Daratumumab-based therapies in R/R MM: age-based subgroup analysis of CASTOR and POLLUX studies

Although new treatments have improved outcomes for patients with multiple myeloma (MM), the benefits are mainly restricted to the younger population.¹  Elderly patients (> 65 years of age) often have lower median survival and more advanced disease.²  Yet, they are frequently considered ineligible for high-dose chemotherapy or autologous stem cell transplant.³ Maria-Victoria Mateos from the University Hospital of Salamanca, Salamanca, ES, and her colleagues reported, in Haematologica, the results of a subgroup analysis of the CASTOR (NCT02136134) and POLLUX (NCT02076009) studies. The manuscript compared outcomes for different patient age groups in these phase III trials.⁴   

Daratumumab (D) is a monoclonal antibody against CD38, which exhibits direct antitumor activity and an immunomodulatory mechanism of action. Both open-label studies were randomized and used D as a second-line treatment in combination with standard-of-care therapies in patients with MM. POLLUX⁵ looked at the benefits of adding D to lenalidomide and dexamethasone (Rd), while CASTOR⁶ focused on the efficacy of D in combination with bortezomib and dexamethasone (Vd).

Study design and patient characteristics⁴

POLLUX

• Patients received lenalidomide (25mg on days 1 to 21 of each cycle) and dexamethasone 40 mg weekly (20 mg weekly in patients aged >75 years) with or without daratumumab (16 mg/kg weekly during cycles 1 and 2, every 2 weeks during cycles 3–6, and every 4 weeks thereafter)
• Patients < 75 received a split dose of dexamethasone during daratumumab dosing weeks (20 mg before infusion and 20 mg the following day)
• Patients aged ≥ 75 years received a lower median dose of lenalidomide (210mg/cycle in the D-Rd arm and 305mg/cycle in the Rd arm) compared to patients aged 65 to 74 (333.93 mg/cycle in the D-Rd arm and 420 mg/cycle in the Rd arm)

CASTOR

• Patients received 8, 21-day cycles of bortezomib (1.3 mg/m2 on Days 1, 4, 8, and 11) and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12; for a total dose of 160 mg/cycle during cycles 1 to 8) with or without daratumumab (16 mg/kg weekly in cycles 1 to 3, every 3 weeks during cycles 4 to 8, and every 4 weeks thereafter)

Table 1. Patient characteristics by age group - POLLUX and CASTOR studies.

Key findings

• In both studies, there was a clinical benefit of adding D to standard therapy, which was maintained in the intent-to-treat (ITT) population for longer
• There was a higher percentage of patients with minimal residual disease (MRD)-negative status amongst those who received D plus the standard therapy
• In POLLUX, median progression-free survival (PFS) at 18 months in the ≥75 population was significantly prolonged in the D-Rd arm compared to Rd (28.9 11.4 months; HR= 0.27; 95% CI, 0.10-0.69; p= 0.0042). Similar benefit was also observed in the 65-74 age group (median PFS not reached vs. 17.1 months; HR= 0.4; 95% CI, 0.27-0.60; p< 0.0001)
• In CASTOR, patients ≥75 had more than double the median PFS with D-Vd compared to Vd (17.9 8.1 months; HR= 0.26; 95% CI, 0.10-0.65; p= 0.0022). The younger cohort also had a more prolonged median PFS with D-Vd (18.9 vs. 6.1 months; HR= 0.25; 95% CI, 0.16-0.40; p< 0.0001)

Table 2. Selected response rates and MRD observed in ITT population in POLLUX and CASTOR studies.

Table 3. Selected response rates and MRD observed in population aged 65-74 years in POLLUX and CASTOR studies.

Table 4. Selected response rates and MRD observed in population aged ≥75 years in POLLUX and CASTOR studies.

Safety

• All patients aged ≥ 75 experienced at least one treatment-emergent adverse event (TEAE)
• POLLUX
  • 2% of older patients on D-Rd reported grade ¾ event compared to 77.1% on Rd
  • Neutropenia was the most common grade ¾ TEAE in patients aged 65-74 and ≥ 75 (D-Rd 55.3%, Rd 39.8% and D-Rd 44.8%, and Rd 31.4%, respectively)
  • Pneumonia was more common with D in both groups of patients
  • Grade 3/4 anemia was more common in the Rd group, and the difference between the treatment arms was doubled in patients aged ≥ 75 (D-Rd 10.3% and Rd 20%)
• CASTOR
  • 90% of older patients on D-Vd reported grade ¾ event compared to 74.3% on Vd
  • Thrombocytopenia was the most common grade ¾ TEAE in patients aged 65-74 and ≥ 75 (D-Rd 52.1%, Rd 32.6% and D-Rd 45.0%, and Rd 37.1%, respectively)

Conclusion

The POLLUX and CASTOR trials showed a greater benefit of adding daratumumab to Rd or Vd for the treatment of patients with R/R MM, aged over 65 years. Differences in efficacy were demonstrated between treatment arms even despite a relatively low number of patients in the group aged 75 years. The safety analysis revealed a similar rate of grade ¾ TEAEs between age groups and the overall study populations. As authors of the manuscript point out, the study could be strengthened by adding the fragility score. Overall, the study provides supporting evidence for the addition of D to the standard-of-care therapies for patients with RRMM aged below and above 75 years.