated durvalumab (Imfinzi), a PD-L1 immune checkpoint inhibitor, in patients with MDS. Unfortunately, the study failed to demonstrate meaningful therapeutic benefit with durvalumab in this patient population, Zeidan said.

Another agent of interest is the TIM-3 inhibitor sabatolimab (MBG453), which was evaluated in treatment-naive patients with higher-risk MDS in the randomized phase 2 STIMULUS-MDS1 trial (NCT03946670). Data published in 

 hypomethylating agents produced early signals of efficacy, includingpotentially durable responses, though it failed to significantly improve progression-free survival or complete response rates, according to Zeidan. Subsequently, the phase 3 STIMULUS-MDS2 trial (NCT04266301), data from which were presented at the 2024 EHA Congress, assessed sabatolimab plus azacitidine (Vidaza) vs azacitidine plus placebo in 530 patients with first-line higher-risk MDS or chronic myelomonocytic leukemia. This trial showed a numerical though not statistically significant increase in overall survival with the investigational combination vs azacitidine plus placebo, Zeidan noted.

Ongoing trials of interest in this field include the phase 3 VERONA study (NCT04401748) investigating azacitidine plus venetoclax (Venclexta) vs azacitidine plus placebo in patients with newly diagnosed, higher-risk MDS. Additionally, the phase 3 ELEMENT-MDS trial (NCT05949684) is evaluating luspatercept-aamt (Reblozyl) in patients who are transfusion independent but remain anemic. Additional early-phase research includes development of the pyruvate kinase activator tebipivat (AG-946) for patients with lower-risk MDS with anemia; as well as the immune checkpoint inhibitors AK117 and bexmarilimab, which target CD47 and Clever-1, respectively, in patients with high-risk MDS, he concluded.

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Amer Zeidan, MBBS, discusses completed and ongoing research evaluating immunotherapy and other novel agents in patients with myelodysplastic syndromes.

Dr Komrokji on the Expanded Indication for Luspatercept in Lower-Risk MDS

“The FDA expanded the label for luspatercept, not just based on the MEDALIST [trial] for post-ESA [progression], but now as upfront [therapy for anemia in patients with lower-risk MDS].”

Rami Komrokji, MD, vice chair of the Malignant Hematology Department and a senior member of the Malignant Hematology and Experimental Therapeutics Program at the Moffitt Cancer Center; as well as a professor in medicine & oncologic sciences in the College of Medicine at the University of South Florida, discussed the evolution of research supporting the FDA approval of luspatercept-aamt (Reblozyl) for the treatment of anemia in patients with lower-risk myelodysplastic syndromes (MDS).

Luspatercept is a recombinant fusion protein that acts as a ligand trap targeting TGF-β ligands, Zeidan began. Its initial FDA approval 

for the treatment of anemia in patients with MDS with ring sideroblasts

 (RS) was based on data from the phase 3 MEDALIST trial (NCT02631070), which enrolled patients with lower-risk RS-positive MDS harboring 

 mutations who were transfusion dependent and had progressed on prior erythropoiesis-stimulating agent (ESA) therapy. In this study, patients were randomly assigned to receive either luspatercept or placebo, and the trial demonstrated a transfusion independence rate of 38% for at least 8 weeks in the luspatercept arm.

Building on the findings from MEDALIST, the phase 3 COMMANDS trial (NCT03682536) evaluated luspatercept in the frontline setting compared with ESAs in patients with lower-risk, transfusion-dependent MDS, regardless of RS status, Komrokji explained. The primary end point was transfusion independence for at least 12 consecutive weeks combined with a hemoglobin level increase of at least 1.5 g/dL, he noted, adding that this end point was more rigorous than that of previous studies. The study population included both RS-positive and RS-negative patients; however, it was enriched for those with RS-positive disease, he stated.

In COMMANDS, luspatercept demonstrated superior efficacy compared with ESAs, particularly in the RS-positive subgroup, according to Komrokji. Notably, the findings suggested comparable, if not more durable, responses with luspatercept in patients with RS-positive disease vs those with RS-negative disease, he reported.

, allowing its use in patients with ESA-naive, lower-risk MDS. Furthermore, updated National Comprehensive Cancer Network guidelines now list luspatercept as the preferred first-line therapy for RS-positive MDS, although they also recognize it as a valid option for RS-negative patients, Komrokji concluded.

