Molecular remission of multiple myeloma patients after allogeneic or autologous transplantation of hematopoietic stem cells.

C. Terragna, G.Martinelli, M. Rossi, S.Soverini, M.Amabile, B.Giannini, E. Ottaviani, S.Buonamici, E.Zamagni, C.Cellini, P. Tosi, D.Cangini, S. Tura and M.Baccarani, M. Cavo.

Institute of Hematology and Medical Oncology Seràgnoli, University of Bologna, Italy.

Introduction: High-dose (HD) chemotherapy with the support of autologous or allogeneic hematopoietic stem cells is commonly used for the treatment of multiple myeloma (MM) patients and significantly improves their survival. However, the majority of patients still harbor detectable minimal residual disease (MRD) following transplantation and ultimately relapse. We investigated the clinical relevance of MRD in 132 MM patients in complete clinical remission (CCR) after autologous (n=99) or allogeneic (n=33) stem cell transplantation, by using a polymerase chin reaction (PCR) based strategy. In 10 autografted patients who were persistently PCR positive, we also performed Real Time PCR. Methods and Results: Molecular monitoring using clonal markers based upon rearranged immunoglobulin heavy-chain genes was performed in 70 of the 132 MM patients in CCR. Eighteen (26%) achieved molecular complete remission (MCR), as defined by at least 2 consecutive negative PCR results. The MCR rate was higher among allografted (53%, 9/17) than among autografted (17%, 9/53) patients (p=0.03). Patients achieving MCR had a slightly lower relapse free survival compared to those who were persistently PCR positive (median, 42 months vs 32 months, respectively), although the difference between the 2 groups was not statistically significant. Real Time PCR was used to quantitatively study 10 autografted CCR patients who were persistently PCR positive. This was performed using tumour specific primers and Syber Green chromophor as universal probe. Relative quantification was performed on DNA in all cases and on RNA in 3 cases. The DDCt method was used, with the albumin gene adopted as an internal control. Five of the 10 patients relapsed. In 2 cases, relapse was preceded by an increase of IgH clonal rearrangements, while in 3 patients we could not see any increase of IgH clonal rearrangement, although in 2 of them the IgH clonal rearrangement expression rate significantly increased (in the remaining case, insufficient material was available for monitoring up to relapse). Conclusions: Stringently defined MCR can be obtained in a relatively high proportion of MM patients receiving allogeneic stem cell transplantation and in a smaller fraction of patients after autografting, a finding which suggests the existence of a beneficial immunological effect exerted by donor T cells present in the allograft. Whether MCR does actually represent a goal of high-dose treatment for MM and correlates with patients clinical outcome still remains to be formally demonstrated; studies on larger series of patients are needed in order to confirm the prognostic relevance of molecular monitoring by PCR strategies. Finally, in patients who remain persistently PCR+, a quantitative monitoring could be of value to identify a threshold level above which there is a significantly higher risk of clinical relapse.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Stem Cell Biology.