BackgroundMost patients with multiple myeloma (MM) are considered to be incurable, and relapse owing to minimal residual disease (MRD) is the main cause of death among these patients. Therefore, new technologies to assess deeper response are required.Patients and methodsWe retrospectively analyzed 125 patients with MM who underwent high-dose melphalan plus autologous stem-cell transplantation (ASCT) to detect MRD in autograft/bone marrow (BM) cells using a next-generation sequencing (NGS)-based method and allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR).ResultsNGS-based method was applicable to 90% and this method had at least one to two logs greater sensitivity compared to ASO-PCR. MRD negative by NGS [MRDNGS(−)] (defined as <10−6) in post-ASCT BM cases (n = 26) showed a significantly better progression-free survival (PFS) (96% at 4 years, P < 0.001) and overall survival (OS) (100% at 4 years, P =0.04) than MRDNGS(+) in post-ASCT BM cases (n = 25). When restricting the analysis to the 39 complete response cases, patients who were MRDNGS(−) (n = 24) showed a significantly better PFS than those that were MRDNGS(+) (n = 15) (P =0.02). Moreover, MRDNGS(−) in post-ASCT BM cases (n = 12) showed significantly a better PFS than MRDNGS(+) cases (n = 7) where MRD was not detected by ASO-PCR (P = 0.001). Patients whose autografts were negative by NGS-based MRD assessment (<10−7) (n = 19) had 92% PFS and 100% OS at 4 years post-ASCT. Conversely, the NGS-based MRD positive patients who received post-ASCT treatment using novel agents (n = 49) had a significantly better PFS (P = 0.001) and tended to have a better OS (P= 0.214) than those that were untreated (n = 33).ConclusionsLow level MRD detected by NGS-based platform but not ASO-PCR has significant prognostic value when assessing either the autograft product or BM cells post-ASCT.
Summary:This report concerns a case of long-lasting pure red cell aplasia (PRCA) with a duration of 178 days after major ABO-incompatible allogeneic peripheral blood stem cell transplantation (PBSCT). The patient needed red blood cell transfusion every week from day 54 following PBSCT. He showed no evidence of GVHD and the dose of cyclosporin A (CsA) was reduced rapidly from day 123, followed by the development of chronic GVHD around day 145. The patient no longer needed transfusions from day 167, the reticulocyte count began to increase on day 179, and antidonor isohemagglutinin titers became undetectable. Chronic GVHD induced by tapering of CsA thus appeared to be related to improvement in PRCA.
Background: Autologous stem cell transplantation (ASCT) in conjunction with therapeutic drugs such as bortezomib, thalidomide, and lenalidomide can dramatically improve response rates and the prognosis of patients with multiple myeloma (MM). However, most patients with MM are considered to be incurable, and relapse owing to minimal residual disease (MRD) is the main cause of death among these patients. Here we utilized a next-generation sequencing (NGS) approach for MRD assessment, which offers at least 1 to 2 logs greater sensitivity (10-6) compared to allele-specific oligonucleotide PCR (ASO-PCR) and flow cytometry, respectively (Faham et al Blood 2012). Previous studies have shown that NGS-based MRD assessment 90 days post-ASCT has prognostic value (Martinez-Lopez et al Blood 2014). In this study, we compared the prognostic value of MRD assessment in autografts and bone marrow (BM) samples from MM patients in the ASCT setting. Methods: One hundred and twenty-three Japanese patients with newly diagnosed MM who received various induction regimens prior to ASCT were retrospectively analyzed. All patients received ASCT and were followed between June 15, 2004 and April 25, 2015. All patients had achieved a partial response (PR) or better after ASCT. Analyzed samples included: (1) BM slides from 96 MM patients at diagnosis, (2) fresh/frozen BM cells from 27 MM patients at diagnosis, (3) autografts and/or (4) post-ASCT BM cells obtained at the time of best response based on serum and urine tests. IGH-based ASO-PCR was performed as described previously (Methods Mol Biol 2009). NGS-based MRD assessment was performed using the immunosequencing platform (Adaptive Biotechnologies, South San Francisco, CA) (Martinez-Lopez et al Blood 2014). Results: We compared MRD results in 51 samples assessed by ASO-PCR and NGS. We observed a high correlation between NGS and ASO-PCR results at MRD levels of 10-5 or higher (r=0.86, P<0.0001). Twenty-seven samples were positive by NGS and negative by ASO-PCR, demonstrating the higher sensitivity of NGS (10-6 or higher) vs ASO-PCR (10-4-10-5). We evaluated the association of clinical outcome with post-ASCT BM MRD assessment. Patients who were MRD negative by NGS (defined as <10-6) in post-ASCT BM cases (N=21) showed a significantly better progression free survival (PFS) compared to MRD positive patients (N=31) (P =0.005) (Fig 1A). When restricting the analysis to the 39 patients in complete response (CR), patients who were MRD negative by NGS (N=20) showed a significantly better PFS than those that were MRD positive (N=19) (P =0.042). We also evaluated the association of clinical outcome with autograft MRD assessment. 53 patients received post-ASCT therapy using novel agents such as bortezomib/lenalidomide/thalidomide, and 45 patients did not. Among the 45 patients who did not receive post ASCT treatment, patients with NGS-based MRD negativity in the autograft (N=11) had a significantly better PFS (P=0.012) and tended to have a better OS (p=0.203) than those who were MRD positive (N=34), with prognosis clearly stratified by the quantitative level of MRD (Figs 1B, 1C). MRD assessment from the 53 patients who did receive post ASCT treatment tended to show a similar pattern. Finally, we studied whether clinical outcomes would have been altered by treatment in this cohort. Patients whose autografts were negative by NGS-based MRD assessment (N=19) had 100% PFS and OS at 5 years post ASCT irrespective of whether or not they received post ASCT treatment. Conversely, post ASCT treatment had a significant effect on the outcome of patients whose autografts were MRD positive by NGS. Specifically, the NGS-based MRD positive patients who received post ASCT treatment (N=45) had a significantly better PFS (P=0.003) and tended to have a better OS than those that were untreated (N=34) (Figs 1D, 1E). Conclusions: In this study, we show the prognostic value of NGS-based MRD assessment in autografts of patients with MM. The NGS platform has improved sensitivity compared with ASO-qPCR in detecting MRD in autografts. Importantly, this retrospective study suggests that therapeutic intervention based on NGS-based MRD positivity has a significant effect on patient outcome in the post-ASCT setting. Disclosures Zheng: Adaptive Biotechnologies Corp.: Employment, Equity Ownership. Moorhead:Adaptive Biotechnologies Corp.: Employment, Equity Ownership. Faham:Adaptive Biotechnologies Corp.: Employment, Other: Stockholder.
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