Rami Komrokji, MD, discusses several trials that supported the FDA approval of luspatercept for the treatment of patients with MDS with anemia.

Research around the first-in-class erythroid maturation agent luspatercept-aamt (Reblozyl

 continues in an effort to solidify its place in the myelodysplastic syndrome (MDS) treatment landscape. Consequently, the phase 3b MAXILUS (NCT06045689) has been initiated with the goal of determining the safety and efficacy of starting treatment with the agent at the maximum approved dose in patients with lower-risk MDS.1

“Enthusiasm for the use of [luspatercept] came from the [phase 3] MEDALIST trial [NCT02631070], which [examined] patients with lower-risk MDS who were refractory to erythropoiesis-stimulating agents [ESAs] or patients who were unlikely to respond to such agents based on baseline serum endogenous erythropoietin levels,” Rory Shallis, MD, an assistant professor of medicine (hematology) at Yale School of Medicine in New Haven, Connecticut, explained in an interview with 

 for the treatment of anemia failing an ESA and requiring at least 2 red blood cell (RBC) units over 8 weeks in patients with very low– to intermediate-risk MDS with ring sideroblasts or with a myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.

 the agent’s indication was expanded by the FDA to include the treatment of anemia without prior ESA use in adult patients with very low– to intermediate-risk MDS who may require regular RBC transfusions.

 The approvals were based on data from MEDALIST and the phase 3 COMMANDS trial (NCT03682536), respectively.

MEDALIST was a multicenter, double-blind, placebo-controlled study that enrolled patients with very low–, low-, or intermediate-risk MDS per Revised International Prognostic Scoring System (IPSS-R) criteria.

 Eligible patients were required to have an inadequate response to prior ESA therapy, be intolerant to ESAs, or have serum erythropoietin levels exceeding 200 U/L. Those who had 5q deletions, white blood cell counts above 13 Gi/L, neutrophil levels below 0.5 Gi/L, platelet counts less than 50 Gi/L, and previous treatment with a disease-modifying agent for MDS were excluded.

Patients were randomly assigned 2:1 to receive luspatercept (n = 153) or placebo (n = 76). In the investigational arm, treatment with subcutaneous luspatercept was initiated at 1 mg/kg every 3 weeks; dose increases were permitted following the completion of the first 2 treatment cycles if the patient received at least 1 RBC transfusion in the previous 6 weeks. The 2 dose level increases allowed were to 1.33 mg/kg and then 1.75 mg/kg. Patients in both arms also received best supportive care, including RBC transfusions as needed.

Data that supported the initial FDA approval in April 2020 showed that 37.9% (95% CI, 30.2%-46.1%) of patients in the investigational arm achieved RBC transfusion independence for at least 8 weeks during weeks 1 through 24 compared with 13.2% (95% CI, 6.5%-22.9%) in the placebo arm (

 < .0001), meeting the primary end point of the study. Moreover, the 12-week RBC transfusion independence rates during weeks 1 through 24 were 28.1% (95% CI, 21.1%-35.9%) and 7.9% (95% CI, 3.0%-16.4%), respectively (

 = .0002); the 12-week transfusion independence rates during weeks 1 through 48 were 33.3% (95% CI, 25.9%-41.4%) and 11.8% (95% CI, 5.6%-21.3%), respectively (

Following the results from MEDALIST, COMMANDS was the first clinical trial to directly compare a therapy for anemia vs an ESA in ESA-naive patients with transfusion-dependent, lower-risk MDS.

 The open-label, global study enrolled adult patients with very low–, low-, or intermediate-risk MDS per IPSS-R criteria who were RBC transfusion dependent and had not undergone prior treatment with an ESA. Patients were required to receive 2 to 6 packed RBC units per 8 weeks for at least 8 weeks prior to random assignment. An endogenous serum erythropoietin concentration of less than 500 U/L was also needed.

Patients were randomly assigned 1:1 to receive luspatercept (n = 182) or epoetin alfa (Epogen; n = 181). Subcutaneous luspatercept was administered at a starting dose of 1.0 mg/kg once every 3 weeks; titration to 1.33 mg/kg and subsequently to 1.75 mg/kg was allowed. Subcutaneous epoetin alfa was given once weekly at a starting dose of 450 IU/kg with dose increases to 787.5 IU/kg and subsequently to 1050 IU/kg permitted for a total dose of 80,000 IU.

