Melphalan-induced DNA damage in vitro as a predictor for clinical outcome in multiple myeloma.
OBJECTIVE
As new therapeutic options for multiple myeloma (MM) emerge, identification of biological markers which could predict clinical response to standard treatment with high-dose melphalan (HDM) supported by autologous stem cell transplantation (ASCT) becomes more important.


METHODS
Melphalan-induced damage formation and repair of monoadducts and interstrand cross-links in the p53 gene were studied in peripheral blood mononuclear cells obtained from 32 patients prior to therapy. The same studies were performed in the peripheral blood cells of these patients immediately after subsequent HDM administration. Clinical response and time to progression were correlated with molecular endpoints obtained in vitro.


RESULTS
Values for all molecular end-points examined in vitro were highly correlated with the respective in vivo results within individual patients. All in vitro end-points indicative of increased DNA damage and slower repair capacity were predictive of a favorable response to HDM; the area under the curve of total adducts (AUC-TA) had the highest predictive ability. Using the cut-off value of 736 adducts/10(6) nucleotides x h for the AUC-TA, the positive predictive value for clinical response to HDM was 100%. Moreover, patients with an AUC-TA equal to or higher than this cut-off value had significantly longer times to progression than had patients with an AUC-TA lower than the cut-off value (hazard ratio 0.19; 95% confidence intervals 0.06 to 0.60).


CONCLUSIONS
An in vitro assay to quantify melphalan-induced p53-specific damage formation/repair can be used to select those patients with MM who are more likely to benefit from HDM supported by ASCT.
Dimopoulos
Meletios A
MA
Department of Clinical Therapeutics, University of Athens, School of Medicine, Athens, Greece. mdimop@med.uoa.gr
Souliotis
Vassilis L
VL
Anagnostopoulos
Athanasios
A
Bamia
Christina
C
Pouli
Anastasia
A
Baltadakis
Ioannis
I
Terpos
Evangelos
E
Kyrtopoulos
Soterios A
SA
Sfikakis
Petros P
PP
D000328:Adult; D000368:Aged; D004249:DNA Damage / Q000187:drug effects*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008558:Melphalan / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis* / Q000628:therapy*; D018579:Patient Selection; D011237:Predictive Value of Tests; D016896:Treatment Outcome
D008558:Melphalan