Once-Weekly Bortezomib Produced Durable Responses, Survival in Relapsed AL Amyloidosis

Results from a phase I/II study of single-agent bortezomib suggest that a once-weekly dosing regimen produced similar efficacy results to a twice-weekly regimen — with the added benefit of improved tolerability. Bortezomib produced a durable hematologic response and promising long-term overall survival in patients with relapsed systemic light chain (AL) amyloidosis.

According to Donna E. Reece, MD, of Princess Margaret Cancer Center, Toronto, Canada, and lead author of the study published in Blood, the current study was not designed to compare a once-weekly and twice-weekly regimen, but “the findings are in accordance with prior studies of once- versus twice-weekly bortezomib administration in patients with multiple myeloma or lymphoma, in which less intensive, once-weekly dosing in the context of combination therapy improved treatment tolerability without compromising efficacy.”

AL amyloidosis is treated with many of the same approaches used in the treatment of multiple myeloma, such as high-dose melphalan followed by stem cell transplantation. However, not all patients are eligible for transplant. In those patients, several early studies have begun to explore the use of bortezomib, a proteasome inhibitor.

Dr. Reece and colleagues enrolled 70 patients with relapsed primary systemic AL amyloidosis into the CAN2007 trial. Patients were treated with increasing doses of bortezomib given once- and twice-weekly.

Prespecified maximum planned dose levels were 1.6 mg/m2 once-weekly and 1.3 mg/m2 twice-weekly, and treatment was planned for a maximum of eight cycles. Notably, 18 patients in the once-weekly and 34 patients in the twice-weekly groups received the maximum planned dose.

Hematologic responses were similar for patients in the maximum dose once-weekly group and the twice-weekly group. About two-thirds of patients responded to bortezomib at higher doses (68.8% in the once-weekly and 66.7% in the twice-weekly group), while only 38.9 percent had a confirmed response. This includes complete response rates of 37.5, 24.2, and 11.1 percent with lower doses.

These responses were durable and rapid, the authors noted: 78.8 percent and 75.5 percent of responders in the once- and twice-weekly maximum-dose groups remaining in remission for at least one year. Time to first response was 2.1 months and 0.7 months, and time to best response was 3.2 months and 1.2 months, in the once- and twice-weekly maximum dose groups. While the twice-weekly regimen appeared to result in more rapid response, toxicity appeared generally lower with the higher, once-weekly dose — with higher rates of grade ≥3 adverse events (79% vs. 50%) and discontinuations (38% vs. 28%) and dose reductions (53% vs. 22%) related to adverse events.

At the time of data cutoff, 19 percent of patients had experienced hematologic disease progression, while the overall one-year progression-free rate was 77.4 percent.

For all 70 patients, the overall one-year survival rate reached 89.6 percent, which included:

  • 93.8 percent in the 1.6 mg/m2 once-weekly group
  • 84.0 percent in the 1.3 mg/m2 twice-weekly group
  • 94.1 percent in the lower-dose group

At a median follow-up of 51.8 months, the median overall survival was 62.1 months in the maximum dose once-weekly group but was not reached in the maximum dose twice-weekly group.

Most patients (57%) went on to receive subsequent AL therapy (most commonly dexamethasone, bortezomib, lenalidomide, cyclophosphamide, melphalan, or thalidomide), leading researchers to believe that the notable overall survival reported in this study may be due, in part, to the greater availability in recent years of additional AL therapies based on novel agents.

“In the future, bortezomib might prove useful as part of initial AL treatment,” Dr. Reece and co-authors concluded, “and possibly as part of extended therapy after HDM-SCT or alternative non-transplantation therapies.”


Reference

  • Reece DE, Hegenbart U, Sanchorawala V, et al. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 September 8. [Epub ahead of print]

SHARE