Sequential analysis of bone marrow and peripheral blood after stem cell transplant for myeloma shows disparate tumor involvement

Abstract

Treatment with combination chemotherapy has not resulted in that PB stem cell harvests are often contaminated with myelong-term remissions in multiple myeloma (MM) despite loma tumor cells. 5,[8][9][10][11] In fact, one study indicated that the advances in drug discovery and protocol improvement over the presence of contaminating tumor cells in the autograft was 10,[18][19][20] We have previously shown that although the BM tumor burden is significantly depleted following high-dose Introduction chemotherapy, MRD can still be detected, even when patients achieve clinical complete remission (CR). 17 In contrast to the Multiple myeloma (MM) is an incurable B cell malignancy significant reduction in BM tumor load post-chemotherapy, in characterized by the clonal expansion of plasma cells within a limited analysis we observed very little tumor reduction the bone marrow (BM) as determined by clonal Ig heavy and within the PB. 4 Furthermore, we found that PB involvement light chain genes in the BM and by the production of a clonal was independent of disease stage and of BM tumor involveimmunoglobulin (Ig) M-protein in the serum. Although the disment. 4,21 Previous analysis of BM and PB post-transplant in ease is responsive to combinations of chemotherapeutic MM using an Ig gene fingerprinting technique has shown that agents and steroids, relapse is inevitable, with a median surpatients achieving CR lack detectable clonal rearrangevival of 36 months. 1 In an attempt to improve outcomes, conments. 22 Caution is necessary regarding this approach for ventional chemotherapy followed by allogeneic or autologous identification of MRD in these patients because Ig gene BM transplants have been used, however, both relapse and fingerprinting is far less sensitive than ASO-PCR. 23 serious toxicity are frequent, yielding improved but still quiteIn an attempt to monitor MRD, predict early relapse, and limited survival. [1][2][3] One potential problem with the use of BMdetermine the involvement of the PB in the disease process, derived stem cells is contamination of the autograft with myewe analyzed serial samples of BM and PB from six patients loma plasma cells.prior to and after autologous PBSCT. We found that while 3-It is becoming increasingly clear from our own data that the to 4-log reductions were common in BM tumor burden postmajority of patients with MM contain circulating tumor cells, transplant, tumor levels in the PB changed only slightly. Morealbeit at significantly lower levels than observed in the BM. 4,5 over, upon sequential analysis, the PB tumor signal remained The use of stem cells from the peripheral blood (PB) for transplantation is becoming widespread due to the enhanced quite stable, was not predictive of BM tumor involvement, and myeloid engraftment and to lower level contamination of the did not correlate to events occurring in the BM, ie it was not autograft. 6,7 Nonetheless, several investigators have reported predictive of relapse. These data further illustrate the autonomy of the tumor in the PB of...

Evaluation of the kinetics of the bone marrow tumor load in the course of sequential high-dose therapy assessed by quantitative PCR as a predictive parameter in patients with multiple myeloma

“…The failure of a second cycle of HDT to further reduce the numbers of clonotypic cells in PB indicates that there is a compartment of circulating cells belonging to the myeloma clone that is resistant even to sequential high-dose melphalan. These data do not match those published by Billadeau et al, 17 who reported fairly stable levels of circulating clonotypic cells in the course of a single cycle of HDT. Previous studies from our group had revealed that, indeed, circulating CD19-positive clonotypic cells did not decline in comparison to the corresponding numbers prior to HDT, while CD19-negative clonotypic cells were reduced significantly.…”

Molecular monitoring of the tumor load predicts progressive disease in patients with multiple myeloma after high-dose therapy with autologous peripheral blood stem cell transplantation

“…To date, studies focusing on a continuous determination of the tumor load up to the development of PD are limited. The study of Billadeau et al 11 described that the PB tumor burden remains rather constant in six MM patients prior to and post transplantation with only one sample analyzed at the time of PD. In line with Billadeau's results, Rasmussen et al 12 reported a reduction of clonal cells in PB after induction therapy with no further changes in the course of the HDT in seven MM patients.…”

Analysis of circulating tumor cells in patients with multiple myeloma during the course of high-dose therapy with peripheral blood stem cell transplantation

“…This study was performed in order to quantitate the amounts of circulating clonotypic CD19 ϩ and CD19 Ϫ cells prior to and post-HDT with PBSCT and to consider both flow cytometry and molecular techniques as a measure of the tumor cell content in PB of patients with MM. A sequential analysis of whole PB mononuclear cell samples before and after PBSCT was performed by Billadeau et al 12 who showed that the tumor content in PB was independent of the disease stage, and that in most patients the number of malignant cells in PB was only minimally altered by intensive therapy including HDT with PBSCT. Using ASO PCR assays they determined tumor cell proportions ranging from below the detection level to 1.35%.…”

“…11 Furthermore, Billadeau et al 12 reported that the number of malignant cells in PB remains fairly stable during the course of high-dose treatment. We addressed the question of fate of tumor cells in the CD19 ϩ B cell compartment during high-dose treatment by comparing tumor cell numbers in samples from patients after conventional chemotherapy with those after HDT.…”