Optimal dosing of bortezomib in multiple myeloma based on the results of an exposure-response analysis

The initial results of the VISTA study, evaluating efficacy and safety of bortezomib-melphalan-prednisone (VMP) compared to melphalan-prednisone (MP), demonstrated that whilst VMP provided a benefit over MP, the intensive dosing of bortezomib (1.3 mg/m² twice weekly for four 6-week cycles followed by once weekly for five 6-week cycles) especially during the first four weeks was associated with increased risk of treatment-related toxicity.¹

However, the received cumulative dose of bortezomib rather than the planned dose was shown to contribute to the optimal clinical outcome with VMP, with reduced toxicity but a similar level of efficacy seen in studies using a less intense, once-weekly dosing.^2,3 Therefore, the recommended dosing schedule was modified and is currently nine 6-week cycles, once-weekly.^4,5 The recent phase III ALCYONE trial, evaluating the combination of daratumumab, a CD38-targeting monoclonal antibody, with VMP vs VMP alone, used a different bortezomib dosing regimen (twice-weekly during Cycle 1 and once weekly during Cycles 2–9).⁶ Read about the updated results from the ALCYONE here.

In order to compare the efficacy of the original bortezomib dosing regimen with the less-frequent regimen over nine 6-week cycles, Dolly Parasrampuria and colleagues conducted a comparison of bortezomib exposure and outcomes using an exposure-response (E–R) analysis of VMP dosing schedule in VISTA and ALCYONE studies.⁷

Study design

The E–R analysis was performed on data from transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM) enrolled in randomized, open-label, multicenter phase III studies VISTA (NCT00111319) and ALCYONE (NCT02195479). The dosing schedules were as follows:

• VISTA– nine 6-week cycles of melphalan (9 mg/m²) and prednisone (60 mg/m²; both orally, once-daily on Days 1–4 of each cycle) +/- bortezomib (1.3 mg/m² intravenously, twice-weekly for four cycles followed by once-weekly for five cycles)
• ALCYONE – nine 6-week cycles of bortezomib (1.3 mg/m² subcutaneously twice-weekly for one cycle followed by once-weekly for eight cycles), melphalan (9 mg/m²) and prednisone (60 mg/m² orally once-daily on Days 1–4 of each cycle) +/- daratumumab (16 mg/kg intravenously, once weekly for Cycle 1, every 3 weeks for Cycles 2–9, and every four weeks thereafter until disease progression)

For consistency in the comparisons to ALCYONE data, the primary endpoint of VISTA, which was time to disease progression, was re-analyzed based on the International Myeloma Working Group (IMWG) criteria. The authors assessed the potential association between cumulative bortezomib dose for VMP dosing schedules and response, including complete response (CR), overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).

Main findings

• Patient characteristics were similar for VMP groups in both studies (Table 1)
• In both trials, there were no significant differences in rates of death during treatment between investigational regimen and control regimen groups

Table 1. Baseline disease and patient characteristics of patients receiving VMP

ISS, International Staging System; VMP, bortezomib-melphalan-prednisone *High cytogenetic risk was defined as the presence of t(4;14), t(14;16), or del17p abnormalities
Characteristics	VISTA (n = 344)	ALCYONE (n = 356)
Age, years Median (range) ≥ 75, %	71 (57–90) 31	71 (50–91) 30
ISS disease stage, % I II III	19 47 35	19 45 36
Cytogenetic profile*, % Standard risk High risk	85 15	85 15

• A summary of cumulative bortezomib dose and treatment duration for patients treated with VMP in VISTA and ALCYONE trial exposure is presented in Table 2
• Patients in ALCYONE study had: ^1,6,7
  • higher median dose exposure to bortezomib compared to VISTA despite the less frequent dosing regimen.
  • significantly longer mean exposure to bortezomib (p < 0.0001)
  • fewer treatment discontinuations due to treatment-emergent AEs (TEAEs)
    • 9% in ALCYONE vs 15% in VISTA

Table 2. Cumulative bortezomib dose and duration of treatment for patients receiving VMP in VISTA and ALCYONE studies

IQR, interquartile range; SD, standard deviation; VMP, bortezomib-melphalan-prednisone
Parameter	VISTA (n = 340)	ALCYONE (n = 354)
Cumulative bortezomib dose, mg/m2 Mean (SD) Median (IQR)	36.6 (20) 38.5 (18.5–54.3)	37.5 (15.2) 42.2 (27.2–50.6)
Number of cycles Mean (SD) Median (IQR)	5.8 (3.1) 6 (2–9)	7.2 (2.8) 9 (5–9)

• The E-R analysis revealed a positive correlation of cumulative bortezomib dose on achieving a clinical response for all efficacy endpoints in both VMP regimens
• The threshold cumulative bortezomib dose to achieve a response was
  • 1 mg/m² for ORR
  • 1 mg/m² for OS
  • 3 mg/m² for PFS
  • For CR the required dose exceeded the dose achieved in the trial
• In the ALCYONE study, 61.6% of patients (p = 0.0215) achieved the required cumulative dose for ORR, 67.2% (p = 0.0013) for OS, and 27.4% (p = 0.2398) for PFS⁶
• In the VISTA study, 53% of patients achieved the required cumulative dose for ORR, 55% for OS, and 31% for PFS¹

Analysis by cumulative dose of bortezomib

Given as ≥ 39 mg/m² vs < 39 mg/m²

• Similar to the results previously reported in VISTA¹, OS in ALCYONE was significantly increased in patients who received ≥ 39 mg/m²
  • OS HR = 0.119; 95% CI, 0.056–0.255; p < 0.0001
  • Age-adjusted HR = 0.112; 95% CI, 0.051–0.243; p < 0.0001)
• In relation to PFS in the VISTA study:
  • PFS: 0.434; 95% CI, 0.299–0.629; p < 0.0001
  • Age-adjusted PFS HR = 0.451; 95% CI, 0.308–0.660; p < 0.0001
  • The median PFS was higher in patients who received the ≥ 39 mg/m², cumulative dose: 23.1 (20.0–not estimable [NE]) vs9 (11.4–NE) months
• In relation to PFS in the ALCYONE study:
  • PFS HR = 0.280; 95% CI, 0.200–0.392; p < 0.0001
  • Age-adjusted PFS HR = 0.26; 95% CI, 0.183–0.370; p < 0.0001
  • The median PFS was also higher in patients who received the ≥ 39 mg/m², cumulative dose: 19.9 (19.1–NE) vs5 (6.8–14.6) months

Conclusion

The data from the E–R analysis of VMP dosing schedule in VISTA and ALCYONE trials suggests that a less frequent bortezomib dosing regimen offers equal benefits to patients as the intense dosing while improving tolerability and allowing longer treatment. However, the authors note that the intensive twice-weekly bortezomib dosing schedule is still the favored option for patients with renal impairment and extensive bone involvement.^7,8