title: Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma.
abstract: OBJECTIVE
  Carfilzomib-lenalidomide-dexamethasone therapy yields deep responses in patients with newly diagnosed multiple myeloma (NDMM). It is important to gain an understanding of this combination's tolerability and impact on minimal residual disease (MRD) negativity because this end point has been associated with improved survival.
  
  
  OBJECTIVE
  To assess the safety and efficacy of carfilzomib-lenalidomide-dexamethasone therapy in NDMM and high-risk smoldering multiple myeloma (SMM).
  
  
  METHODS
  Clinical and correlative pilot study at the National Institutes of Health Clinical Center. Patients with NDMM or high-risk SMM were enrolled between July 11, 2011, and October 9, 2013. Median follow-up was 17.3 (NDMM) and 15.9 months (SMM).
  
  
  METHODS
  Eight 28-day cycles were composed of carfilzomib 20/36 mg/m2 on days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg on days 1 through 21; and dexamethasone 20/10 mg (cycles 1-4/5-8) on days 1, 2, 8, 9, 15, 16, 22, and 23. Patients who achieved at least stable disease subsequently received 24 cycles of lenalidomide extended dosing.
  
  
  METHODS
  Primary end points were neuropathy of grade 3 or greater (NDMM) and at least very good partial response rates (SMM). Minimal residual disease was also assessed.
  
  
  RESULTS
  Of 45 patients with NDMM, none had neuropathy of grade 3 or greater. Of 12 patients with high-risk SMM, the most common of any-grade adverse events were lymphopenia (12 [100%]) and gastrointestinal disorders (11 [92%]). All patients with SMM achieved at least a very good partial response during the study period. Among the 28 patients with NDMM and the 12 with SMM achieving at least a near-complete response, MRD negativity was found in 28 of 28 (100% [95% CI, 88%-100%]), 11 of 12 (92% [95% CI, 62%-100%]) (multiparametric flow cytometry), 14 of 21 (67% [95% CI, 43%-85%]), and 9 of 12 (75% [95% CI, 43%-94%]) (next-generation sequencing), respectively. In patients with NDMM, 12-month progression-free survival for MRD-negative vs MRD-positive status by flow cytometry and next-generation sequencing was 100% vs 79% (95% CI, 47%-94%; P < .001) and 100% vs 95% (95% CI, 75%-99%; P = .02), respectively.
  
  
  CONCLUSIONS
  Carfilzomib-lenalidomide-dexamethasone therapy is tolerable and demonstrates high rates of MRD negativity in NDMM, translating into longer progression-free survival in patients achieving MRD negativity. Carfilzomib-lenalidomide-dexamethasone therapy also demonstrates efficacy in high-risk SMM.
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York2Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Neha
authors.initials: N
authors.lastname: Korde
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York.
authors.forename: Mark
authors.initials: M
authors.lastname: Roschewski
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York.
authors.forename: Adriana
authors.initials: A
authors.lastname: Zingone
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York.
authors.forename: Mary
authors.initials: M
authors.lastname: Kwok
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York3Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Elisabet E
authors.initials: EE
authors.lastname: Manasanch
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York4Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland5Department of Hemato.
authors.forename: Manisha
authors.initials: M
authors.lastname: Bhutani
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York4Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Nishant
authors.initials: N
authors.lastname: Tageja
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York.
authors.forename: Dickran
authors.initials: D
authors.lastname: Kazandjian
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York4Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Sham
authors.initials: S
authors.lastname: Mailankody
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York.
authors.forename: Peter
authors.initials: P
authors.lastname: Wu
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York.
authors.forename: Candis
authors.initials: C
authors.lastname: Morrison
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York.
authors.forename: Rene
authors.initials: R
authors.lastname: Costello
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York.
authors.forename: Debra
authors.initials: D
authors.lastname: Burton
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York.
authors.forename: Marcia
authors.initials: M
authors.lastname: Mulquin
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York.
authors.forename: Diamond
authors.initials: D
authors.lastname: Zuchlinski
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York.
authors.forename: Liz
authors.initials: L
authors.lastname: Lamping
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York.
authors.forename: Ashley
authors.initials: A
authors.lastname: Carpenter
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Wall
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York.
authors.forename: George
authors.initials: G
authors.lastname: Carter
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York.
authors.forename: Schuyler C
authors.initials: SC
authors.lastname: Cunningham
authors.affiliation: Hematology Service, Department of Laboratory Medicine, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
authors.forename: Verena
authors.initials: V
authors.lastname: Gounden
authors.affiliation: Department of Pharmacokinetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Tristan M
authors.initials: TM
authors.lastname: Sissung
authors.affiliation: Department of Pharmacokinetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Cody
authors.initials: C
authors.lastname: Peer
authors.affiliation: Hematology Service, Department of Laboratory Medicine, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
authors.forename: Irina
authors.initials: I
authors.lastname: Maric
authors.affiliation: Hematology Service, Department of Laboratory Medicine, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Calvo
authors.affiliation: Hematology Service, Department of Laboratory Medicine, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
authors.forename: Raul
authors.initials: R
authors.lastname: Braylan
authors.affiliation: Lab of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Constance
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Lab of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Maryalice
authors.initials: M
authors.lastname: Stetler-Stevenson
authors.affiliation: Lab of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Diane C
authors.initials: DC
authors.lastname: Arthur
authors.affiliation: Sequenta Inc, San Francisco, California.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Kong
authors.affiliation: Sequenta Inc, San Francisco, California.
authors.forename: Li
authors.initials: L
authors.lastname: Weng
authors.affiliation: Sequenta Inc, San Francisco, California.
authors.forename: Malek
authors.initials: M
authors.lastname: Faham
authors.affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Liza
authors.initials: L
authors.lastname: Lindenberg
authors.affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Karen
authors.initials: K
authors.lastname: Kurdziel
authors.affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Peter
authors.initials: P
authors.lastname: Choyke
authors.affiliation: Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: Department of Pharmacokinetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: William
authors.initials: W
authors.lastname: Figg
authors.affiliation: Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York2Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ola
authors.initials: O
authors.lastname: Landgren
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000235:genetics; D003907:Dexamethasone / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008396:Maryland; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D009316:National Institutes of Health (U.S.); D018365:Neoplasm, Residual; D009842:Oligopeptides / Q000008:administration & dosage* / Q000009:adverse effects; D010865:Pilot Projects; D061988:Proteasome Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D012307:Risk Factors; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D013792:Thalidomide; C524865:carfilzomib; D003907:Dexamethasone; D000077269:Lenalidomide