Primum non nocere: a critical analysis of early intervention clinical trials in smoldering multiple myeloma.

The approach to the management of smoldering multiple myeloma has changed over the years, which has evolved from observation towards early therapeutic intervention. Yet, a comprehensive examination of several key clinical trials reveals methodological challenges and limitations, ranging from inconsistent risk stratification of SMM to biased interpretations of results due to artifactual inflation of benefit arising from lead-time bias. Intervention for patients with a largely asymptomatic disease needs to be re-assessed carefully, where toxicities arising from treatment are not well justified. Until a more precise risk stratification is developed, the principle of "primum non nocere" (first, do no harm) should curb enthusiasm for early intervention in a condition in which a substantial number of patients will remain progression-free without treatment.