! 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%; 

 <.0001), 24-week RBC transfusion independence rate (48% vs 31%; 

 = .0003), and the rate of RBC transfusion lasting at least 12 weeks (68% vs 49%; 

 < .0001). The median duration of RBC transfusion independence lasting at least 12 weeks was 126.6 weeks (95% CI, 93.0-not estimable) vs 89.7 weeks (95% CI, 62.9-157.3), respectively (HR, 0.61; 95% CI, 0.40-0.95; log-rank 

In terms of safety, any-grade treatment-emergent adverse effects (TEAEs) occurred at rates of 98% in the luspatercept arm vs 93% in the epoetin alfa arm. The most common any-grade TEAEs included asthenia (15% vs 16%), diarrhea (20% vs 14%), and fatigue (19% vs 8%). Serious TEAEs were present at rates of 49% vs 43%, respectively, the most common of which included pneumonia (5% vs 7%) and COVID-19 (4% vs 6%).

MEDALIST enrolled patients with IPSS-R very low-, low-, or intermediate-risk MDS with ring sideroblasts who were intolerant of or had an inadequate response to ESAs or had a serum erythropoietin greater than 200 U/L. Patients were randomly assigned 2:1 to receive subcutaneous luspatercept at a starting dose of 1 mg/kg every 3 weeks, with 2 dose level increases to 1.33 mg/kg and 1.75 mg/kg permitted after completion of the first 2 cycles if the patient needed at least 1 RBC transfusion in the previous 6 weeks, or placebo; all patients also received best supportive care. The primary end point was the proportion of patients who achieved RBC transfusion independence for at least 8 weeks during weeks 1 through 24.

At the time of the 2020 FDA approval, patients in the luspatercept arm (n = 153) achieved the primary end point at a rate of 37.9% (95% CI, 30.2%-46.1%) compared with 13.2% (95% CI, 6.5%-22.9%) among patients in the placebo arm (n = 76), for a common risk difference of 24.6% (95% CI, 14.5%-34.6%; 

 < .0001). Additionally, patients achieved RBC transfusion independence for at least 12 weeks during weeks 1 to 24 at rates of 28.1% (95% CI, 21.1%-35.9%) vs 7.9% (95% CI, 3.0%-16.4%), respectively, and RBC transfusion independence for at least 12 weeks during weeks 1 to 48 at rates of 33.3% (95% CI, 25.9%-41.4%) vs 11.8% (95% CI, 5.6%-21.3%), respectively. These increases corresponded to respective common risk differences of 20.0% (95% CI, 10.9%-29.1%; 

 = .0002) and 21.4% (95% CI, 11.2%-31.5%; 

The most common any-grade adverse effects (AEs) in the luspatercept and placebo arms included fatigue (41% vs 22%), musculoskeletal pain (20% vs 14%), and dizziness/vertigo (18% vs 7%). Among all patients who received luspatercept (n = 242), 2.1% died, 4.5% were forced to discontinue treatment, and 2.9% had a dose reduction, due to AEs.

“The label for luspatercept [provides] patients with an indication for transfusion, even if they are not yet transfusion dependent,” Garcia-Manero said. “The field is moving towards early intervention in patients with anemia and low-risk MDS, because all of the data that we are accumulating suggest that if you start these drugs at the time or before these patients become dependent, the results will be much better.”

“The toxicity profile that we saw in MEDALIST and COMMANDS was excellent; there were no deaths, early mortality, or increased risk of transformation to AML with this intervention. [Therefore], we feel that it’s not dangerous or unethical to start this drug in this context in patients who we used to observe because the drug is safe and well tolerated,” he added.

ELEMENT-MDS Looks to Expand Luspatercept to Non-Transfusion Dependent MDS

The open-label, multicenter ELEMENT-MDS study is recruiting patients with IPSS-R very low-, low-, or intermediate-risk MDS with anemia who are non-transfusion dependent and have not received an ESA. To be eligible for the trial, patients must also have less than 5% blasts in bone marrow and less than 1% blasts in peripheral blood, a baseline endogenous serum erythropoietin level of no greater than 500 U/L, symptoms of anemia, and a baseline hemoglobin concentration of no greater than 9.5 g/dL prior to random assignment. Those with secondary MDS, and/or a history or diagnosis of AML, pure red cell aplasia and/or antibody against erythropoietin, cerebrovascular accident, transient ischemic attack, deep venous thrombosis, pulmonary or arterial embolism, arterial thrombosis, or other venous thrombosis within 6 months prior to random assignment, will be excluded.

