[Patient] A 65-year-old man. [History of present illness] An abnormal chest shadow was noted in March of 2011, and hoarseness was observed in November of 2017. Both times, AL amyloidosis was diagnosed by biopsy. The patient was admitted to our department for treatment in March 2018, and received 6 cycles of melphalan plus dexamethasone for systemic AL amyloidosis in May. His condition was good, but a blood test in August 2019 showed white blood cells 50,000/µl and 44.9% blasts in the peripheral blood, leading to a diagnosis of treatment-related acute leukemia (AML with inv (16)(p13.1q22);CBFB::MYH11). He achieved complete remission with standard treatment, but relapsed in May 2020, CNS relapsed in September 2020, CNS relapsed again in July 2021, and CNS relapsed a third time in May 2022. He underwent intensive chemotherapy, whole brain radiation therapy, 13 rounds of intrathecal injection, and five cycles of venetoclax plus azacitidine, but his general condition gradually worsened. He was transferred to best supportive care in November and died in June 2023. [Discussion] Although advances in treatment have extended survival in systemic AL amyloidosis, long-term follow-up for secondary cancer is important for patients with long-term exposure, as in this case.

INTRODUCTION:Some treatments are associated with cytomegalovirus (CMV) reactivation (CMVRA) in patients with multiple myeloma (MM). However, no reports exist on the association between elotuzumab and CMVRA. Therefore, we assessed the incidence of CMVRA in patients with MM who received elotuzumab therapy. METHODS:The medical records of 85 patients who underwent elotuzumab therapy were included in the retrospective analysis for CMV positivity. RESULTS:Thirty patients were tested for CMV antigenemia during elotuzumab therapy, and 16 were positive for CMV antigenemia; the cumulative incidence rate of CMVRA 6 months after elotuzumab initiation was 18.4%. The history of allogeneic stem cell transplantation (allo-HSCT) was significantly more common in the CMVRA group (31.2%) than that of the group without CMVRA (8.7%). However, even among patients who did not undergo allo-HSCT, the cumulative incidence rate of CMVRA at 6 months was 15.1%. During CMVRA, the symptoms included fever in 8 cases, while retinitis was observed in 1 case. Five patients required antiviral therapy and CMV antigenemia resolved in all but 1 case. CONCLUSION:Although the patient population was heterogeneous, CMVRA cannot be underestimated during elotuzumab therapy, and evaluation of CMVRA, especially in symptomatic cases, is clinically important.

