Detection of minimal residual disease in multiple myeloma

Abstract

Multiple myeloma (MM) is a hematological malignancy arising from uncontrolled proliferation of neoplastic plasma cells in bone marrow (BM). Despite enormous advances in treatment, MM remains incurable. Patients achieving complete response (CR) still relapse due to persistence of minimal residual disease (MRD)that has been shown to be prognostically important. Allele-specific oligonucleotide (ASO)RQ-PCR has been frequently employed for MRD detection in acute lymphoblastic leukaemia and MM. However, applicability is much lower in MM due to presence of somatic hypermutation. Therefore, this first aim of the study was to improve the applicability of ASO RQ-PCR in MM. In 13patients, through a systematic analysis of mismatches against consensus primers and probes used in RQ-PCR, thereby enabling design of fully patient-specific primers/probes, and construction of RQ-PCR standard curve using plasmid-cloned patient-specific immunoglobulin sequence, the applicability was improved to 92%. Recently, consolidation after autologous stem cell transplant (ASCT)has been introduced. However, the role of consolidation, especially on MRD, has not been extensively studied and defined. Therefore, the second objective was to study whether post-ASCT consolidation could reduce MRD, especially in patients achieving CR post-ASCT. Of 16patients enrolled, MRD was successfully measured in 12 patients. After consolidation, MRD was significantly reduced in seven cases, persistently negative in two, but increased in three. Overall, MRD was reduced by 3.2-fold. Among five patients achieving CR before consolidation, MRD was decreased in one but increased in three. Thirdly, the study aimed to investigate whether ASCT after induction could further reduce MRD in those achieving CR/nCR pre-ASCT. Ten patients were studied, with MRD detected in seven. After ASCT, MRD decreased in two patients, persistently negative in two, not significantly changed in one, but increased in two. Overall, MRD was reduced after ASCT by about 3.7-fold. Furthermore, MRD after ASCT has been demonstrated as a prognostic factor for survival in MM. However, this has not been tested in Chinese MM patients, particularly in patients achieving CR post-ASCT. Therefore, the fourth objective was to study the prognostic impact of MRD after ASCT. Forty-four Chinese MM patients undergoing ASCT, with majority achieving CR post-ASCT/consolidation (for those receiving post-ASCT consolidation), were enrolled. MRD detection after ASCT/consolidation was successful in 35 patients. Using a threshold of 5x10-4, overall survival in MRD-low group was significantly superior to that in MRD-high group (median not reached vs. 27 months, p=0.014). Surprisingly, MRD was not prognostic for progression-free survival, for which, instead, post-induction response and ISS stage were both prognostic. Finally, paired BM buffy coats and ficolled BMs were tested for MRD detection, showing MRD in ficolled BM was about three times that in paired buffy coat. In conclusion, ASO RQ-PCR was applicable in about 90% of MM. Consolidation after ASCT led to a modest but further reduction of MRD, and its role, especially CR patients, warrants further studies. The role of ASCT in patients achieving CR post-induction warrants further study. Furthermore, post-ASCT/consolidation MRD is significantly prognostic for overall survival in Chinese MM. Finally, ficolled BM is more sensitive for MRD detection.