“[In COMMANDS], findings from patients with low erythropoietin levels and a low transfusion burden prompted enthusiasm for ELEMENT-MDS,” Shallis said. “What about introducing [luspatercept] before a patient becomes RBC transfusion dependent, which is most patients with low-risk MDS at diagnosis? This is what ELEMENT-MDS is attempting to answer.”

Approximately 360 eligible patients will be randomly assigned 1:1 to receive either luspatercept once every 3 weeks at a starting dose of 1.0 mg/kg, with dose escalation up to 1.75 mg/kg, or epoetin alfa once a week at a starting dose of 450 IU/kg, with dose escalation up to 1050 IU/kg.6

The primary end point is the proportion of patients who become transfusion dependent, defined as needing at least 3 RBC units per 16 weeks, during any continuous 16-week interval during weeks 1 through 96. The proportion of patients with hemoglobin increase of at least 1.5 g/dL sustained for at least 16 weeks during weeks 1 through 48 is the key secondary end point; other secondary end points include time to RBC transfusion dependence, transfusion-free survival, time to achieve modified hematologic improvement-erythroid response, transfusion independence of at least 24 weeks, time to AML progression, safety, and quality of life.

“To be on this trial, [patients] can’t be transfusion dependent and 1 of the key eligibility criteria is symptomatic anemia, defined in 1 of 4 ways: fatigue, dizziness, weakness, or shortness of breath,” Shallis added. “It’s subjective and patients also need to have hemoglobin [levels] of less than 9.5 g/dL. This might be a point [in treatment] that patients may not have reached yet, and it might take time to accrue [patients] in this trial.”

Zeidan AM, Komrokji RS, Buckstein R, et al. The ELEMENT-MDS trial: a phase 3 randomized study evaluating luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, non-transfusion-dependent, lower-risk myelodysplastic syndromes. 

. 2023;142(suppl 1):6503. doi:10.1182/blood-2023-178635

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 August 30, 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

FDA approves luspatercept-aamt for anemia in adults with MDS. FDA. April 3, 2020. Accessed August 30, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-luspatercept-aamt-anemia-adults-mds

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

Reblozyl. Prescribing information. Celgene; 2020. Accessed September 3, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761136orig2lbl.pdf

ELEMENT-MDS: a study to compare the efficacy and safety of luspatercept in participants with myelodysplastic syndrome (MDS) and anemia not receiving blood transfusions (ELEMENT-MDS). ClinicalTrials.gov. Updated September 2, 2024. Accessed September 3, 2024. https://clinicaltrials.gov/study/NCT05949684

Articles

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

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

Guillermo Garcia-Manero, MD, discusses the investigation of luspatercept dose levels in patients with low-risk myelodysplastic syndrome who require red blood cell transfusions.

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

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, discusses the rationale for evaluating the maximum approved dose level of luspatercept-aamt (Reblozyl) in the phase 3 MAXILUS study (NCT06045689) for patients with low-risk myelodysplastic syndrome (MDS) who require red blood cell (RBC) transfusions.

MAXILUS is enrolling patients who have a documented diagnosis of MDS according to World Health Organization (WHO) classification and meet Revised International Prognostic Scoring System (IPSS-R) classification of very low-, low-, or intermediate-risk disease. Cohorts 1 and 2 will enroll patients who are naive to or have been previously treated with erythropoiesis-stimulating agents, respectively. All patients will receive luspatercept at the maximum approved dose of 1.75 mg/kg. The primary objective of the study is to identify the number of participants who achieve RBC transfusion independence for 8 weeks with a simultaneous mean hemoglobin increase of at least 1 g/dL from week 1 to week 24.

