Denosumab compared with zoledronic acid on PFS in multiple myeloma: exploratory results of an international phase 3 study

Abstract

An exploratory end point from a recent trial in patients with newly diagnosed multiple myeloma showed that median progression-free survival (PFS) was increased by 10.7 months with denosumab vs zoledronic acid. We performed additional analyses to identify factors that may have contributed to the favorable PFS with denosumab. Ad hoc analyses were performed for patients intending to undergo autologous stem cell transplantation (ASCT; ASCT intent), not intending to undergo ASCT (ASCT no intent), and intent-to-treat according to age (<70 or ≥70 years) and baseline renal function (≤60 mL/min or >60 mL/min creatinine clearance [CrCl]). Of 1718 patients, 930 (54.1%) were in the ASCT-intent subgroup, and 788 (45.9%) were in the ASCT-no-intent subgroup. In the ASCT-intent subgroup, frontline triplet (median PFS, not estimable vs 35.7 months; hazard ratio [HR] [95% confidence interval (CI)], 0.65 [0.47-0.90]; descriptive P = .009) or bortezomib-only (median PFS, not estimable vs not estimable; HR [95% CI], 0.61 [0.39-0.95]; descriptive P = .029) induction regimens demonstrated the strongest PFS benefit favoring denosumab vs zoledronic acid. In the ASCT-no-intent subgroup, no benefit with denosumab vs zoledronic acid was observed. PFS favored denosumab vs zoledronic acid in patients with CrCl >60 mL/min and in patients <70 years old, but no difference was observed in patients with CrCl ≤60 mL/min or patients ≥70 years old. The PFS difference observed with denosumab is one of the notable benefits reported in newly diagnosed multiple myeloma and was most pronounced in patients intending to undergo ASCT and those who received proteasome inhibitor (PI)-based triplet regimens. This study was registered at www.clinicaltrials.gov as #NCT01345019.

Conflict of interest statement

Conflict-of-interest disclosure: E.T. has received research funding from Amgen, Genesis, Janssen, and Takeda; honoraria from Amgen, Celgene, Genesis, Janssen, Medison, and Takeda; and travel expenses from Genesis, Janssen, and Takeda. N.R. has served as a consultant for Amgen, Bristol Myers Squibb, Celgene, Janssen, and Karyopharm. P.C. has served as a consultant and on the speakers’ bureau for Amgen and has received research funding from Amgen. R.G.-S. has received honoraria from Gilead, Amgen, Janssen, and Takeda; has served as a consultant for Gilead and Janssen; has received research funding from Gilead, Novartis, Amgen, Janssen, and Takeda (SEHH); has patents, royalties, or other intellectual property from Biomed-2 primers for clonality assessment; has provided expert testimony for IVS Technologies (patent recognition); and has received travel expenses from Gilead, Amgen, Janssen, and Takeda. X.L. has received honoraria from and has served as a consultant for Janssen, Celgene, Sanofi, Amgen, Takeda, Roche, Oncopeptides, Karyopharm, Harpoon Therapeutics, Novartis, and CARsgen Therapeutics. W.P. is an employee and owns stock in Amgen GmbH. Y.W. and A.G. are employees and own stock in Amgen. J.C. is an employee and owns stock in Amgen; has received research funding from Amgen; and has patents, royalties, or other intellectual property from Amgen. C.P. has received honoraria from Amgen and Janssen; has served as a consultant for Amgen, Celgene, and Janssen; and has received travel expenses from Amgen, Celgene, and Janssen.

© 2021 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Study design, treatment schema, and subgroups.aSC dose adjustments were not permitted. bPer protocol and zoledronic acid label, IV product was dose adjusted for baseline CrCl, and subsequent dose intervals were determined by serum creatinine levels. PBSC, peripheral blood stem cell; Q4W, every 4 weeks; SC, subcutaneous.

Figure 2.

Progression-free survival by intent to undergo transplant. PFS in the ASCT-intent subgroup (A) and ASCT-no-intent subgroup (B).

Figure 3.

Progression-free survival according to renal function. PFS in patients with baseline CrCl ≤60 mL/min (A), patients with baseline CrCl >60 mL/min (B), and by baseline CrCl (C).