Garcia-Sanz, R., et al. Zoledronic acid as compared with observation in multiple myeloma patients at biochemical relapse: results of the randomised AZABACHE Spanish trial. Haematologica, 2015. 100(9):1207-1213. Abstract.

Background to paper:

Intravenous bisphosphonate treatment is the standard of care to reduce the risk of bone disease in myeloma patients. In addition to their role in preventing skeletal-related events, bisphosphonates have been shown in a number of studies to exert clinical benefit when administered alongside conventional anti-myeloma treatments. For example, in the Myeloma IX trial1 newly diagnosed myeloma patients on zoledronic acid (ZA) had longer progression free survival (PFS) and overall survival (OS) than those on sodium clodronate. However, interpretation of these data are complicated because patients were also receiving conventional anti-myeloma treatment, making it difficult to determine whether there was a direct anti-tumour effect of ZA.

When myeloma relapses, the best time to initiate salvage treatment and reintroduce bisphosphonates can be uncertain. If there is no evidence of high tumour burden or aggressive relapse, observation with close monitoring is a suggested approach2, 3; such patients therefore represent an ideal group in which to investigate the anti-myeloma effect of ZA.

What the paper looked at:

This paper is based on the AZABACHE (Analysis of Zoledronic Acid therapy in MM in BioChemical relapse) trial2 and analysed the anti-myeloma effect of ZA monotherapy by investigating patients at the time of asymptomatic biochemical relapse, defined as 25% increase in the paraprotein from the lowest response value without clinical symptoms or myeloma defining events4.

This was a randomised, open-label, Phase IV trial of standard supportive care alone (control arm) against supportive care plus ZA. Patients in the ZA arm received 4mg every four weeks, for a total of 12 doses. One hundred patients in biochemical relapse were recruited, 51 to the ZA arm and 49 to the control arm. The groups were well matched for past history and prognostic features. Four patients, all from the ZA arm, left the trial early.

The main trial endpoint was time to next treatment; a significant increase in paraprotein levels5 was considered an indication for treatment. The trial also looked at time to clinical symptoms, nature of clinical relapse, and skeletal-related events.

Main findings:

Myeloma responses in terms of time to next treatment and emergence of clinical symptoms were not significantly different between the ZA and control groups. However, the proportion of patients progressing to symptomatic disease was significantly lower in the ZA treated group. The table below summarises the key endpoints assessed.

Outcomes by trial arm

Zoledronic acid
(n=51)		 Supportive care only (n=49) p value
Time to clinical symptoms 16 months 10 months 0.161
Progression to symptomatic disease 67% 83% 0.05
Time to next treatment 13.4 months 10.1 months 0.360
3-year projected treatment free rate 22% 16% 0.360
4-year projected SRE 6% 40% <0.001
Nature of clinical relapse

 

 More anaemia More advanced bone disease and hypercalcaemia
Projected overall survival at 3 years 73% 46% 0.161

The three year overall survival in those with a new SRE was 31% against 66% in those without (P=0.047).

Discussion:

This study showed that ZA did not lead to a reduction in biochemical markers or significantly delay time to next treatment in patients at biochemical relapse, and therefore does not support a direct anti-tumour effect of ZA. However, it did show that ZA significantly reduced progression to symptomatic disease and incidence of SRE; this benefit was most striking in patients with advanced myeloma bone disease. The authors suggest this reduction in SREs may help explain the trend to a longer overall survival observed for patients in the ZA group. The evidence of clinical benefit adds weight to the argument for the use of ZA for patients at biochemical relapse. The authors of the paper propose that ZA monotherapy should be considered a new standard of care for asymptomatic biochemical relapse of myeloma.

 

 

Reflection points

  • Many myeloma patients experience asymptomatic biochemical relapse which does not necessarily indicate an immediate need to start anti-myeloma treatment
  • Practice currently varies in the use of bisphosphonates in myeloma, including optimal duration and reintroduction of treatment
  • These data suggest ZA alongside standard supportive care may be beneficial in this group of patients by reducing the incidence of SRE and may improve outcome
  • ZA monotherapy at asymptomatic biochemical relapse should be considered as a new standard of care

Relevant resources:

Myeloma UK Nursing Best Practice Guides: Myeloma bone disease

Guidelines:

Guidelines for the diagnosis and management of multiple myeloma 2014

Guidelines for supportive care in multiple myeloma 2011

References

  1. Morgan, G.J., et al., First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet, 2010. 376(9757): p. 1989-99.
  2. Nooka, A.K., et al., Treatment options for relapsed and refractory multiple myeloma. Blood, 2015.
  3. Dimopoulos, M.A., et al., Current treatment landscape for relapsed and/or refractory multiple myeloma. Nat Rev Clin Oncol, 2015. 12(1): p. 42-54.
  4. Palumbo, A., et al., International myeloma working group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J Clin Oncol, 2014. 32(6): p. 587-600.
  5. Rajkumar, S.V., et al., Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood, 2011. 117(18): p. 4691-5.