Association of Morbid Progression With Overall Survival Among Patients With Multiple Myeloma: Validation of the Progression-free Survival Endpoint.

Introduction: Multiple myeloma (MM) is an incurable malignancy, marked by end-organ damage that is frequently irreversible. Progressive disease (PD) can be defined as morbid PD, associated with new-onset hypercalcemia, renal insufficiency, anemia, or lytic bone lesions (CRAB symptoms), or as asymptomatic biochemical progression. The frequency of morbid versus asymptomatic PD and its effect on survival is unknown. Our aim was to determine the incidence of morbid PD, and to evaluate if this influences survival.

Patients And Methods: Data from 2 phase III trials of transplant-ineligible patients with newly diagnosed MM were included in a post hoc analysis.

Results: Of 2082 patients enrolled, 1243 (59.7%) experienced PD. At first progression, 543 (43.7%) patients had morbid PD; 12 (2.2%) had hypercalcemia, 271 (49.9%) had renal insufficiency, 370 (68.1%) developed anemia, and 79 (14.5%) developed new or enlarged bone lesions. A total of 700 (56.3%) patients had asymptomatic PD. Patients with morbid PD had worse second progression-free survival (PFS) versus patients with asymptomatic biochemical PD (median second PFS, 11.5 months vs. 20.0 months; hazard ratio, 1.63; 95% confidence interval, 1.43-1.85; P < .0001) and worse overall survival (OS) (median OS, 23.2 months vs 39.3 months; hazard ratio, 1.51; 95% confidence interval, 1.30, 1.74; P < .0001).

Conclusions: Morbid PD occurs frequently and is associated with inferior second PFS and OS. As CRAB symptoms may not reverse with therapy, morbid PD is a meaningful event, and its association with a shortened PFS adds validity to PFS as a relevant endpoint in patients with MM.