AMBER

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White D, et al. "Results from AMBER, a randomized phase 2 study of bevacizumab and bortezomib versus bortezomib in relapsed or refractory multiple myeloma". Cancer. 2012. 119(2):339-347.
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Clinical Question

In patients with relapsed or refractory multiple myeloma (MM), does bevacizumab added to bortezomib improve progression free survival (PFS)?

Bottom Line

The addition of bevacizumab to bortezomib in unselected patients with pretreated multiple myeloma did not result in significant improvements in efficacy outcomes.

Major Points

Angiogenesis is thought to be important in multiple myeloma. Anti-angiogenic agents such as bevacizumab have been postulated to have a benefit in multiple myeloma. This study suggests a lack of benefit combined with the proteasome inhibitor bortezomib in unselected patients. The combination was well tolerated.

Design

  • Multicenter, blinded, randomized, placebo-controlled phase 2 trial
  • Randomization stratified according to the number of prior treatments received (1 or >1) and the β2-microglobulin level (<3.5 mg/L or ≥3.5 mg/L)
  • N=102
    • Bortezomib+bevacizumab (n=49)
    • Bortezomib+placebo (n=53)
  • Setting: 36 centers in Canada (2) and the United States (34)
  • Enrollment: 2007-2009
  • Follow-up: 13.3 months
  • Analysis: Intention-to-treat
  • Primary outcome: Progression-free survival (PFS)

Population

Inclusion Criteria

  • Age ≥18 years
  • Relapsed or refractory MM (after 1-3 prior treatment regiments)
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Measurable disease (M-spike ≥1 g/dL and UPEP ≥ 200 mg/dL)

Exclusion Criteria

  • Cytopenias
  • Normal renal and liver function
  • No MM therapies within 21 days before initiation of study treatment
  • History of hypertensive crisis
  • Uncontrolled hypertension
  • Ongoing congestive heart failure or decrease in left ventricular ejection fraction
  • A history of myocardial infarction, stroke, or transient ischemic attack within 6 months
  • Bleeding
  • Significant vascular disease

Baseline Characteristics

  • Mean age: 65 years
  • Approximately Half had >1 prior treatment
  • Prior bortezomib treatment: 18.9% (placebo arm) vs. 16.3% (bevacizumab arm)
  • See Table 1 in manuscript for additional details.

Interventions

  • Randomized to bortezomib+bevacizumab or bortezomib+placebo
    • Bortezomib dosing: 1.3 mg/m² IV on days 1, 4, 8, 11, and q21d
    • Bevacizumab or placebo dosing: 15 mg/kg IV q21d
  • Maximum of 8 cycles
  • Treatment until disease progression, unacceptable toxicity, off study treatment, or withdrawal of consent

Outcomes

Comparisons are bortezomib+bevacizumab therapy vs. bortezomib+placebo therapy.

Primary Outcomes

Median PFS
6.2 months vs. 5.1 months (stratified H: 0.743, 95%CI, 0.43-1.28, log-rank P=0.2804)

Secondary Outcomes

Overall response rate (ORR, defined as stringent complete remission, complete remission, very good partial response)
51% vs. 43.4% (95% CI for difference -11.7% to 27%; P=0.4029)
Median duration of response
6.9 months vs. 6.0 months (stratified HR 0.956; 95% CI 0.404-2.261)
Overall survival (OS), median
Not estimable vs. 24.0 months (estimated stratified HR 0.633; 95%CI 0.258-1.552; log-rank test, P=0.3134)
Safety and tolerability -- any adverse event (AE), ≥grade 3
82% vs. 68%

Two patients who were randomized to the bortezomib-plus-placebo arm received 1 dose of bevacizumab in error while on study and were analyzed as bevacizumab-treated patients.

Adverse Events

The combination was well tolerated, and no new safety concerns for either agent were identified. More grade 5 (death) events were reported in the bortezomib+bevacizumab arm.

Criticisms

  • Bortezomib may lower tumor cell VEGF secretion on its own and therefore further anti-angiogenic therapy may not add to clinical benefit
  • Given ~20% of patients had prior bortezomib treatment, this population may have required more extensive proteasome inhibition and/or the addition of dexamethasone to produce a greater response
  • Other trials/authors have suggested that future trials of anti-VEGF therapy in MM should focus on patients with higher expressing VEGF myeloma cells. The AMBER results may reflect an unselected population (for VEGF expresion).
  • A randomized phase 2 study may not be adequately powered to show differences in PFS
  • Median PFS was improved with the addition of bevacizumab, just not statistically significant -- stratified HR of PFS for bortezomib+placebo arm was 0.743 (95% CI 0.43-1.28; log rank P=0.2804).

Funding

Sponsored by Genentech. Three of four authors are Genentech employees, and the fourth received lecture fees from Genentech.