The primary end point was 12-week RBC transfusion independence with a concurrent mean hemoglobin increase of at least 1.5 g/dL during weeks 1 through 24. Hematological improvement–erythroid (HE-I) for at least 8 weeks as well as 24- and 12-week RBC transfusion independence represented key secondary end points in the first 24 weeks. Other secondary end points included 24-week RBC transfusion independence during weeks 1 through 48, time to RBC transfusion during treatment, and safety.

Data from the primary analysis of COMMANDS published in 

 demonstrated that at a median follow-up of 17.2 months (range, 10.4-27.7) in the investigational arm and 16.9 months (range, 10.1-26.6) in the control arm, 60% of patients in the experimental arm vs 35% in the control arm reached the primary end point (odds ratio [OR], 3.1; 95% CI, 2.0-4.8; 

 < .0001). The HE-I response rates were 74% vs 53%, respectively (OR, 2.8; 95% CI, 1.8-4.5; 

 < .0001). The 24-week RBC transfusion independence rates during weeks 1 through 24 were 48% vs 31%, respectively (OR, 2.3; 95% CI, 1.4-3.7; 

 = .0003); the 12-week rates were 68% vs 49%, respectively, during this time period (OR, 2.5; 95% CI, 1.6-4.0; 

 < .0001). The respective 24-week RBC transfusion independence rates during weeks 1 through 48 were 64% vs 42% (OR, 2.7; 95% CI, 1.7-4.4; 

“The toxicity profile [of luspatercept] that we saw during MEDALIST and COMMANDS [was] excellent. There were no deaths, early mortality, or increased risk of transformation to acute leukemia with this kind of intervention,” Guillermo Garcia-Manero, MD, professor, chief, Section of Myelodysplastic Syndromes, deputy chair, Translational Research, fellowship program director, Department of Leukemia, Division of Cancer Medicine, chair, faculty senate, The University of Texas MD Anderson Cancer Center in Houston, commented in a separate interview with 

MAXILUS Aims to Characterize the Profile of the Maximum Approved Dose of Luspatercept

MAXILUS is a global, open-label, nonrandomized study that is enrolling adult patients with very low–, low-, or intermediate-risk MDS according to IPSS-R criteria.

 Eligible patients are also required to have an ECOG performance status of 2 or less and receive RBC transfusions according to study criteria. Patients with clinically significant anemia, a known history or diagnosis of acute myeloid leukemia (AML), uncontrolled hypertension, and a previous allogeneic or autologous stem cell transplant are not eligible.

“[The prior studies of luspatercept] were designed with the approach of using a dose of 1 mg/kg before increasing to 1.33 mg/kg and then 1.75 mg/kg,” Garcia-Manero explained. “However, we know from MEDALIST and COMMANDS that the majority of the patients will need dose escalation. The question is, ‘Is 1 mg/kg the proper dose?’ What happens if you start luspatercept at 1.75 mg/kg?”

Eligible patients will be divided into 2 cohorts: cohort 1 is comprised of patients who did not receive prior treatment with ESAs, and cohort 2 includes patients who are relapsed or refractory to a prior ESA.

 All patients will be treated with subcutaneous luspatercept once every 3 weeks at a starting dose of 1.75 mg/kg; dose reductions will occur based on tolerance and safety.

The primary end point is RBC transfusion independence for 8 weeks with a simultaneous mean hemoglobin increase of at least 1 g/dL from week 1 to 24.

 Secondary end points include safety, number of patients who progress to AML, time to AML progression, and additional RBC transfusion independence outcomes.

“The study is well designed in terms of safety; if we see that there are no cerebrovascular events [or] other [similar] events, perhaps the dose [of luspatercept] could be increased. I am not sure that 1.75 mg/kg is the highest dose that we can use,” Garcia-Manero said. “We [tested this approach] with the ESAs 20 years ago. We used lower doses, and then we ended with significantly higher doses of these compounds. [MAXILUS] is a very important study, and I'm looking forward to the results.”

MAXILUS will enroll approximately 100 patients. The study is currently recruiting, and the estimated primary completion date is January 2026.

