General MM,   Patients non-eligible for transplant

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

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

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

  • 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

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)

IQR, interquartile range; SD, standard deviation; VMP, bortezomib-melphalan-prednisone

  • 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 ER 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

References
  1. San Miguel JF. et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008 Aug 28; 359(9):906–17. DOI: 10.1056/NEJMoa0801479
  2. Mateos MV. et al. Effect of cumulative bortezomib dose on survival in multiple myeloma patients receiving bortezomib-melphalan-prednisone in the phase III VISTA study. Am J Hematol. 2015 Apr; 90(4):314–9. DOI: 10.1002/ajh.23933
  3. Mateos MV. et al. Bortezomib cumulative dose, efficacy, and tolerability with three different bortezomib-melphalan-prednisone regimens in previously untreated myeloma patients ineligible for high-dose therapy. Haematologica. 2014 Jun; 99(6):1114–22. DOI: 10.3324/haematol.2013.099341
  4. VELCADE (2017) VELCADE_ (bortezomib) for injection [package insert]. Cambridge, MA: Millenium Pharmaceuticals
  5. Moreau P. et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017 Jul 1; 28(suppl_4):iv52–iv61. DOI: 10.1093/annonc/mdx096
  6. Mateos MV. et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2018 Feb 8; 378(6):518–528. DOI: 10.1056/NEJMoa1714678
  7. Parasrampuria DA. et al. Comparison of efficacy from two different dosing regimens of bortezomib: an exposure-response analysis. Br J Haematol. 2020 Feb 18. DOI: 10.1111/bjh.16446
  8. Ludwig H. et al. European perspective on multiple myeloma treatment strategies in 2014. Oncologist. 2014 Aug;19(8):829–44. DOI: 10.1634/theoncologist.2014-0042

Expert Opinion

The VISTA trial was the phase III randomized trial published more than 10 years ago and demonstrated that bortezomib added to melphalan and prednisone in the non-transplant eligible population prolonged not only the PFS but the OS. Bortezomib was given twice a week during the first four cycles followed by weekly administration during the following five cycles and this resulted in a 13% and 14% of Grade 34 peripheral neuropathy and gastrointestinal toxicity, respectively. The Spanish Myeloma Group prompted a trial in 2005 to prove that twice a week bortezomib administration during the first cycle followed by weekly administration was equally effective and safer. The explanation was the bortezomib cumulative dose. The median was 39 mg/m2 in the VISTA, similar to that reported in the Spanish Myeloma Group and in the VISTA trial, patients receiving at least 39 mg/m2 as cumulative dose had a longer OS.

This was the rationale for using the same scheme in the ALCYONE trial based on bortezomib twice a week for the first cycle followed by weekly administration for the subsequent eight cycles and the median bortezomib cumulative dose was 42.2 mg/m2 indicating that the cumulative bortezomib dose is warranted.

In the ALCYONE study it was also demonstrated that the bortezomib cumulative dose higher than 39 mg/m2 was associated with longer OS

Conclusion

The bi-weekly administration of bortezomib during the first cycle of treatment followed by weekly administration in the non-transplant eligible population allow the patients to receive a less intensive scheme with better safety profile. This allows to maintain the scheme with lower rates of discontinuations and higher bortezomib cumulative doses with impact in the survival outcomes.

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