title: Activity of 129 single-agent drugs in 228 phase I and II clinical trials in multiple myeloma.
abstract: BACKGROUND
  More than 400 preclinical studies report ≥ 1 compound as cytotoxic to multiple myeloma (MM) cells; however, few of these agents became relevant in the clinic. Thus, the utility of such assays in predicting future clinical value is debatable.
  
  
  METHODS
  We examined the application of early-phase trial experiences to predict future clinical adoption. We identified 129 drugs explored as single agents in 228 trials involving 7421 patients between 1961 and 2013.
  
  
  RESULTS
  All drugs in common use in MM (melphalan, dexamethasone, prednisone, cyclophosphamide, bendamustine, thalidomide, lenalidomide, pomalidomide, bortezomib, carfilzomib, and doxorubicin) demonstrated a best reported response rate of ≥ 22%. Older agents, including teniposide, fotemustine, paclitaxel, and interferon, also appear active by this criterion; however, if mean response rates from all reported trials for an agent are considered, then only drugs with a mean response rate of 15% partial response are in clinical use.
  
  
  CONCLUSIONS
  Our analysis suggests that thresholds of 20% for best or 15% for mean response are highly predictive of future clinical success. Below these thresholds, no drug has yet reached regulatory approval or widespread use in the clinic. Thus, this benchmark provides 1 element of the framework for guiding choice of drugs for late-stage clinical testing.
authors.affiliation: Division of Hematology, Mayo Clinic, Scottsdale, AZ.
authors.forename: K Martin
authors.initials: KM
authors.lastname: Kortuem
authors.affiliation: Division of Hematology, Mayo Clinic, Scottsdale, AZ.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Zidich
authors.affiliation: Division of Hematology, Mayo Clinic, Scottsdale, AZ.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Schuster
authors.affiliation: Division of Hematology, Mayo Clinic, Scottsdale, AZ.
authors.forename: Meaghan L
authors.initials: ML
authors.lastname: Khan
authors.affiliation: Division of Hematology-Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
authors.forename: Victor H
authors.initials: VH
authors.lastname: Jimenez-Zepeda
authors.affiliation: Division of Hematology, Mayo Clinic, Scottsdale, AZ.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Mikhael
authors.affiliation: Division of Hematology, Mayo Clinic, Scottsdale, AZ.
authors.forename: Rafael
authors.initials: R
authors.lastname: Fonseca
authors.affiliation: Division of Hematology, Mayo Clinic, Scottsdale, AZ. Electronic address: Stewart.Keith@mayo.edu.
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
mesh_terms: D000970:Antineoplastic Agents / Q000145:classification / Q000494:pharmacology / Q000627:therapeutic use*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents
keywords: Drugs; Early clinical trials; Multiple myeloma; Phase 1; Single-agent activity