Bortezomib, Dexamethasone, and Rituximab Combination Is Effective for Newly Diagnosed Waldenström Macroglobulinemia

In a report of long-term follow-up from a phase II trial of patients with newly diagnosed Waldenström macroglobulinemia (WM), the combination of bortezomib, dexamethasone, and rituximab (BDR) led to an overall survival (OS) rate of 66 percent at seven years. These results suggest that this regimen provides a long treatment-free interval in the frontline setting, according to the study authors, led by Maria Gavriatopoulou, of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine in Greece.

“Rituximab has become a key treatment component of WM, however, it is associated with a modest response rate of about 30 percent and [a] long time to response,” Ms. Gavriatopoulou and authors wrote, leading them to combine rituximab with bortezomib, hypothesizing that the two agents may lead to “synergistic, rapid activity” in patients with newly diagnosed WM.

The authors enrolled 59 patients from 10 sites in Europe as part of the European Myeloma Network between March 2007 and June 2010. BDR combination therapy consisted of:

  • 1.3 mg/m2 of intravenous (IV) bortezomib on days 1, 4, 8, and 11 during the first 21-day cycle
  • 1.6 mg/m2 of IV bortezomib on days 1, 8, 15, and 22 during four 35-day consecutive cycles (cycles 2-5)
  • 40 mg of IV dexamethasone during cycles 2 and 5
  • 375 mg/m2 of IV rituximab on days 1, 8, 15, and 22 during cycles 2 and 5

Treatment lasted 23 weeks with no planned maintenance therapy.

Monoclonal immunoglobulin M levels were evaluated prior to each treatment cycle, and computed tomography scans were performed at three timepoints: within three months of enrollment, after BDR completion, and when disease progression was suspected.

Most patients were >65 years of age (61%) and had adverse prognostic factors (82% with a hemoglobin <11.5 g/dL; 64% with a ß2-microglobulin ≥3 mg/dL). Per the International Prognostic Scoring System for WM (IPSS WM), 45.5 percent were high-risk and 40 percent were intermediate-risk.

With a median follow-up of 86 months, 85 percent of patients in the intent-to-treat population responded to BDR treatment:

  • 3% had a complete response (CR)
  • 7% had a very good partial response (VGPR)
  • 58% had a PR
  • 17% had a minor response

The major response rate (any response better than PR) was 68 percent.

The median time to first response was three months, “however, four of these responders (8%) achieved their best response six months after treatment completion,” the authors reported.

The median time to best response was five months, and the median duration of a major response was 64.5 months.

The median progression-free survival (PFS) was 43 months (95% CI 23-63), and 10 patients (17%) were still in remission after a median of 90 months (range = 73.5-112 months).

When investigators looked at PFS according to IPSS risk stage, they found that “response rates were not affected by IPSS WM and depth of response did not correlate with PFS, but the number of patients who achieved CR/VGPR was relatively small.” Seven-year PFS was 62.5 percent for low-risk, 42 percent for intermediate-risk, and 15 percent for high-risk disease; OS was 87.5 percent for low-risk, 68.2 percent for intermediate-risk, and 48 percent for high-risk disease.

Treatment-related adverse events included peripheral neuropathy (46%) and neuropathic pain (20%). “At the time of last follow-up, peripheral neuropathy resolved completely or to grade 1 in all patients,” Dr. Gavriatopoulou noted.

Forty patients (68%) had progressive disease or died due to WM, while nine patients (15%) died due to unrelated causes. Among the patients who progressed, 21 received second-line treatment with rituximab-based regimens (n=17), rituximab monotherapy (n=1), fludarabine (n=1), or alemtuzumab (n=2). Median time to next treatment was 73 months, and most patients (80.9%; n=17) responded to second-line treatment.

Given these results, the authors concluded that “BDR given for 23 weeks induced responses even in high-risk patients with a long PFS of 43 months,” the authors wrote. “Moreover, patients who relapse after BDR have high probability of response to other rituximab-based regimens.”

The study is limited by its small patient population and single arm design, and the authors noted that future studies should evaluate whether adding ibrutinib (which was recently approved by the U.S. FDA for treatment-naïve and relapsed/refractory WM patients) could “improve disease control and increase CR rate in potentially ‘curable’ patients,” Dr. Gavriatopoulou concluded.

Based on the results from this phase II study, the European WM Consortium is conducting a phase III study of dexamethasone, rituximab, and cyclophosphamide with or without bortezomib in this patient population.


Reference

Gavriatopoulou M, García-Sanz R, Kastritis E, et al. BDR in newly diagnosed patients with WM: final analysis of a phase 2 study after a minimum follow up of 6 years. Blood. In press.

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