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Study Summary: Carfilzomib + Dexamethasone Versus Bortezomib (SC or IV) + Dexamethasone in Relapsed or Refractory Multiple Myeloma (ENDEAVOR Secondary Analysis)

Article

Background

In 2016, more than 30,000 Americans were diagnosed with multiple myeloma (MM) and more than 12,000 Americans died from the disease. Despite the development of additional treatment options, most patients will experience relapse and the 5-year survival rate is 48.5%. One of the most common treatment regimens for relapsed or refractory MM is bortezomib and dexamethasone. Study results suggest that subcutaneous (SC) bortezomib may be better tolerated than intravenous (IV) bortezomib with similar efficacy.1

Carfilzomib, an irreversible proteasome inhibitor that is approved for patients with MM who previously received multiple lines of therapy, has shown robust activity in patients with MM, both as a monotherapy and in combination with other anti-myeloma agents.1

In the phase 3 ENDEAVOR trial, patients received carfilzomib plus dexamethasone or bortezomib plus dexamethasone; bortezomib was administered via either the SC or IV route. This secondary analysis of the ENDEAVOR trial data compared outcomes among patients who received carfilzomib plus dexamethasone or bortezomib (SC or IV) plus dexamethasone.1

Study Design

The ENDEAVOR trial was a phase 3, open-label, multicenter trial of patients with relapsed or refractory MM who had received 1 to 3 previous lines of therapy. In this trial, patients were randomized 1:1 to receive either carfilzomib plus dexamethasone or bortezomib plus dexamethasone. To balance patient baseline characteristics, prior to randomization to carfilzomib or bortezomib, patients were preselected to receive either SC bortezomib or IV bortezomib if randomized to the bortezomib arm. Thus, there were 4 patient subgroups: 1) patients who were randomized to receive carfilzomib but had been preselected for SC bortezomib, 2) patients who were randomized to receive carfilzomib but had been preselected for IV bortezomib, 3) patients who received SC bortezomib, and 4) patients who received IV bortezomib.

In the carfilzomib plus dexamethasone arm, patients received carfilzomib on days 1, 2, 8, 9, 15, and 16 of each cycle (20 mg/m2 on days 1 and 2 of cycle 1 and 56 mg/m2 thereafter), and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle. In the bortezomib plus dexamethasone arm, patients received either SC or IV bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 during each cycle.1

The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate, duration of response (DoR), rate of grade ≥2 peripheral neuropathy, and safety.1

Results

Baseline Characteristics

Of the 435 patients who received bortezomib plus dexamethasone, 360 patients received SC bortezomib and 75 patients received IV bortezomib. Patient baseline characteristics were generally similar among all subgroups.1

Efficacy

PFS was significantly improved with carfilzomib plus dexamethasone versus bortezomib plus dexamethasone, regardless of the route of administration of bortezomib (P <.0001). Median PFS was not reached among patients who received carfilzomib but had been preselected for SC bortezomib, 22.2 months for patients who received carfilzomib but had been preselected for IV bortezomib, 9.5 months for patients who received SC bortezomib, and 8.5 months for patients who received IV bortezomib. Likewise, PFS was significantly improved with carfilzomib plus dexamethasone versus bortezomib plus dexamethasone in patients who previously received bortezomib (SC, P = .0018; IV, P = .0002) and in those who were bortezomib-naïve (SC, P <.0001; IV, P = .0084). Among patients with prior bortezomib exposure, median PFS was 13.4 months among patients who received carfilzomib but had been preselected for SC bortezomib, 22.2 months for patients who received carfilzomib but had been preselected for IV bortezomib, 8.4 months for patients who received SC bortezomib, and 6.5 months for patients who received IV bortezomib. Among patients who were bortezomib-naïve, median PFS was not reached among patients who received carfilzomib but had been preselected for SC bortezomib, 17.7 months for patients who received carfilzomib but had been preselected for IV bortezomib, 11.2 months for patients who received SC bortezomib, and 9.4 months for patients who received IV bortezomib.1

There were higher rates of complete responses or better with carfilzomib plus dexamethasone (SC, 11.8%; IV, 14.8%) versus either formulation of bortezomib plus dexamethasone (SC, 6.1%; IV, 6.7%); results were similar for patients with prior bortezomib exposure. Likewise, median DoR was improved with carfilzomib plus dexamethasone (SC, not reached; IV, 21.3 months) versus either formulation of bortezomib plus dexamethasone (SC, 11.1 months; IV, 10.0 months); this was true regardless of prior bortezomib exposure.1

Safety

Of the 20 patients who switched from IV bortezomib to SC bortezomib, 14 experienced peripheral neuropathy (any grade). The rate of grade ≥2 peripheral neuropathy was lower with carfilzomib plus dexamethasone versus either formulation of bortezomib plus dexamethasone. Over 90% of patients in each subgroup experienced ≥1 treatment-emergent adverse event (AE). Herpes zoster (any grade) was reported in 0.3% (SC) and 0.9% (IV) of carfilzomib plus dexamethasone-treated patients and in 4.2% (SC) and 1.3% (IV) bortezomib plus dexamethasone-treated patients. Regardless of the route of bortezomib administration, rates of grade ≥3 hypertension, cardiac failure, and acute renal failure were higher with carfilzomib plus dexamethasone versus bortezomib plus dexamethasone. The percentages of patients who experienced treatment discontinuations due to AEs or AEs leading to death were similar with carfilzomib plus dexamethasone and bortezomib plus dexamethasone.1

Conclusion

Treatment with carfilzomib plus dexamethasone was superior to treatment with bortezomib plus dexamethasone, regardless of the route of administration (SC or IV) of bortezomib.1

Reference

1. Goldschmidt H, Moreau P, Ludwig H, et al. Carfilzomib-dexamethasone versus subcutaneous or intravenous bortezomib in relapsed or refractory multiple myeloma: secondary analysis of the phase 3 ENDEAVOR study. Leuk Lymphoma. 2018;59(6):1364-1374. doi: 10.1080/10428194.2017.1376743.

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