Carfilzomib dosing in patients with relapsed or refractory multiple myeloma

Carfilzomib alone, and in combination with dexamethasone (Kd) or lenalidomide plus dexamethasone (KRd), is approved for the treatment of patients with relapsed and refractory multiple myeloma (RRMM).¹ Two dosing regimens are available for the Kd combination. Initially biweekly (BIW) carfilzomib dosed at 56 mg/m² plus dexamethasone at 20 mg per dose (Kd56 BIW) was approved, based on the positive results from the ENDEAVOR trial. Subsequently, CHAMPION-1 demonstrated comparable clinical benefits of weekly (QW) carfilzomib 70 mg/m² dosing plus dexamethasone at 40 mg weekly (Kd70 QW).² The results were confirmed in the larger ARROW study, which showed improved overall survival (OS) in patients who received Kd70 QW vs Kd with 27 mg/m² carfilzomib BIW (Kd27 BIW).³

Convenience of dosing regimen is recognized as an important factor in treatment adherence and patient quality of life.^4-6 Therefore, less frequent dosing would be a more convenient way to treat patients with RRMM. However, the data comparing QW and BIW regimens is limited.

Recently, two studies with such comparisons of carfilzomib regimens were published. With the lack of direct comparison of Kd70 QW and Kd56 BIW in a randomized trial, Philippe Moreau and colleagues carried out post-hoc analysis of efficacy and safety of dosing regimens used in ARROW, CHAMPION-1, and ENDEAVOR clinical trials. The results were reported in Cancer Medicine.⁷ The second study, comparing Kd70 QW and Kd27 BIW, was a subgroup analysis of the ARROW trial performed by Meletios A. Dimopoulos and published in the Blood Cancer Journal.⁸

Kd70 QW vs Kd56 BIW⁷

Methods

Data for Kd70 QW was pooled from CHAMPION-1 (NCT01677858), a phase I/II dose-finding study of QW carfilzomib, and ARROW (NCT02412878), a phase III study comparing Kd70 QW vs Kd27 BIW.^2,3 Data from a phase III study ENDEAVOR (NCT01568866), which investigated Kd vs bortezomib + dexamethasone was used for analysis of Kd56 BIW.⁹ Patients with RRMM were eligible if they received 1–3 prior lines of therapy (2–3 in ARROW) and were not refractory to bortezomib.

In total, 240 patients in ARROW and 104 patients in CHAMPION-1 were randomized to receive Kd70 QW, and 464 patients were randomized to receive Kd56 BIW as a part of ENDEAVOR trial.

Overall response rate (ORR), progression-free survival (PFS), and the rate of treatment-emergent adverse events (TEAEs) were assessed for Kd70 QW and Kd56 BIW regimens, with July 20, 2017, as the data cut-off for ARROW, August 30, 2016, for CHAMPION-1, January 31, 2015, for PFS and ORR, and February 8, 2017, for safety for ENDEAVOR.

Main findings

• For the analysis, only data from patients with 2–3 prior lines of therapy who were not refractory to bortezomib were used, with 146 patients in the Kd70 QW group and 217 patients in the Kd56 BIW group
• Patient characteristics were generally similar between Kd70 QW and Kd56 BIW, except for a higher number of patients who had received three prior therapies (42.5% vs8%), had prior treatment with bortezomib (95.2% vs 64.1%), and were refractory to lenalidomide (79.5% vs 38.2%), respectively

Efficacy

• The ORR and PFS were similar between the groups (Table 1)

Table 1. ORR and PFS

• Regression analysis performed on data from all patients who received Kd70 QW (n = 344) or Kd56 BIW (n = 464) across all the three trials showed
  • no significant difference in PFS between Kd70 QW vs Kd56 BIW, with HR 0.91 (95% CI, 0.69–1.19; p = 0.47)
  • age, International Staging System (ISS) stage, and lenalidomide-refractory status were associated with PFS
    • Age (≥ 75 vs < 65 years), HR 0.64 (95% CI, 0.47–0.88; p = 0.006)
    • ISS stage (2–3 vs 1), HR 1.83 (95 % CI, 1.45–2.31; p < 0.001)
    • Lenalidomide refractory status (yes vs no), HR 0.45 (95% CI, 0.35–0.58; p < 0.001)
  • age, ISS stage, and lenalidomide- and bortezomib-refractory status were significantly associated with ORR
    • Age (≥ 75 vs < 65 years), HR 1.82 (95% CI, 1.14–2.92; p = 0.012)
    • ISS stage (2–3 vs 1), HR 0.51 (0.36–0.72; p < 0.001)
    • Bortezomib-refractory status (yes vs no), HR 1.96 (95% CI, 1.27–3.02, p = 0.002)
    • Lenalidomide-refractory status (yes vs no), HR 2.21 (95% CI, 1.54–3.17; p < 0.001)

