The Reason Why High-Dose Melphalan Followed by Autologous Stem-Cell Transplantation Produces Good Response in Multiple Myeloma.
Authors: Kuroda Yoshiaki , Sakai Akira , Okikawa Yoshiko , Munemasa Shoso , Katayama Yuta , Takimoto Yasuo , Okita Hajime , Kimura Akiro 
Published: October 2019

Abstract
Multiple myeloma (MM) is the result of a clonal proliferation of plasma cells. And myeloma cells have been shown to be heterogeneous with regard to their morphology and biological character. Recently, correlations between molecular subtypes and prognosis have been identified as a good prognosis with t(11;14) and a poor prognosis with t(4;14) and t(14;16) besides chromosome 13 abnormalities. But it is still unclear how those molecular events work on the prognosis of MM patients. And it is difficult to find the heterogenesity of myeloma cells in each MM case by molecular analysis. Twenty years ago Greipp et al. classified myeloma cells as mature, intermediate, immature and plasmablastic type, and then they showed that plasmablastic morphology is an independent predictor of poor survival rate after autologous stem-cell transplantation. On the other hand, Kawano et al. classified myeloma cells into three types by their phenotype (Huang N, Blood82: 3721, 1993, Kawano MM, Blood82: 564, 1993); immature (MPC1−, CD49e−, CD45−/+), intermediate (MPC1+, CD49e−, CD45−), and mature (MPC1+, CD49e+/−, CD45+). This classification according to the phenotype is good correlation with that by morphology. And they indicated that immature myeloma cells have activity of proliferation. We analyzed both phenotypic and morphological findings of myeloma (plasma) cells consecutively before and after chemotherapy in 23 MM cases in order to find what kind of drug might be useful to reduce the main population of heterogeneous myeloma cells. The phenotypic and morphological analysis were performed before and after ten-cycles of melphalan-predonine (MP) in 2 cases, three or four-cycles of vincristine-doxorubicin-dexamethasone (VAD) in 10 cases, high-dose cyclophosphamide (HD-CPA) for stem cell harvest after three or four cycles of VAD in 5 cases, high-dose melphalan followed by autologus stem-cell transplantation (HD-Mel+ASCT) in 6 cases, and administration of thalidomide at least for two months in 7 cases. First, total myeloma cells decreased after VAD, however, immature myeloma cells increased relatively (9/10). Second, HD-CPA was not effective in reducing myeloma cells furthermore after VAD (5/5). Third, HD-Mel+ ASCT could reduce immature myeloma cells clearly (4/6). In particular, a less than 5% reduction of immature myeloma cells after this course were important for the long duration of good response, but the residue of immature myeloma cells was a predictor of progressive disease (PD). Interestingly, MP was also useful to reduce immature myeloma cells (2/2). Finally, thalidomide was effective in reducing mature and intermediate myeloma cells (3/6), but not effective in immature myeloma cells. In conclusion, melphalan, if it is high-dose, has more effects on immature myeloma cells compared with those of other drugs, which might be a reason of the superiority of HD-Mel+ASCT over conventional treatment in terms of the response rate and event-free survival.