Levels of minimal residual disease detected by quantitative molecular monitoring herald relapse in patients with multiple myeloma.
OBJECTIVE
Detection of minimal residual disease (MRD) has helped to improve the treatment of patients with leukemia. At present MRD testing in patients with multiple myeloma (MM) is not applied as a standard diagnostic or prognostic method.


METHODS
Immunoglobulin heavy chain (IgH) polymerase chain reaction (PCR) using patient-specific TaqMan probes together with LightCycler technology was performed to quantify minimal residual disease in MM. Relative levels of clonotypic cells were assessed as IgH/2beta-actin ratios with a sensitivity of 10(-4) to 10(-5).


RESULTS
Following stem cell transplantation, a significant reduction of clonotypic cells was observed in bone marrow (BM) and peripheral blood (PB) samples of 11 patients, comparing pre-treatment values with those of best response (median: 13% to 0.09% and 0.03% to 0%, respectively). In 5 patients with ongoing clinical remission IgH/2beta-actin ratios remained stable at a low level, while in 6 patients an increase to 2% in BM and 0.4% in PB was associated with progression of the disease. In 4 of these 6 patients the increase of clonotypic cells in PB was detectable a median of 3 months (range: 0.5-6) before relapse. Furthermore, time-to-progression of patients with pre-transplantation IgH/2b-actin ratios > 0.03% in BM was significantly shorter than that of patients with lower MRD levels.


CONCLUSIONS
MRD in patients with MM can be quantified reliably using TaqMan chemistry adapted to the LightCycler system. Residual tumor cell levels before transplantation as well as results of sequential molecular monitoring are predictive of relapse.
Fenk
Roland
R
Dept. of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany. fenk@med.uni-duesseldorf.de
Ak
Muharrem
M
Kobbe
Guido
G
Steidl
Ulrich
U
Arnold
Carolin
C
Korthals
Mark
M
Hünerlitürkoglu
Ali
A
Rohr
Ulrich-Peter
UP
Kliszewski
Slawomir
S
Bernhardt
Alf
A
Haas
Rainer
R
Kronenwett
Ralf
R
D000199:Actins / Q000097:blood; D000328:Adult; D000368:Aged; D001854:Bone Marrow Cells / Q000166:cytology; D045744:Cell Line, Tumor; D002999:Clone Cells / Q000166:cytology; D015342:DNA Probes / Q000097:blood; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000097:blood; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood / Q000150:complications*; D018365:Neoplasm, Residual / Q000150:complications / Q000175:diagnosis*; D016133:Polymerase Chain Reaction / Q000379:methods*; D012008:Recurrence; D012680:Sensitivity and Specificity; D033581:Stem Cell Transplantation
D000199:Actins; D015342:DNA Probes; D007143:Immunoglobulin Heavy Chains