In Multiple Myeloma, Carfilzomib Bests Bortezomib, But Bortezomib Bests Observation

Two multiple myeloma (MM) studies – one in relapsed disease and the other in newly diagnosed disease after autologous stem cell transplantation (ASCT) – support the use of proteasome inhibitor therapy in these settings.

The first, the phase III, open-label, multicenter ENDEAVOR study, compared carfilzomib plus dexamethasone (Kd) with bortezomib plus dexamethasone (Vd) in 929 patients with relapsed MM – all of whom had received up to three prior treatments.1

While Kd is approved in the United States for relapsed and refractory MM at 20/27 mg/m2 over 2-10 minutes, earlier-phase studies determined that a dose of 20/56 mg/m2 over 30 minutes (the maximum tolerated dose of Kd) led to higher response rates in this population, said study presenter Meletios A. Dimopoulos, MD, from the University of Athens in Greece during the American Society of Clinical Oncology meeting (ASCO).

Patients were randomized 1:1 to cycles of Kd or Vd repeated until disease progression or unacceptable toxicity. Nearly one-fourth had high-risk cytogenetic features.

After a median follow-up of 11.2 months, the primary endpoint of progression-free survival (PFS) was 18.7 months for Kd and 9.4 months for Vd (p<0.0001), with twice as many patients achieving a complete response (CR; 13% vs. 6%) or very good partial response (VGPR; 54% vs. 29%).

While Kd had increased rates of grade ≥3 hypertension (9% vs. 3%), dyspnea (5% vs. 2.2%), and cardiac failure (5% vs. 1.8%) than Vd, rates of grade ≥2 peripheral neuropathy were significantly lower with Kd (6% vs. 32%; p<0.0001).

“Carfilzomib with dexamethasone was superior to bortezomib with dexamethasone regardless of age or prior bortezomib exposure,” Dr. Dimopoulos concluded, noting that the drug combination could represent a new standard of care for MM.

For patients with newly diagnosed MM following ASCT, however, bortezomib is an effective consolidation therapy, according to an analysis of two phase III trials comparing bortezomib with observation conducted by Christian Straka, MD, and colleagues, which was also presented at ASCO’s annual meeting. The first trial (MMY3012) included 222 patients ≤60 years old, and the second trial (MMY3013) included 158 patients 61-75 years old.2

Dr. Straka, from Schön Klinik Starnberger See in Berg, Germany, noted that, while high-dose therapy followed by ASCT remains the standard treatment in this patient population, consolidation therapy is an attractive treatment option that warrants further investigation.

In both studies, patients (total N=371; median age = 59 years) were randomized 1:1 to receive bortezomib (1.6 mg/m2 IV on days 1, 8, 15, 22 in four 35-day cycles) or observation only.

At the end of treatment, response rates (including “very good partial responses” and higher, both before and after consolidation therapy) were greater for the 186 patients treated with bortezomib than those in the 185 patients undergoing observation (p=0.0035). The same was true for PFS from the start of induction therapy, the study’s main endpoint: 33.6 months versus 27.8 months (HR=0.70; 95% CI 0.55-0.90; p=0.0058).

Hazard ratios favored bortezomib consolidation for all subgroups assessed (age, with/without cytogenetic abnormalities, degree of response at randomization). At a median follow-up of 51 months, overall survival had not been met in either treatment group.

The bortezomib dosing regimen was “generally well-tolerated,” the study authors wrote, with the most common treatment-related adverse events being gastrointestinal events.

After bortezomib consolidation therapy, Dr. Straka concluded, a higher proportion of patients achieved a VGPR or greater, PFS was improved by about six months, and particular benefit was seen in patients with less than a VGPR and those with “high-risk” cytogenetics.


References

  1. Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in patients (pts) with relapsed multiple myeloma (RMM): Results from the phase III study ENDEAVOR. Abstract #8509. Presented at the 2015 American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, June 1, 2015.
  2. Straka C, Vogel M, Muller J, et al. Results from two phase III studies of bortezomib (BTZ) consolidation vs observation (OBS) post-transplant in patients (pts) with newly diagnosed multiple myeloma (NDMM). Abstract #8511. Presented at the 2015 American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, June 1, 2015.

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