Garcia-Manero states that this study holds importance, given the concerns raised during the initial phase 1/2 trials. When luspatercept was first being evaluated, the FDA expressed concern about the potential for significant increases in hemoglobin levels, which may lead to serious complications such as strokes or other toxicities. These concerns were pertinent in the context of treating patients with early-stage or lower-risk MDS or anemia, where the risk of adverse effects must be weighed against the benefits of treatment; a single death due to treatment-related complications would be unacceptable, Garcia-Manero emphasizes.

To address these concerns, early-phase trials of luspatercept were designed with a cautious approach to dosing. The dosing regimen for luspatercept starts at 1 mg/kg, with the option to escalate to 1.33 mg/kg and then to 1.75 mg/kg if needed. However, data from the phase 3 MEDALIST (NCT02631070) and COMMANDS (NCT03682536) trials have shown that the majority of patients require dose escalation to achieve the desired therapeutic effect. This raises an important question about the appropriateness of the initial 1 mg/kg dose, Garcia-Manero explains. Given the need for many patients to escalate their dose, it is worth considering whether starting at a higher dose might be more effective in maximizing the drug’s benefits from the outset, rather than using a potentially suboptimal dose for several weeks, he adds.

Starting at a higher dose may lead to quicker and more robust responses, but it also comes with the risk of exacerbating the FDA’s initial concerns about hemoglobin levels rising too rapidly. Ultimately, reevaluating the starting dose and dose escalation of luspatercept is critical in optimizing the use of this drug and ensuring that it is both effective and safe for patients, Garcia-Manero concludes.

Videos

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

Rory Shallis, MD, assistant professor, medicine (hematology), Yale School of Medicine, Yale New Haven Health, discusses the utility of luspatercept-aamt (Reblozyl) as evaluated in the phase 3 ELEMENT-MDS trial (NCT05949684) for patients with myelodysplastic syndrome (MDS).

the FDA approved treatment with luspatercept for adult patients with anemia who present with very low– to intermediate-risk MDS)

 and may require regular red blood cell (RBC) transfusions; these patients will not have had prior treatment with an erythropoiesis-stimulating agent (ESA). The initial excitement for luspatercept in this patient population emerged from the phase 3 MEDALIST trial (NCT02631070), Shallis begins. The trial showed impressive responses in a placebo-controlled setting and was followed by the phase 3 COMMANDS trial (NCT03682536), he reports.

COMMANDS enrolled RBC-dependent patients with MDS who had not previously received ESAs, Shallis continues, adding that patients were randomly assigned to receive either luspatercept or an ESA. The primary end point, which was achieved in the luspatercept arm, measured at least 12 weeks of transfusion independence across various patient subgroups, including those with low endogenous erythropoietin (EPO) levels or low transfusion burdens, he states. Those 2 patient characteristics sparked investigators’ interest in using luspatercept earlier in treatment, Shallis emphasizes.

The ELEMENT-MDS trial will assess whether luspatercept can be introduced before patients become transfusion dependent, a common situation for patients with low-risk MDS at diagnosis, he explains. This randomized trial focuses on reducing progression to transfusion dependence in ESA-naive, non–transfusion-dependent patients with low-risk MDS, Shallis imparts. Low risk is defined using the revised International Prognostic Scoring System (IPSS-R), and the trial excludes patients with low-risk MDS with deletion 5q.

Patients must have a baseline EPO level below 500 U/L to be eligible for enrollment. The trial stratifies patients by baseline EPO level, ring sideroblast status, and IPSS-R risk category, he expands. ELEMENT-MDS will include some patients with intermediate-risk MDS per IPSS-R, who represent approximately 20% of all low-risk MDS cases, Shallis notes. The primary end point will evaluate the proportion of patients who become transfusion dependent during any continuous 16-week period in weeks 1 to 96.

There is confidence that using luspatercept earlier could prevent patients from becoming transfusion dependent, theoretically delaying the accumulation of significant transfusion burdens, he says. This delay is important as it may improve post-transplant outcomes by reducing iron overload, a factor that negatively affects stem cell transplant success, Shallis concludes.

Rory Shallis, MD, discusses the utility of luspatercept in the context of the phase 3 ELEMENT-MDS trial for patients with myelodysplastic syndrome.

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

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