For the past decade, it has become commonplace to provide rapid answers and early patient access to innovative treatments in the absence of randomized clinical trials (RCT), with benefits estimated from single-arm trials. This trend is important in oncology, notably when assessing new targeted therapies. Some of those uncontrolled trials further include an external/synthetic control group as an innovative way to provide an indirect comparison to a pertinent control group. We aimed to provide some guidelines as a comprehensive tool for critical appraisal of those comparisons or for performing one. We used the example of ciltacabtagene autoleucel for the treatment of adult patients with relapsed or refractory multiple myeloma after three or more treatment lines as an illustrative example. A 3-step guidance is proposed. The first step includes the definition of an estimand, which encompasses the treatment effect and targeted population (whole population or restricted to single-arm trial or external controls), reflecting a clinical question. The second step relies on the adequate selection of external controls from previous RCTs or real-world data from patient cohorts, registries, or electronic patient files. The third step consists of choosing the statistical approach targeting the treatment effect defined above, and depends on the available data (individual-level data or aggregated external data). The validity of the treatment effect derived from indirect comparisons heavily depends on careful methodological considerations included in the proposed 3-step procedure. Because the level of evidence of a well-conducted RCT cannot be guaranteed, the evaluation is more important than in standard settings.