Adverse Metaphase Cytogenetics Can Be Overcome by Adding Bortezomib and Thalidomide to Fractionated Melphalan Transplants.
Purpose:To determine whether a reduction in the intensity of Total Therapy (TT) reduces toxicity and maintains efficacy.Experimental Design:A total of 289 patients with gene expression profiling (GEP70)-defined low-risk multiple myeloma were randomized between a standard arm (TT4-S) and a light arm (TT4-L). TT4-L employed one instead of two inductions and consolidations. To compensate for potential loss of efficacy of TT4-L, bortezomib and thalidomide were added to fractionated melphalan 50 mg/m2/d for 4 days.Results:Grade ≥3 toxicities and treatment-related mortalities were not reduced in TT4-L. Complete response (CR) rates were virtually identical (P= 0.2; TT4-S, 59%; TT4-L, 61% at 2 years), although CR duration was superior with TT4-S (P= 0.05; TT4-S, 87%; TT4-L, 81% at 2 years). With a median follow-up of 4.5 years, there was no difference in overall survival (OS) and progression-free survival (PFS). Whereas metaphase cytogenetic abnormalities (CAs) tended to be an adverse feature in TT4-S, as with predecessor TT trials, the reverse applied to TT4-L. Employing historical TT3a as training and TT3b as test set, 51 gene probes (GEP51) significantly differentiated the presence and absence of CA (q < 0.0001), seven of which function in DNA replication, recombination, and repair. Applying the GEP51 model to clinical outcomes, OS and PFS were significantly inferior with GEP51/CA in TT4-S; such a difference was not observed in TT4-L.Conclusions:We identified a prognostic CA-linked GEP51 signature, the adversity of which could be overcome by potentially synergizing anti-multiple myeloma effects of melphalan and bortezomib. These exploratory findings require confirmation in a prospective randomized trial.Clin Cancer Res; 23(11); 2665-72. ©2016 AACR.
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Yogesh S
YS
Jethava
Cancer Research and Biostatistics, Seattle, Washington.
Alan
A
Mitchell
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Joshua
J
Epstein
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Maurizio
M
Zangari
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Shmuel
S
Yaccoby
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Erming
E
Tian
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Sarah
S
Waheed
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Rashid
R
Khan
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Xenofon
X
Papanikolaou
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Monica
M
Grazziutti
Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Michele
M
Cottler-Fox
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Nathan
N
Petty
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Douglas
D
Steward
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Susan
S
Panozzo
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Clyde
C
Bailey
Cancer Research and Biostatistics, Seattle, Washington.
Antje
A
Hoering
Cancer Research and Biostatistics, Seattle, Washington.
John
J
Crowley
Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Jeffrey
J
Sawyer
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Gareth
G
Morgan
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Bart
B
Barlogie
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas. vanrheefrits@uams.edu.
Frits
F
van Rhee
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D000069286:Bortezomib / Q000008:administration & dosage* / Q000009:adverse effects; D002869:Chromosome Aberrations / Q000187:drug effects; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage* / Q000009:adverse effects; D008677:Metaphase / Q000187:drug effects; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics; D011379:Prognosis; D011446:Prospective Studies; D013792:Thalidomide / Q000008:administration & dosage* / Q000009:adverse effects
D009363:Neoplasm Proteins; D013792:Thalidomide; D000069286:Bortezomib; D008558:Melphalan