多发性骨髓瘤中的微小残留疾病：加速批准的关键监管里程碑

Minimal Residual Disease in MultipleMyeloma: A Pivotal Regulatory Milestonefor Accelerated Approval SARI HEITNER ENSCHEDE, MD, Head of Hematology, Senior Medical Strategy Lead,Hematology-Oncology Center of ExcellenceMEGAN MCCAUSLAND, Director, Flow Cytometry, IQVIA LaboratoriesFRANKLIN SEDARAT, MD, Global Head, Hematopathology, IQVIA LaboratoriesBRADLEY SMITH, PhD, Vice President Therapeutic Strategy, IQVIA Drug Development andRegulatory Strategy Table of contents Introduction1Key insights1Increasing investments and rapidadvances1Using MRD as a surrogate primary endpoint for accelerated approval3Assessing MRD at prespecified times4Using a validated MRD assay5Evolving requirements for acceleratedapproval6Recommendations for sponsors8Consider a single- or dual-trial model in the accelerated approval pathway8Engage with the FDA early in development9Summary9References10 Introduction In January 2026, the U.S. Food and Drug Administration (FDA) published draftguidance on using minimal residual disease (MRD), also known asmeasurableresidual disease, as primary endpoint to support the potential acceleratedapproval of novel treatments for Multiple Myeloma (MM).1This new guidancereflects the agency’s evolving position that MRD negativity in complete response(CR) may serve as a reasonably likely surrogate for progression-free survival(PFS) for accelerated approval, provided that evidentiary and assay validationstandards are met. For sponsors, the opportunity is significant:appropriately designed trials leveraging MRD negativitymay shorten development timelines and enableearlier product differentiation and commercialization.In this white paper, we examine the clinical andtechnical issues sponsors may need to consider whenincorporating MRD as a primary endpoint in clinical trialsfor MM. We also outline key regulatory, operational,and statistical considerations for sponsors seekingaccelerated approval based on MRD negativity inCR. Recommendations for sponsors follow, includingconsideration of sequential or parallel study designs, whether randomized or single-arm, and the importanceof early, proactive engagement with the FDA andotherstakeholders. Key insights Increasing investments andrapidadvances The MM therapeutics market is estimated at more than$20 billion. The U.S. is the largest market segment,and expectations are high for sizeable internationalgrowth(Figure 1).2 Multiple myeloma therapeutics market growth and projections Over the last two decades, the median life expectancyfor MM has more than tripled — from approximatelythree to 10 years — with many patients survivingmore than 15 years after diagnosis.3Such long-termsurvival often requires initiating or switching to adifferent treatment when disease progression occurs.Since 2000, the FDA has approved more than 20 newtherapies for MM, 10 of which were approved in the last five years (Figure 2). These approvals and the highefficacy demonstrated increase the burden on sponsorsnew to the indication with drugs entering research inlate lines of therapy. With novel treatment and higherrates of response, overall response rate (ORR), and CR,MRD can help differentiate new drugs that can achievedeeperresponses. Despite the improved outcomes achieved forMM, several unmet needs remain. Treatments areneededthat: •Continue to improve progression-free survival (PFS)and overall survival (OS)•Address MM classes with high-risk of suboptimalresponse to current treatments•Reduce toxicity and the cumulative burden oftreatment and improve quality of life•Overcome treatment resistance•Achieve demonstratable durable remission or a cure •Impact disease course earlier, especially during clinicalprecursors to MM, including: »monoclonal gammopathy of undeterminedsignificance (MGUS) »smoldering MM (SMM) •Improve long-term immune surveillance to treatprogression more rapidly Using MRD as a surrogate primaryendpoint for accelerated approval Considering the improved survival rates and increasedlife expectancy for patients with MM, developingtreatments to address the remaining unmet needscould require clinical trials that last more than 10 years.The accelerated approval pathway for serious or life-threatening diseases has offered an alternative usingORR — a surrogate endpoint that predicts clinicalbenefits and requires post-approval verification ofclinical effect or an alternative surrogate endpoint,depending on the disease. In recent trials, however, ORRrates with contemporary standard-of-care treatmenthave also increased substantially. This success is adouble-edged sword, making differentiation betweeninvestigational and control arms for novel treatmentsmore challenging within feasible timelines andstudy population sizes.4The new FDA draft guidancerecommending MRD negativity in patients with CR asa surrogate primary endpoint to support acceleratedapproval may help sponsors address this challenge.1 the new guidance refers to presentations discussedat the April 2024 Oncology