Hematological OncologyVolume 42, Issue 1 e3248 LETTER TO THE EDITOR Prognostic value of the second revision of the international staging system (R2-ISS) in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation Taku Kikuchi, Corresponding Author Taku Kikuchi [email protected] orcid.org/0000-0002-3210-7756 Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan Correspondence Taku Kikuchi, Department of Hematology, Japanese Red Cross Medical Center, 4-chōme-1-22 Hiroo, Tokyo 150-8935, Japan. Email: [email protected]Search for more papers by this authorNobuhiro Tsukada, Nobuhiro Tsukada Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this authorKodai Kunisada, Kodai Kunisada Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this authorMoe Yogo, Moe Yogo Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this authorYuki Oda, Yuki Oda Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this authorKota Sato, Kota Sato Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this authorTomomi Takei, Tomomi Takei Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this authorMizuki Ogura, Mizuki Ogura Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this authorYu Abe, Yu Abe Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this authorKenshi Suzuki, Kenshi Suzuki Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this authorTadao Ishida, Tadao Ishida Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this author Taku Kikuchi, Corresponding Author Taku Kikuchi [email protected] orcid.org/0000-0002-3210-7756 Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan Correspondence Taku Kikuchi, Department of Hematology, Japanese Red Cross Medical Center, 4-chōme-1-22 Hiroo, Tokyo 150-8935, Japan. Email: [email protected]Search for more papers by this authorNobuhiro Tsukada, Nobuhiro Tsukada Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this authorKodai Kunisada, Kodai Kunisada Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this authorMoe Yogo, Moe Yogo Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this authorYuki Oda, Yuki Oda Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this authorKota Sato, Kota Sato Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this authorTomomi Takei, Tomomi Takei Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this authorMizuki Ogura, Mizuki Ogura Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this authorYu Abe, Yu Abe Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this authorKenshi Suzuki, Kenshi Suzuki Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this authorTadao Ishida, Tadao Ishida Department of Hematology, Japanese Red Cross Medical Center, Tokyo, JapanSearch for more papers by this author First published: 12 January 2024 https://doi.org/10.1002/hon.3248Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Open Research PEER REVIEW The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1002/hon.3248. DATA AVAILABILITY STATEMENT The data that support the findings of this study are available from the corresponding author upon reasonable request. Supporting Information Filename Description hon3248-sup-0001-fig_s1.pptx310.7 KB Figure S1 hon3248-sup-0002-table_s1.xlsx11.2 KB Table S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1Cowan AJ, Green DJ, Kwok M, et al. Diagnosis and management of multiple myeloma: a review. JAMA. 2022; 327(5): 464-477. https://doi.org/10.1001/jama.2022.0003 10.1001/jama.2022.0003 CASPubMedWeb of Science®Google Scholar 2Maples KT, Scott SA, Lonial S. Novel approaches to the treatment of multiple myeloma. Clin Adv Hematol Oncol. 2023; 21(5): 247-256. PubMedWeb of Science®Google Scholar 3Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol. 2005; 23(15): 3412-3420. https://doi.org/10.1200/jco.2005.04.242 10.1200/JCO.2005.04.242 PubMedWeb of Science®Google Scholar 4Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised international staging system for multiple myeloma: a report from international myeloma working group. J Clin Oncol. 2015; 33(26): 2863-2869. https://doi.org/10.1200/jco.2015.61.2267 10.1200/JCO.2015.61.2267 CASPubMedWeb of Science®Google Scholar 5D'Agostino M, Cairns DA, Lahuerta JJ, et al. 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Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard- and high-risk myeloma. Blood. 2021; 137(1): 49-60. https://doi.org/10.1182/blood.2020006731 10.1182/blood.2020006731 CASPubMedWeb of Science®Google Scholar 9Cavo M, Gay F, Beksac M, et al. Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study. Lancet Haematol. 2020; 7(6): e456-e468. https://doi.org/10.1016/S2352-3026(20)30099-5 10.1016/S2352-3026(20)30099-5 PubMedWeb of Science®Google Scholar 10de Tute RM, Pawlyn C, Cairns DA, et al. Minimal residual disease after autologous stem-cell transplant for patients with myeloma: prognostic significance and the impact of lenalidomide maintenance and molecular risk. 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Introduction AL (Amyloid Light chain) amyloidosis is a rare disease characterized by the misfolding and aggregation of light chain from monoclonal immunoglobulins into amyloid deposits. These deposits are associated with monoclonal plasma cell, leading to organ dysfunction. Current therapeutic strategies focus on eliminating monoclonal plasma cell neoplasms. High-dose melphalan and autologous stem cell transplantation (HDM/SCT) for patients with AL amyloidosis has been employed, but the eligibility criteria for HDM/SCT have been tightened because of the significantly higher mortality rate due to organ dysfunction and decreased Performance status. Furthermore, with the recent advent of anti-CD38 antibodies, the significance of HDM/SCT has been reexamined and the role of HDM/SCT in the treatment paradigm of transplant-eligible patients with AL amyloidosis is not sufficient evidences. This retrospective study aims to determine the prognosis of AL amyloidosis patients who underwent HDM/SCT in our hospital. Methods This retrospective, non-interventional cohort study includes data from the electronic medical records of AL amyloidosis patients treated at the Japanese Red Cross Medical Center (JRCMC). The study was approved by the JRCMC Institutional Review Board and conducted under an informed consent procedure with an opt-out option. Overall survival (OS) was defined as the time between the first day of HDM/SCT (day 0) and date of death from any cause or last follow-up. Treatment-related mortality (TRM) was defined as death from any cause between day 0 and day +100. Treatment efficacy was evaluated at 3 months after transplantation. Comparisons of categorical variables were made using the Chi-square test or Fisher test depending on the number of observations. Comparisons of continuous variables were made with the Mann Whitney U Test. The outcome measure was odds ratio (OR) with a 95% confidence interval (CI). OS was calculated using the Kaplan-Meier method and estimates between groups were compared by the log-rank test. The Cox-proportional hazard regression method was used to fit univariable and multivariable models for OS; the outcome measure was hazard ratio (HR) with 95% CI. p-values <.05 were considered statistically significant. All calculations were obtained using the EZR software version 4.33. Results The study included 121 patients with systemic AL amyloidosis who underwent HDM/SCT from June 2006 to December 2023. The median age was 57 years (range: 32-70 years) and 63 patients (51.2%) were male. The distribution of free light chain types was 98 patients (81.0%) with lambda chains. Organ involvement included the cardiac involvement in 40 patients (33.1%), renal involvement in 88 patients (72.7%), gastrointestinal tract involvement in 44 patients (36.4%), and liver involvement in 25 patients (20.7%). Organ response rates were 76.9% for cardiac involvement, 76.5% for renal involvement, and 54.2% for liver involvement. The median follow-up duration was 56.44 months (range: 0.26-185.45 months). The median overall survival was not reached (95% CI, 12.54 years-not reached [NR]), with a 10-year overall survival rate of 69.2% (95% CI, 56.2-79.1%). Since 2021, there have been no TRM among 21 patients. The overall hematologic response rate was 94% (84/89 patients), with complete response in 52 patients (58.4%), very good partial response in 16 patients (18.0%), and partial response in 16 patients (18.0%). Univariate analysis indicated that cardiac involvement, lower dose (< 200 mg/m2) of melphalan, revised Mayo stage, and sex significantly associated shorter OS. Specifically, cardiac involvement parameters including ejection fraction <70%, brain natriuretic peptide >400 pg/ml, and interventricular septal thickness >13 mm significantly impacted OS (P = 0.012, 0.0027, < 0.0001, respectively). Multivariate analysis indicated cardiac involvement, lower dose of melphalan, and sex as significant OS factors (P = 0.0223, 0.0168, 0.0335, respectively). Conclusion Despite the increasing availability of anti-CD38 antibody-based therapies that may reduce the necessity for HDM/SCT, HDM/SCT remains an effective treatment for patients with AL amyloidosis who have sufficient cardiac function and are deemed suitable for receiving 200 mg/m2 of melphalan.

