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

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 OncLive^®.

Luspatercept first earned FDA approval in April 2020 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.² In August 2023, 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.³ 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.⁴ 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 (P < .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 (P = .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 (P = .0003).

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.⁵ 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 The Lancet Hematology 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; P < .0001). The HE-I response rates were 74% vs 53%, respectively (OR, 2.8; 95% CI, 1.8-4.5; P < .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; P = .0003); the 12-week rates were 68% vs 49%, respectively, during this time period (OR, 2.5; 95% CI, 1.6-4.0; P < .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; P < .0001).

“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 OncLive.

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.¹ 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.⁶ 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 24.¹ 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.

References

1. 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
2. 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
3. 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
4. Rebolozyl. Prescribing information. Celgene Corporation; 2020. Accessed November 22, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761136orig2lbl.pdf
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. 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.