Safety

• The mean relative dose intensity was 92.7 ± 9% for Kd70 QW vs 87.0 ± 14.5 for Kd56 BIW
• Overall, Grade ≥ 3 and serious TEAEs were more common in patients who received Kd56 BIW compared to those who received Kd70 QW (Table 2)
• The proportion of patients who discontinued treatment was similar for both regimens

Table 2. TEAEs in patients who received Kd70 QD in ARROW and CHAMPION-1 trials and Kd56 BIW in ENDEAVOR

Conclusion

The use of Kd70 QW and Kd56 BIW dosing regimens in patients with RRMM resulted in comparable ORR and PFS rates. However, the safety profile was more favorable with the less frequent Kd70 QW dose.

Kd70 QW vs Kd27 BIW⁸

Methods

Patients with RRMM after 2–3 lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, refractory to most recent therapy and with measurable disease were randomized to Kd70 QW or Kd27 BIW in the ARROW study. Patients in both study arms received dexamethasone 40 mg.

PFS, ORR, and safety were assessed in this preplanned subgroup analysis of patients from the intention-to-treat (ITT) population, according to age, renal function, number of prior lines of therapy, sensitivity to bortezomib, Eastern Cooperative Oncology Group performance status (ECOG PS), and ISS stage.

Main findings

• The data cut-off was June 15, 2017
• In total, from the ITT population (N = 478), 240 patients received Kd70 QW and 238 patients Kd27 BIW
• Baseline characteristics were generally balanced between treatment arms across subgroups

Efficacy

• The response rates and PFS by subgroup are presented in Tables 3 and 4
  • Compared to Kd27 BIW, Kd70 QW dosing resulted in improved clinical responses when looking at age, renal function, and prior therapies
  • Younger patients, those with better renal function, and patients who had received two prior lines of therapy appeared to particularly benefit from Kd70 QW
  • The benefit of a QW schedule was independent of bortezomib status

Table 3. Response rates and PFS by age and renal function

Table 4. Response rates and PFS by prior lines of therapy and bortezomib-refractory status

Safety

• TEAEs for QW and BIW carfilzomib by subgroup are presented in Tables 5 and 6
• The median number of cycles (Kd70 QW vs Kd27 BIW) was
  • 11 vs 6 cycles in patients aged < 65 years
  • Nine cycles for both regimens in patients aged 65–74 years
  • Ten cycles for both regimens in patients aged ≥ 75 years
• The incidence of Grade ≥ 3 TEAEs, including cardiac failure, was similar with both treatment regimens, regardless of ECOG PS (0 vs 1) and ISS stage (1/2 vs 3)

Table 5. Selected safety of QW and BIW carfilzomib by age and renal function

Table 6. Selected safety of QW and BIW carfilzomib by prior lines of therapy and bortezomib-refractory status

Conclusion

The results of subgroup analyses from the ARROW study showed similar improvements in PFS and ORR across different subgroups of patients with RRMM with QW carfilzomib dosing at 70 mg/m² vs BIW dosing at 27 mg/m², in combination with dexamethasone. The safety profile of the QW regimen in different subgroups of patients was generally consistent with that previously reported for the overall population.

Overall conclusion^7,8

Authors of both studies concluded that a QW carfilzomib dosing schedule demonstrated superior efficacy, without any additional safety concerns. The Kd70 QW regimen is a well-tolerated, effective, and convenient regimen that can benefit patients of any age, irrespective of the number of prior lines therapy or bortezomib-refractory status. The increased convenience of this regimen may lead to increased treatment adherence, especially among elderly patients, patients with restricted mobility, or those with work or other commitments.

Notably, during the COVID-19 outbreak, for patients for whom carfilzomib-containing treatment must continue due to a clinical need, QW dosing reduces the number of hospital visits and hence reduces the risk of infection.