The introduction of daratumumab has improved the treatment outcomes for multiple myeloma (MM). However, infectious complications such as pneumonia are a concern in patients receiving daratumumab. Although some reports have explored the association between daratumumab and cytomegalovirus (CMV) infection, most of these have focused on relapsed or refractory cases. There are few reports on patients with newly diagnosed MM (NDMM). In this study, we retrospectively analyzed CMV infections in 53 patients with NDMM who received daratumumab as induction therapy. CMV infection was defined as CMV antigenemia positivity. Patients who did not undergo CMV antigenemia testing were considered to have no CMV infection. The frequency of CMV infection was calculated as the cumulative incidence rate, considering death during daratumumab administration without CMV infection as a competing event. The median age at treatment initiation was 71 years (range, 50–82 years), and 50.9% of the patients were female. The median duration of daratumumab administration was 10.0 months (range, 0.3–63.8 months). Nine patients developed CMV infection, and the cumulative incidence rate at six months was 18.1% (95% confidence interval: 8.9–30.1%). One patient experienced CMV retinitis and required antiviral therapy, while the remaining eight patients did not require treatment and could be managed through observation. During daratumumab treatment for NDMM, very few cases of CMV infection required treatment. However, the incidence of CMV infection was relatively high, suggesting that regular monitoring of CMV is worth considering for more appropriate management with daratumumab treatment.

To retrospectively analyze whether the second revision of the international staging system (R2-ISS) influenced prognosis at treatment initiation in patients with multiple myeloma (MM) receiving anti-CD38 antibody-based triplet treatments. High-risk chromosomal abnormalities were examined from diagnosis to treatment initiation and considered positive if detected once. R2-ISS was recalculated at the initiation of treatment and defined as "dynamic R2-ISS." Data from 150 patients who underwent the defined treatments were analyzed. The median progression-free survival (PFS) was 19.5 months, and the median overall survival (OS) was 36.5 months. Dynamic R2-ISS significantly stratified prognoses for both PFS and OS. The median PFS for patients with dynamic R2-ISS IV was 3.3 months, and the median OS was 11.7 months, indicating extremely poor outcomes. Although the Revised International Staging System (R-ISS) calculated at the initiation of treatment significantly stratified treatment outcomes, the patients classified as R-ISS could be further stratified by R2-ISS to provide better prognostic information. Dynamic R2-ISS showed potential as a prognostic tool in patients with MM who are treated with anti-CD38 antibody-based triplet therapies.

