3D CNN-based Deep Learning Model-based Explanatory Prognostication in Patients with Multiple Myeloma using Whole-body MRI.

Although magnetic resonance imaging (MRI) data of patients with multiple myeloma (MM) are used to predict prognosis, few reports have applied artificial intelligence (AI) techniques for this purpose. We aimed to analyze whole-body diffusion-weighted MRI data using three-dimensional (3D) convolutional neural networks (CNNs) and Gradient-weighted Class Activation Mapping (Grad-CAM), an explainable AI, to predict prognosis and explore the factors involved in prediction. We retrospectively analyzed the MRI data of a total of 142 patients with MM obtained from two medical centers. We defined the occurrence of progressive disease after MRI evaluation within 12 months as a poor prognosis and constructed a 3D CNN-based deep learning model to predict prognosis. Images from 111 cases were used as the training and internal validation data; images from 31 cases were used as the external validation data. Internal validation of the AI model with stratified 5-fold cross-validation resulted in a significant difference in progression-free survival (PFS) between good and poor prognostic cases (2-year PFS, 91.2% versus [vs.] 61.1%, P = 0.0002). The AI model clearly stratified good and poor prognostic cases in the external validation cohort (2-year PFS, 92.9% vs. 55.6%, P = 0.004), with an area under the receiver operating characteristic curve of 0.804. According to Grad-CAM, the MRI signals of the spleen and bones of the vertebrae and pelvis contributed to prognosis prediction. This study is the first to show that image analysis of whole-body MRI using a 3D CNN without any other clinical data is effective in predicting the prognosis of patients with MM.

Eight-color multiparameter flow cytometry (EuroFlow-NGF) is as sensitive as next-generation sequencing in detecting minimal/measurable residual disease in autografts of patients with multiple myeloma.

The prognostic value of minimal/measurable residual disease (MRD) detection in autografts of patients with multiple myeloma (MM) in an autologous stem-cell transplantation setting has been reported. Next-generation flow (NGF) cytometry has lower sensitivity (2 × 10-6) to detect MRD than next-generation sequencing (NGS) (<10-6). We compared the clinical value of high-sensitivity NGF (cutoff: <10-6) and NGS (cutoff: 10-6) for the detection of MRD in the cryopreserved autografts of 49 patients with newly diagnosed MM. The sensitivity test using frozen/thawed autografts revealed a strong correlation among MRD levels of 5 × 10-7 and 1 × 10-4 (r = 0.9997, p < 0.0001) when an adequate number of cells were analyzed. Autograft MRD levels determined using NGF and NGS were highly correlated (r = 0.811, p < 0.0001). MRD-negative patients identified with NGF (cutoff: <10-6) showed significantly longer progression-free survival (PFS) than MRD-positive patients (p = 0.026). The PFS of MRD-negative patients determined by NGS (cutoff: 10-6) was similar to that determined by NGF. These results show that the high-sensitivity NGF method can assess MRD in frozen/thawed autografts, and its prognostic value is comparable to that of NGS.

Measurable Residual Disease Assessment Using Next-Generation Flow in Patients With Relapsed and Refractory Multiple Myeloma Treated With a Combination of Carfilzomib, Lenalidomide, and Dexamethasone.

BACKGROUND/AIM: Carfilzomib, lenalidomide, and dexamethasone (KRD) therapy is widely used for patients with relapse/refractory multiple myeloma (RRMM). However, the response in patients who underwent assessment for measurable residual disease (MRD) has not been elucidated in a prospective study. We aimed to clarify the response rate and outcome of KRD therapy in patients in RRMM, including those with MRD. PATIENTS AND METHODS: Twenty-one consecutive RRMM patients treated with KRD at 4 Japanese Centers between September 2016 and October 2018 were enrolled and assessed for MRD in the bone marrow (cut-off: 1×10-5) using the EuroFlow-next-generation flow (NGF) method. RESULTS: The median number of therapy lines before KRD was 3 (range=1-6), and the median number of KRD cycles was 4 (range=1-22). As the best overall response post-KRD therapy, 52% (11/21) of patients achieved a MRD negative complete response, 71% (15/21) achieved stringent complete response/complete response, and 14% (3/21) achieved a very good partial response. MRD negativity was achieved in 12 of 16 (75%) and 14 of 21 (67%) patients during and after KRD treatment, respectively. The 2-year progression-free survival and overall survival from the start of KRD therapy were 100% and 100%, respectively, in MRD-positive cases and 88% and 100%, respectively, in MRD-negative cases (median follow-up=1.8 years). Grade 3/4 toxicities were reported in 15 patients (71%), with thrombocytopenia being the most frequent toxicity (6 patients, 29%). CONCLUSION: This is the first study that prospectively assessed MRD of patients with RRMM after KRD therapy. KRD treatment achieved a high MRD negativity rate and good outcomes with manageable toxicities.

