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Melphalan-induced DNA damage in vitro as a predictor for clinical outcome in multiple myeloma

From the Department of Clinical Therapeutics, University of Athens, School of Medicine, Athens, Greece (MAD, AA); Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Athens, Greece (VLS, SAK); Department of Hygiene and Epidemiology, University of Athens, School of Medicine, Athens, Greece (CB); Greek Myeloma Study Group, Athens, Greece (AP, IB); First Department of Propedeutic Medicine, University of Athens, School of Medicine, Athens, Greece (PPS)

Correspondence: Meletios A. Dimopoulos, M.D., 227, Kifissias Ave., Kifissia, 145 61, Athens, Greece. E-mail: mdimop{at}med.uoa.gr

Background and Objectives: 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.

Design and 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/10⁶ 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).

Interpretation and 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.

Key words: melphalan, multiple meyloma, prediction of clinical outcome, in vitro-induced adducts, p53-specific damage formation/repair.