Background: Conditioning regimens including high-dose chemotherapy and/or total body irradiation (TBI) often harm the gonads leading to infertility after hematopoietic stem cell transplantation (HSCT). Therefore, strategies to preserve fertility have been investigated to improve the quality of life of patients after HSCT. For female patients, oocyte collection followed by cryopreservation of oocytes or embryos is recommended in guidelines, but collecting oocytes before or during chemotherapy is challenging in patients with acute leukemia. For patients planned to receive TBI, ovarian shielding has been shown to achieve early ovarian function recovery after HSCT. However, only a few large-scale studies have evaluated the outcome of these strategies. Methods: We retrospectively investigated information on fertility preservation strategy and its outcome using a questionnaire among female recipients aged 16-42 years at HSCT, performed between 2001 and 2020 at 18 institutions in the Kanto Study Group for Cell Therapy. Results: This study included 201 autologous and 1421 allogeneic HSCT in 1379 patients with a median age of 32 years at HSCT. Oocytes or embryos were cryopreserved in 76 patients in total. Ovarian tissue cryopreservation was performed in 12. Of the 286 and 193 patients who underwent allogeneic HSCT with reduced-intensity conditioning (mainly for aplastic anemia) and who underwent autologous HSCT, respectively, 52 (18.2%) and 20 (10.3%) recovered menstruation and 8 (2.8%) and 13 (6.7%) became pregnant. On the other hand, of the 900 patients who underwent allogeneic HSCT with myeloablative conditioning, 26 (2.9%) recovered menstruation exclusively using TBI-regimens (>8Gy, 19 with ovarian shielding), but none who received busulfan-based regimens did so, and 10 (1.1%) became pregnant including spontaneous pregnancy in 5 (all after TBI with ovarian shielding), and 2 each using cryopreserved oocytes and egg donation, respectively. Overall, 42 pregnancies in 31 patients resulted in 32 deliveries. With regard to the feasibility of oocytes/embryos cryopreservation, 125 (11%) of the 1147 patients with available information were referred to a fertility specialist. The oocyte or ovarian tissue collection for cryopreservation was actually attempted in 49% (61 of 125 cases). Among patients with an available information on the number of cryopreserved oocytes/embryos, the median number of cryopreserved oocytes and embryos was 5 and 3, respectively, and the rate of cryopreserving at least 10 oocytes or at least 3 embryo was 41% of patients with cryopreserved oocytes/embryos. Information on the reason for no-referral was not collected, but may include low probability to harvest enough oocytes, refusal by the patients including those who already had children, and so on.Conclusion: Although cryopreservation of oocytes and embryos is challenging in patients with hematological malignancies, these assisted reproductive technologies and ovarian shielding during TBI appeared to contribute to pregnancy and delivery after HSCT.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a curative treatment option for multiple myeloma (MM), but few patients are eligible due to its high risk of treatment-related toxicity and relapse. Here, we report the feasibility and efficacy of allo-SCT after myeloablative conditioning with 8 Gy of total body irradiation (TBI) for reducing relapse of MM. We retrospectively analyzed data from 30 consecutive patients who received allo-SCT for MM after 8 Gy of TBI at Japanese Red Cross Medical Center between 2012 and 2021. Median age at allo-SCT was 47 (range 31-61) years. Stem-cell sources were peripheral blood from an HLA-matched related donor (MRD, n=5), bone marrow from an HLA-matched unrelated donor (MUD, n=5), bone marrow from an HLA-mismatched unrelated donor (MMUD, n=13), and cord blood (n=7). All patients received conditioning with 8 Gy of TBI combined with Flu/Mel (n=28) or others (n=2). Five-year PFS and 5-year OS were 36.7% and 46.2%, respectively. Sixteen patients died during the observation period (12 of primary disease and 4 of treatment-related toxicity). Patients with VGPR or better before allo-SCT had significantly better PFS (p=0.009) and OS (p=0.01) than others. Patients who received MMUD cells tended to have better PFS than those with other cell sources. Our report showed that allo-SCT for MM after 8 Gy of TBI is feasible, and the better PFS of MMUD suggests graft-versus-myeloma effects.

