Early Serum Free Light Chain Response in Newly Diagnosed Multiple Myeloma: Documented Earlier Than MRD and Complementary in Prognosis

ABSTRACT

Minimal residual disease (MRD) is the standard for deep response assessment in multiple myeloma but requires bone marrow sampling. Whether early serum free light chain (sFLC) response provides independent prognostic information in real‐world, predominantly non‐transplant patients remains unclear. We retrospectively analyzed 701 patients with newly diagnosed multiple myeloma treated at a single Chinese center (2015–2021). sFLC ratio normalization (IMWG range 0.26–1.65) during the first four induction cycles was assessed using a 4‐month landmark to mitigate immortal time bias. Multivariable Cox models adjusted for R‐ISS and age, with prespecified sensitivity analyses and direct comparison with established markers and MRD. Among 701 patients (median age 64 years; ASCT 12.6%), 433 (61.8%) were classified as FLC‐normalized during C1‐C4. FLC non‐normalization was associated with inferior PFS (HR 2.10, 95% CI 1.60–2.76) and OS (HR 1.96, 95% CI 1.32–2.90) after adjustment for R‐ISS stage and age. The association persisted in baseline‐abnormal patients and after MRD adjustment. Adding sFLC status produced a modest improvement in model discrimination, supporting a complementary rather than stand‐alone prognostic role. sFLC normalization was documented earlier than MRD negativity, a pattern that persisted in a paired‐visit‐restricted sensitivity analysis, although timing comparisons remain subject to retrospective assessment schedules. Early sFLC response was associated with outcomes in newly diagnosed multiple myeloma and provided complementary, incremental prognostic information beyond established risk factors and MRD. These findings support further prospective evaluation of sFLC normalization as a pragmatic blood‐based marker for early risk stratification.