“[It’s important to know] that these trials exist. There’s a growing enthusiasm that this is the golden age for [MDS], but we can’t move the field forward if patients are not getting [enrolled] on these trials,” Shallis concluded.

A study to assess luspatercept in lower-risk myelodysplastic syndrome participants (MAXILUS). ClinicalTrials.gov. Updated November 11, 2024. Accessed November 22, 2024. https://clinicaltrials.gov/study/NCT06045689

FDA approves luspatercept-aamt for anemia in adults with MDS. FDA. April 3, 2020. Accessed November 22, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-luspatercept-aamt-anemia-adults-mds

U.S. FDA approves Bristol Myers Squibb’s Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes (MDS) who may require transfusions. News release. Bristol Myers Squibb. August 28, 2023. Accessed November 22, 2024. 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

Rebolozyl. Prescribing information. Celgene Corporation; 2020. Accessed November 22, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761136orig2lbl.pdf

Della Porta MG, Garcia-Manero G, Santini V, et al. Luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): primary analysis of a phase 3, open-label, randomised, controlled trial. 

. 2024;11(9):e646-e658. doi:10.1016/S2352-3026(24)00203-5

Della Porta MG, Platzbecker U, Venugopal, et al. The MAXILUS study: a trial in progress for luspatercept at maximum approved dose in patients with transfusion-dependent lower-risk myelodysplastic syndromes. Presented at: 2024 European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract PB2622.

Luspatercept-aamt (Reblozyl) is being evaluated in the phase 3b MAXILUS trial to determine its safety and efficacy at the maximum approved dose for lower-risk myelodysplastic syndrome (MDS). Previous trials, MEDALIST and COMMANDS, demonstrated its effectiveness in achieving red blood cell transfusion independence in patients with MDS, leading to FDA approvals. MAXILUS aims to explore the potential benefits of starting treatment at a higher dose, with primary endpoints focusing on transfusion independence and hemoglobin increase. The study is currently recruiting, with completion expected in January 2026.

The MAXILUS study will evaluate the maximum approved dose of luspatercept in lower-risk myelodysplastic syndrome.

MAXILUS Study Looks to Further Elucidate the Role of Luspatercept in MDS

! I’m your host today, Caroline Seymour.

, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, 

 covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

In today’s episode, supported by Bristol Myers Squibb, we had the pleasure of speaking with Rory Shallis, MD, an assistant professor of medicine and hematology at Yale School of Medicine, part of Yale New Haven Health in Connecticut.

Shallis sat down with us to share some of the research that has been generated in myelodysplastic syndrome (MDS) over the past year or so, touching on the evolution of clinical trial end points and where the field is headed in terms of therapeutic classes. He also spoke to the investigation of the late-stage erythroid maturation agent luspatercept-aamt (Reblozyl) in this population in the phase 3 ELEMENT-MDS (NCT05949684) and MAXILUS (NCT06045689) trials.

In our exclusive interview, Shallis discussed the research basis for the ELEMENT-MDS trial in MDS, the potential of intervening with luspatercept before patients become red blood cell transfusion dependent, and aspects of the trial to be aware of for patient enrollment.

That’s all we have for today! Thank you for listening to this episode of 

, supported by Bristol Myers Squibb. Check back on Mondays and Thursdays for exclusive interviews with leading experts in the oncology field.

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Dr Shallis discusses the ELEMENT-MDS trial in MDS and the potential of intervening with luspatercept before patients become RBC transfusion dependent.  

How Luspatercept Could Shake Up MDS Management—With Rory Shallis, MD

Investigators have initiated the phase 3 ELEMENT-MDS trial (NCT05949684) with the aim of expanding access to the late-stage erythroid maturation agent luspatercept-aamt (Reblozyl) to patients with non-transfusion dependent lower-risk myelodysplastic syndrome (MDS) for the treatment of anemia.

“Over the past 4 to 5 years, we have seen an uptick in our ability to approve drugs for patients with MDS,” Guillermo Garcia-Manero, MD, said in an interview with 

®. “Oral decitabine and cedazuridine [Inqovi] is now approved for MDS and is now approved for acute myeloid leukemia [AML] in Europe. Around the same time, [as the decitabine/cedazuridine approval we saw] the first indication for luspatercept [in MDS based] on [data from] the [phase 3] MEDALIST trial [NCT02631070]. Then, we had the second indication for luspatercept in frontline [MDS] for basically all-comers with transfusion dependent [MDS]. [In October 2023], we saw the approval of ivosidenib [Tibsovo] in 

-mutated MDS, and the telomerase inhibitor imetelstat [Rytelo] in second-line, transfusion-dependent disease [in June 2024].”