Abstract Recently, the second revision of the International Staging System (R2-ISS) has emerged as a prognostic tool for multiple myeloma (MM) and is known to be useful for prognostication at the time of diagnosis. Treatment outcomes for MM have significantly improved with the introduction of novel agents; however, eventual relapses nevertheless occur frequently, leading to refractory disease. Clonal evolution during relapse often results in high-risk cytogenetic abnormalities (HRCAs). Hence, a patient’s disease risk may change during their treatment course. We retrospectively analyzed whether R2-ISS influenced prognosis at treatment initiation in patients receiving anti-CD38 antibody, carfilzomib, and dexamethasone (Kd) treatments. HRCAs were examined from diagnosis to treatment initiation and considered positive if detected once. R2-ISS was recalculated at treatment initiation and defined as dynamic R2-ISS. Data from 60 patients who underwent the defined treatments were analyzed. The median observation period was 13.0 months, with a median progression-free survival (PFS) of 20.7 months. Median overall survival (OS) was not reached. Dynamic R2-ISS significantly stratified prognoses for both PFS and OS (P = 0.00011 and 0.023, respectively). The median PFS for patients with dynamic R2-ISS IV was 4.4 months, and the median OS was 14.6 months, indicating extremely poor outcomes. Multivariate analysis considering disease progression at treatment initiation, triple-class refractory status, and dynamic R2-ISS showed that only R2-ISS significantly affected both PFS and OS (P = 0.0041 and 0.019, respectively). Dynamic R2-ISS therefore shows potential as a prognostic tool in patients with MM who are treated via anti-CD38 antibody + Kd therapy.

A 28-year-old female was diagnosed with acute myeloid leukemia (AML) due to t (8;21) (q22;q22.1); RUNX1-RUNX1T1 at 21 weeks of gestation. Because no adverse prognostic genetic mutations were discovered, we decided to continue the pregnancy without chemotherapy for as long as possible. After careful monitoring with blood tests every two weeks, the disease did not progress until full-term, and a cesarean section was performed at 39 weeks of gestation. About two months after delivery, blasts in the peripheral blood increased to 46.5%, and myeloblasts in the bone marrow increased to 21.2%. The patient received idarubicin and cytarabine induction therapy, followed by three cycles of high-dose cytarabine consolidation therapy, and complete remission was maintained. Here we report a rare case who could avoid chemotherapy until full-term labor without progression of AML.

Isatuximab and daratumumab are anti-CD38 monoclonal antibodies used to treat refractory multiple myeloma. Isatuximab is often used after unsuccessful daratumumab treatment; however, the clinical benefits of receiving isatuximab after daratumumab treatment have not been fully evaluated. Therefore, this retrospective cohort study assessed the clinical outcomes of 39 patients with multiple myeloma who were administered isatuximab after daratumumab. The median follow-up period was 8.7 months (range 0.1–25.0 months). The overall response rate was 46.2

Objective Elotuzumab is used to treat relapsed and/or refractory multiple myeloma (MM). However, the optimal patient selection and sequencing in MM therapy are less clear. Therefore, this retrospective cohort study assessed the clinical outcomes of patients with MM who underwent elotuzumab-based therapy. Methods We reviewed the medical records of 85 patients with relapsed/refractory MM who received elotuzumab for the first time. Participants were divided into progressive disease (PD group) and those without PD (non-PD group) at elotuzumab treatment initiation, and each group was analyzed separately. Survival rates were calculated using Kaplan-Meier curves and compared using log-rank tests.Results The median follow-up period was 33.6 (range: 0.5-72.0) months. The median progression-free survival (PFS) and overall survival (OS) of PD and non-PD groups at elotuzumab therapy initiation were 5.3 months and not reached (NR), respectively (P < 0.0001), and 26.8 months and NR, respectively. Patients with triple-class refractory disease in both groups had worse PFS and OS. Twenty-one patients in the non-PD group received elotuzumab as post-hematopoietic stem cell transplantation, whose PFS and OS were NR (95% CI, 21.4 months-NR) and NR (95% CI, NR-NR), respectively.Conclusions Elotuzumab exhibited limited therapeutic efficacy in patients with triple-class refractory MM but better treatment outcomes in situations with adequate disease control and post-transplant treatment.

The IFM/DFCI group reported that VRD induction followed by up-front autologous peripheral blood stem cell transplantation (ASCT) and maintenance therapy led to median PFS of 50 months, which established up-front ASCT as the standard of care even in the era of novel agents. We conducted a retrospective analysis on outcomes of patients who received triplet induction therapy followed by up-front ASCT at our institution. A total of 124 patients received ASCT between November 2016 and December 2021 at Japanese Red Cross Medical Center. Patient characteristics, treatment response before and after ASCT, and PFS and OS were retrospectively analyzed. VRD-based induction therapy was used for 94%. Among 118 evaluable patients, 116 (98%) received either consolidation and/or maintenance therapy. Best responses were ≥CR 77% and ≥VGPR 94%, respectively. Sixty-eight out of 104 patients achieved MRD-negativity by multiparameter FCM (<10-5). Five-year estimated PFS and OS were 54.7% and 80.2%, respectively. Age ≥65, high-risk cytogenetic abnormalities, and <VGPR before ASCT were identified as worse prognostic factors for PFS. Patients who achieved MRD negativity had significantly PFS (p=0.0048, 4-yr PFS 86.4% vs. 49.8%). The negative impact on PFS in the high-risk group can be overcome by achieving MRD-negativity. Prospective research is warranted to evaluate the effectiveness of consolidation therapy.