Correction to: Comparison of minimal residual disease detection in multiple myeloma by SRL 8-color single-tube and EuroFlow 8-color 2-tube multiparameter flow cytometry.

The authors would like to correct the error in the publication of the original article. The corrected detail is given below for your reading.

Comparison of minimal residual disease detection in multiple myeloma by SRL 8-color single-tube and EuroFlow 8-color 2-tube multiparameter flow cytometry.

We sought to determine the efficacy of a new, inexpensive, single-tube 8-color multiparameter flow cytometry (MFC) method (SRL-Flow), which is based on the EuroFlow next-generation flow (NGF) (tube 2 only), to assess minimal residual disease (MRD)-negative status. MRD-negative status is considered a treatment milestone in multiple myeloma (MM). We used 45 bone marrow samples from patients with MM, including 11 cases treated with anti-CD38 monoclonal antibody. The SRL-Flow sample preparation protocol was identical to that of EuroFlow-NGF. The antibody panel for SRL-Flow was as follows: CD138V450/CD27V500/CD38ME (multiepitope)FITC/CD56PE/CD45PerCP-Cy5.5/CD19PE-Cy7/cytoplasmic (Cy) immunoglobulin (Ig) κAPC/CyIgλAPC-H7. To identify abnormal plasma cells (aPCs) of patients with MM who received anti-CD38 monoclonal antibody, we used a panel of anti-CD45 and anti-CD138 antibodies (Abs) rather than a panel of anti-CD45 and anti-CD38 Abs. We comparatively analyzed the total nucleated cell numbers, total PC levels, and MRD levels between the SRL-Flow and EuroFlow-NGF. High correlations (r > 0.9) in total PC and MRD levels were noted among SRL-Flow, original EuroFlow-NGF (2 tubes), and EuroFlow-NGF (tube 2 only), suggesting that SRL-Flow is an inexpensive (< $200 USD/sample as of January of 2019) alternative to EuroFlow-NGF (< $350 USD/sample) for assessing MRD in MM.

Post-transplantation consolidation and maintenance therapy with lenalidomide for Japanese patients with multiple myeloma.

BACKGROUND: Post-autologous stem cell transplantation (ASCT) consolidation and maintenance therapies in multiple myeloma (MM) have recently been the central focus of studies. However, there have been no reports of Japanese patients with MM treated with post-ASCT consolidation/maintenance therapies. PATIENTS AND METHODS: We retrospectively evaluated eight Japanese patients with newly-diagnosed symptomatic MM who received ASCT after high-dose melphalan, and three to four courses of bortezomib-plus-dexamethasone and two courses of lenalidomide-plus-dexamethasone followed by maintenance lenalidomide for 6-24 months. RESULTS: Four patients achieved complete response (CR) after ASCT, and five patients (63%) achieved stringent CR after the consolidation and maintenance therapy; two out of these five were in molecular CR. At the median follow-up of 38 months, all patients were alive and only one patient had disease progression following post-ASCT therapy. CONCLUSION: Post-ASCT consolidation and maintenance therapy using lenalidomide may be effective in the treatment of Japanese patients with MM.

Detection of minimal residual disease in patients with multiple myeloma using clonotype-specific PCR primers designed from DNA extracted from archival bone marrow slides.

Polymerase chain reaction (PCR)-negative molecular complete remission (mCR) can be induced by stem cell transplantation in some patients with multiple myeloma (MM) and is associated with long-term progression-free survival (PFS). The detection of molecular minimal residual disease (MRD), however, requires fresh or frozen materials for designing clone-specific primers, which are not always readily available. In this study, we used DNA extracted from archival bone marrow (BM) slides for PCR to detect MRD in 50 patients with MM who received various induction therapies and autologous peripheral blood stem cell transplantation (ASCT). Clonotype-specific immunoglobulin (Ig) H PCR primers were prepared for 32 of 50 cases (64%) using BM slides, and for 9 of 14 cases (64%) using fresh BM cells. DNA in peripheral blood stem cell autografts of the 22 patients who achieved at least a partial response after ASCT was subjected to PCR to amplify clonotype-specific rearranged IgH gene sequences. The median PFS of the eight patients with MRD-positive autografts was 18 months, whereas that of 14 patients with MRD-negative autografts was not reached at a median follow-up of 27 months (p = 0.012). Post-ASCT PFS of the four patients who achieved mCR was 100% at a median follow-up of 47 months. These results indicate that archival BM slides can serve as a source of DNA for preparing clonotype-specific primers for MRD monitoring in patients with MM whose cryopreserved myeloma cells are not available for DNA preparation. Our results also suggest that patients with MM who received MRD-negative autografts and achieved mCR have a long PFS.