Oncologists Choose Top Goals and Therapies for Treating MDS

Myelodysplastic syndrome (MDS) is a heterogeneous clonal hematologic neoplasm defined by cytopenias, dysplasia, and clonal cytogenetic and molecular abnormalities.¹ The heterogeneity is evident in that prognosis can range from months to over 10 years, depending on the features of the MDS. Therefore, making the diagnosis and risk stratification as precise as possible is imperative in the selection of treatment.

MDS had a refinement in diagnosis with an update from the World Health Organization and International Consensus Criteria (ICC) in 2022, in addition to a new risk stratification system called Molecular International Prognostic Scoring System (IPSS-M). One of the defining features of the new diagnosis system includes the definition of MDS based on specific molecular abnormalities such as SF3B1 and TP53. In the case of ICC, there was the creation of a new subgroup called MDS/AML.

The IPSS-M added specific molecular abnormalities known to be either higher risk or lower risk to further define from the Revised IPSS system.² These systems are important as they define recommended treatment, with lower-risk MDS (LR-MDS) treatment goals centered around improving symptoms and cytopenias for patients. In higher-risk patients, the goal is centered on disease modification.

Treatment Options in LR-MDS

For many years, options for anemia-predominant settings were transfusion support and erythroid-stimulating agents (ESAs), including darbepoetin and epoetin. After ESAs were no longer effective, there were not many options. However, more recently there has been the rise of multiple new agents.

One of these agents is luspatercept (Reblozyl), a fusion protein consisting of modified activin receptor and Fc of human immunoglobulin-1, which inhibits SMAD2/3 signaling, leading to the stimulation of red blood cell production and maturation. Luspatercept is now approved in both the ESA-refractory population via the MEDALIST trial (NCT02631070)³ and frontline via the COMMANDS trial (NCT03682536).^4-6

The MEDALIST trial was a phase 3 study with patients with ESA-refractory, low-risk MDS who require transfusions. In this trial, 38% of patients on luspatercept met the primary end point of transfusion independence for at least 8 weeks vs 13% in the placebo arm, and luspatercept was approved by the FDA in 2020.^3,7

The COMMANDS trial was a frontline trial of luspatercept vs epoetin in the ESA-naive population. The primary end point was met at primary analysis with 60% of luspatercept vs 35% on the epoetin arm (P < .0001),⁵ and luspatercept was approved by the FDA in 2023 for frontline use.⁸ The effects were more pronounced in the ring sideroblast (RS)-positive and SF3B1-mutated populations. Initial data showed similar response rates in the RS-negative population and SF3B1 populations, but long-term data showed a trend toward a longer duration of higher rates for red blood cell transfusion independence (RBC-TI) at 1.5 years or more with luspatercept in those populations (Figure).^6,7

Figure. Transfusion Independence at 1.5 Years in COMMANDS Trial Subgroups^6,7

Beyond luspatercept, there has also been the recent approval and rise of a different anemia-predominant agent in imetelstat (Rytelo). Imetelstat is an oligonucleotide telomerase inhibitor. It was approved based on the IMerge trial (NCT02598661), a phase 3 double-blind, placebo-controlled trial conducted in ESA-relapsed, ESA-refractory, or ESA-ineligible LR-MDS (low or intermediate-1 risk disease as per IPSS).⁹ The primary end point was 8-week RBC-TI, defined as the proportion of patients without RBC transfusions for at least 8 consecutive weeks. The 8-week transfusion independence rate was 39.8% vs 15.0% (P < .001). The data were consistent across the subgroups in terms of benefit and persistence over time. The median duration of transfusion independence was 51.6 vs 13.3 weeks (P < .001).

Survey Results From Case-Based Roundtable Events

The treatment paradigms in lower-risk patients with anemia have shifted in recent times. This is evident in recent discussions with oncologists.What has long been the goals for patients with LR-MDS with anemia—the main goals per oncologists in Case-Based Roundtable events from 2025—were RBC-TI and improvement in patients' quality of life (Polling Question 1). These go hand-in-hand because enough improvement in anemia to achieve transfusion independence will decrease symptoms and the time gained by patients from not having to go to transfusions will improve the patients’ quality of life.