BACKGROUND:To treat diseases caused by genetic variants, it is necessary to identify disease-causing variants in patients. However, since there are a large number of disease-causing variants, the application of AI is required. We propose AI to solve this problem and report the results of its application in identifying disease-causing variants. METHODS:To assist physicians in their task of identifying disease-causing variants, we propose an explainable AI (XAI) that combines high estimation accuracy with explainability using a knowledge graph. We integrated databases for genomic medicine and constructed a large knowledge graph that was used to achieve the XAI. RESULTS:We compared our XAI with random forests and decision trees. CONCLUSION:We propose an XAI that uses knowledge graphs for explanation. The proposed method achieves high estimation performance and explainability. This will support the promotion of genomic medicine.

The treatment outcomes of multiple myeloma (MM) have drastically improved with the use of novel agents, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies. However, ultimately, the disease relapses and results in a fatal outcome. Even in cases of relapse, treatment outcomes have improved with the use of novel agents. However, in situations where novel agents have been exhausted or when the disease rapidly progresses, bortezomib (Velcade), thalidomide, dexamethasone, platinum (cisplatin), adriamycin (doxorubicin), cyclophosphamide, and etoposide (VTD-PACE) is frequently utilized, with reported effectiveness. However, its outcomes in the era of monoclonal antibodies remain unclear. Therefore, this retrospective cohort study assessed the clinical outcomes of 60 patients with RRMM (median four prior treatment lines) administered VTD-PACE at the Japanese Red Cross Medical Center between June 2016 and April 2023. The characteristics of the 60 patients are shown in Table 1. The VTD-PACE regimen consisted of 1 mg/m 2 of bortezomib on days 1, 4, 8, and 11 administered subcutaneously; 200 mg of thalidomide administered orally on days 1-4; 40 mg of dexamethasone administered orally on days 1-4; and a 4-day continuous intravenous infusion of 10 mg/m 2 cisplatin, 40 mg/m 2 cyclophosphamide, 40 mg/m 2 etoposide, and 10 mg/m 2 doxorubicin. The cisplatin dose was adjusted based on renal function, as determined by the treating physician. The responses were evaluated according to the International Myeloma Working Group response criteria. High-risk cytogenetic abnormalities (HRCA) included del (17p), t(4;14), and t(14;16). Double-class refractory disease was defined as refractoriness to PIs and IMiDs, whereas triple-class refractory disease was defined as refractoriness to PIs, IMIDs, and anti-CD38 monoclonal antibodies. Penta-drug refractory disease was defined as refractoriness to bortezomib, carfilzomib, lenalidomide, pomalidomide, and anti-CD38 antibodies. The median follow-up period was 11.1 months (range, 0.5-72.0 months), during which they received a median of two cycles of VTD-PACE. The overall response (ORR), stringent complete response, complete response, and very good partial response rates were 66.7% (40 patients), 13.3% (8 patients), 5% (3 patients), and 20% (12 patients), respectively. The results of univariate analysis for factors associated with response rate are shown in Table 2. The ORRs in patients with ≥4 and ≤3 prior lines were 53.1% and 82.1%, respectively ( P = 0.027). Extramedullary disease (EMD), refractoriness to anti-CD38 antibody, HRCA, and triple-class/penta-drug refractory disease did not significantly reduce the ORR. The median overall survival (OS) was 17 months with a median progression-free survival (PFS) of 9.8 months. The median PFS in patients with and without receiving hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T-cell therapy (CART) following VTD-PACE were 9.8 and 5.1 months, respectively ( P = 0.023). The median OS in patients with and without renal dysfunction were 10.7 months and 21.5 months, respectively ( P = 0.0091). A trend for longer OS was observed in patients with HSCT or CART following VTD-PACE (P = 0.18). Therefore, VTD-PACE is useful as a bridging therapy for HSCT or CART, as a response is expected regardless of organ damage, disease risk, or history of anti-CD38 antibody use. However, the response rate decreased in late lines; therefore, its use in early lines is recommended.