Mateos, M.V., 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. 90(4): 314-9. Abstract

Background to paper:

This paper reports a retrospective analysis of a subgroup of patients enrolled on the VISTA trial [1]. This trial demonstrated that for previously untreated, transplant-ineligible myeloma patients, bortezomib, melphalan and prednisone (VMP) was superior to melphalan-prednisone (MP) in in terms of response rate, time to progression (TTP) and overall survival (OS) [1, 2] but patients on the VMP arm experienced greater toxicity.

Since the approval of bortezomib, attempts have been made to reduce toxicity and maintain efficacy by modifying treatment schedules. Bortezomib is now given subcutaneously (SC) which has reduced the toxicity profile and improved tolerability. However, there is no clear consensus on the optimal duration of bortezomib treatment and the significance of the actual cumulative dose received.

What the paper looked at:

This paper looked to see whether an increased cumulative bortezomib dose (CBD) could improve OS in this group of patients.

A higher CBD reflected longer duration of treatment, higher dose intensity or both. The trial reviewed the 340 patients who received at least one dose of bortezomib in the VMP arm of the VISTA trial. In this group, the total CBD ranged from 1.3 to 71.2 mg/m2. The median CBD was 39 mg/m2 and this was selected as the cut off for analysis of OS in the higher and lower dose groups. The higher (≥ 39 mg/m2) and lower (< 39 mg/m2) CBD groups were well matched apart from age; the mean age in the higher dose group was 71 years vs. 74 years in the lower dose group. A statistical adjustment was applied to correct for the difference in age in the two groups.

Main findings:

OS was longer in patients who received a higher CBD than those who received a lower CBD (median 66.3 vs. 46.2 months); those receiving a lower CBD was associated with a significantly lower OS. The most common reasons for receiving a lower CBD were discontinuation or dose-reduction due to treatment-related adverse events (AEs) with 27% of patients in the lower CBD group and 4% of patients in the higher CBD group discontinuing treatment due to AEs. The most common AEs in the lower CBD group were peripheral neuropathy, neuralgia, thrombocytopenia and fatigue and in the higher CBD group, thrombocytopenia.


This is the first published report considering the impact of CBD on treatment outcome. As such, it suggests that a higher CBD, either through increased dose intensity or prolonged duration of treatment, is associated with improved survival. As this analysis was retrospective there was no randomisation between the patients who received higher or lower CBD. The only significant difference between the two groups was age and the results were robust when adjusted for this.

The analysis only considered one CBD value, 39mg/m2, which was the median dose received. It is possible that the optimal CBD is higher or lower than 39mg/m2. Ideally, a future analysis should consider more than one cut-off point to determine the significant level.

The authors described the following strategies which might achieve a higher CBD in clinical practice including SC bortezomib administration; weekly bortezomib administration; bortezomib maintenance treatment, and proactive toxicity management.

The possible impact of CBD on OS is a consideration when planning bortezomib treatment. Any review of scheduling and dose should be made on the basis of shared decision-making, taking into account individual patient factors, including current toxicity profile.

Reflection points:

  • Current UK guidelines recommend subcutaneous bortezomib use [3]
  • Weekly bortezomib was associated with a lower rate of peripheral neuropathy, a higher CBD and equal efficacy compared to twice-weekly dosing in a paper comparing bortezomib-based regimens [4]
  • There is no marketing authorisation for bortezomib as a maintenance treatment and UK access to bortezomib for maintenance is limited to available clinical trials. There is a UK Myeloma Forum position statement on the use of consolidation and maintenance treatment in myeloma [5]
  • Proactive bortezomib toxicity management includes regular assessment and timely supportive care to manage thrombocytopenia, peripheral neuropathy, fatigue and gut toxicities
  • Healthcare professionals should educate patients to be vigilant for AEs and to report these early


UKMF position statement on the use of consolidation and maintenance treatment in myeloma


NICE guidance on bortezomib and thalidomide for the first-line treatment of myeloma


  1. San Miguel, J.F., et al., Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med, 2008. 359(9): p. 906-17.
  2. San Miguel, J.F., et al., Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol, 2013. 31(4): p. 448-55.
  3. Pratt, G., et al., Updates to the guidelines for the diagnosis and management of multiple myeloma. Br J Haematol, 2014. 167(1): p. 131-3.
  4. Mateos, M.V., 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. 99(6): p. 1114-22.
  5. Rabin, N., et al., United Kingdom Myeloma Forum position statement on the use of consolidation and maintenance treatment in myeloma. Int J Lab Hematol, 2014. 36(6): p. 665-75.