Garcia-Manero is the chief of the Section of Myelodysplastic Syndromes, the deputy chair of translational research, the fellowship program director, and a professor all in the Department of Leukemia, Division of Cancer Medicine, as well as the chair of the faculty senate, at The University of Texas MD Anderson Cancer Center in Houston.

“MDS is among the most heterogeneous diseases we treat, [with] a number of molecular lesions and it’s a disease of epigenetics, which has led to an absence of truly blanket approaches, beyond hypomethylating agents,” Rory Shallis, MD, an assistant professor of medicine (hematology) at Yale School of Medicine, in New Haven, Connecticut, added in a sperate interview with 

“We are seeing a transition to targeted therapies, largely borrowing from AML-style therapies, [such as] IDH inhibition, and I believe the role [of these therapies] will increase to some degree.”

In August 2023, luspatercept was approved by the FDA for the treatment of anemia in adult patients with very low- to intermediate-risk MDS who may require regular red blood cell (RBC) transfusions. The expanded indication built upon the April 2020 FDA approval of the agent for the treatment of patients with very low- to intermediate-risk MDS with ring sideroblasts or with a myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, and anemia after failure with an erythropoiesis stimulating agent who required at least 2 RBC units over 8 weeks. The regulatory decisions were supported by findings from the phase 3 COMMANDS trial (NCT03682536) and MEDALIST studies, respectively.

COMMANDS was an open-label, multicenter study that enrolled adult patients with Revised International Prognostic Scoring System (IPSS-R) very low-, low-, or intermediate-risk MDS who did not receive a prior erythropoiesis-stimulating agent (ESA), were RBC transfusion dependent, and had a serum erythropoietin concentration of less than 500 U/L. Eligible patients were randomly assigned 1:1 to receive either subcutaneous luspatercept at a dose of 1.0 to 1.75 mg/kg of body weight once every 3 weeks or once-weekly epoetin alfa at a dose of 450 to 1050 IU/kg for a maximum total dose of 80,000 IU for at least 24 weeks. The primary end point was the rate of 12-week RBC transfusion independence with a concurrent mean hemoglobin increase of at least 1.5 g/dL during weeks 1 to 24.

At respective median follow-up times of 17.2 months (range, 10.4-27.7) and 16.9 months (range, 10.1-26.6), findings from the primary analysis of COMMANDS demonstrated that patients in the luspatercept arm (n = 182) achieved the primary end point at a rate of 60% compared with 35% in the epoetin alfa arm (n = 181), with a common risk difference on response rate of 25.4% (95% CI, 15.8%-35.0%; 

 < .0001) and an odds ratio of 3.1 (95% CI, 2.0-4.8). Additionally, during weeks 1 through 24, luspatercept was found to be superior vs epoetin alfa in terms of the rate of hematologic improvement-erythroid response for at least 8 weeks (74% vs 53%; 

The phase 3 ELEMENT-MDS trial aims to expand access to luspatercept for anemia in non-transfusion dependent lower-risk MDS.

Research Efforts Seeking to Raise the Bar in Low-Risk MDS | Supplements and Featured Publications

Genetic Insights and Novel Trial Designs Contribute to an Era of Individualized MDS Management

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

Dr Zeidan on the Evaluation of Immunotherapy and Other Novel Therapies in MDS

Dr Komrokji on the Expanded Indication for Luspatercept in Lower-Risk MDS

MAXILUS Study Looks to Further Elucidate the Role of Luspatercept in MDS

How Luspatercept Could Shake Up MDS Management—With Rory Shallis, MD

Luspatercept Is Under Evaluation in Non-Transfusion Dependent Lower-Risk Myelodysplastic Syndrome

Dr Garcia-Manero on the Investigation of Luspatercept Dose Levels in Low-Risk MDS

Dr Shallis on the Utility of Luspatercept in the ELEMENT-MDS Trial in MDS