Polling Question 1.

What is the main treatment goal for patients with LR-MDS with anemia?

In terms of when to initiate treatment, the main characteristics of concern were hemoglobin level and patient symptoms. However, there was a wide variety of factors identified (Polling Question 2). This is representative of the recent trend of considering treatment at levels of symptomatic anemia, rather than just transfusion dependence alone.

Polling Question 2.

Which patient characteristics most influence your treatment of anemia in LR-MDS? (Choose all that apply)

Finally, when it comes to what drugs were selected, ESA agents were favored over luspatercept in the frontline setting (Polling Question 3), although, the overall numbers were not too different with 36 votes (54.55%) vs 30 votes (45.45%). In the second-line setting, luspatercept was overwhelmingly the drug most commonly used, with 91% of respondents choosing it for ESA-refractory patients (Polling Question 4).

Polling Question 3.

What is your first-line treatment choice for patients with LR-MDS and a serum erythropoietin level under200 U/L?

Polling Question 4.

What treatment option would you offer an ESA-refractory patient?

Luspatercept usage and dosing is another area of interest that may also influence treatment decisions. The starting treatment dose per the FDA approval is 1 mg/kg. It is up-titrated to 1.33 mg/kg and finally to 1.75 mg/kg based on the patient’s response. For those who utilized luspatercept, only 38% of respondents (27/70) titrated to the 1.75-mg/kg dose (Polling Question 5).

Polling Question 5

If you currently use luspatercept for your patients with LR-MDS, what dose do you titrate to?

This can affect how many patients respond, as most patients need their dose titrated to the maximum dose from the MEDALIST and COMMANDS studies. Due to this, the MAXILUS study (NCT06045689) is looking at starting at a full dose of 1.75mg/kg at initiation. The study has closed to enrollment and is awaiting data readout once patients have been on the medication long enough.

Conclusions

Options continue to expand for anemia-predominant MDS. While the COMMANDS data were positive for luspatercept vs epoetin, in the poll data ESAs were still favored in the front line. The rationale for that is multifactorial. One of the reasons is familiarity with ESAs. Clinicians are comfortable using them, as they have used them for many years. ESAs also have a low adverse events profile and while luspatercept does not cause that many adverse events, there are more than with ESAs.

Next, the subanalysis data are still not convincing enough for some. Therefore, some may selectively use it in RS-positive and SF3B1-mutated populations. There are enough data to support the clear superiority of luspatercept in those populations.

Regardless of which treatment is chosen, it is an exciting time in MDS to have so many more new drugs available for patients that can provide meaningful response, improving symptoms and quality of life.

_REFERENCES:

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_{2. Bernard E, Tuechler H, Greenberg PL, et al. Molecular International Prognostic Scoring System for myelodysplastic syndromes. NEJM Evid. 2022;1(7):EVIDoa2200008. doi:10.1056/EVIDoa2200008}

_{3. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382(2):140-151. doi:10.1056/NEJMoa1908892}

_{4. Platzbecker U, Della Porta MG, Santini V, et al. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial. Lancet. 2023;402(10399):373-385. doi:10.1016/S0140-6736(23)00874-7}

_{5. 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. Lancet Haematol. 2024;11(9):e646-e658. doi:10.1016/S2352-3026(24)00203-5}

_{6. Garcia-Manero G, Santini V, Zeidan AM, et al. Long-term transfusion independence with luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, lower-risk myelodysplastic syndromes in the COMMANDS trial. Adv Ther. 2025;42(7):3576-3589. doi:10.1007/s12325-025-03208-5}

_{7. FDA approves luspatercept-aamt for anemia in adults with MDS. FDA. Updated April 6, 2020. Accessed September 9, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-luspatercept-aamt-anemia-adults-mds}

_{8. 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 September 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}

_{9. Platzbecker U, Santini V, Fenaux P, et al. Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;403(10423):249-260. doi:10.1016/S0140-6736(23)01724-5}