The impact of daratumumab pretreatment on multiple myeloma patients undergoing autologous transplantation.

The anti-CD38 antibody daratumumab (Dara) has been reported to improve the prognosis of multiple myeloma (MM) patients, but its use before autologous stem cell transplantation (ASCT) remains controversial. To clarify the prognostic impact of Dara before ASCT on MM, we performed a retrospective observational analysis. We analyzed 2626 patients who underwent ASCT between 2017 and 2020. In the comparison between patients not administered Dara (Dara- group) and those administered Dara (Dara+ group), the 1-year progression-free survival (PFS) rates were 87.4% and 77.3% and the 1-year overall survival (OS) rates were 96.7% and 90.0%, respectively. In multivariate analysis, age <65 years (p = 0.015), low international staging system (ISS) stage (p < 0.001), absence of unfavorable cytogenic abnormalities (p < 0.001), no Dara use before ASCT (p = 0.037), and good treatment response before ASCT (p < 0.001) were independently associated with superior PFS. In matched pair analysis, the PFS/OS of the Dara- group were also significantly superior. For MM patients who achieved complete or very good partial response (CR/VGPR) by Dara addition before ASCT, both PFS and OS significantly improved. However, in patients who did not achieve CR/VGPR before ASCT, the PFS/OS of the Dara+ group were significantly inferior to those of the Dara- group.

Cytomegalovirus Reactivation during Elotuzumab Therapy in Patients with Multiple Myeloma.

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.

Cytomegalovirus infection during daratumumab therapy in patients with newly diagnosed multiple myeloma.

The introduction of daratumumab has improved treatment outcomes for multiple myeloma (MM). However, infectious complications 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, and few describe 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. 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. Few cases of CMV infection during daratumumab treatment for NDMM required treatment. However, the incidence of CMV infection was not negligible, suggesting that regular monitoring for CMV is worth considering to ensure more appropriate management during daratumumab treatment.

Prototype and evaluation of automatic fingertip-blood-sampling system that uses fingertip blood-vessel images to determine puncture position.

We are developing an automatic fingertip-blood-sampling system to reduce the burden on trained medical personnel. For this system to withdraw a consistent volume of sampled blood for blood tests, we developed a mechanism for our system to select and puncture the vicinity of a large blood vessel from the blood-vessel image of an individual's fingertip. We call this mechanism the fingertip-vessel-puncture mechanism. From the results of an experiment in which the fingertips of 20 individuals (men and women in their 20 s to 60 s) were manually punctured at near and far locations from the blood vessel selected with our mechanism, the following conclusions were obtained. The fingertip-vessel-puncture mechanism tends to increase the volume of sampled blood, thus is effective in sampling more than 650 µL of blood for automatic blood analyzers. It was also found that it is more effective in increasing the volume of sampled blood in the men and those who were younger.

[A retrospective analysis of 124 patients with multiple myeloma who received up-front autologous hematopoietic cell transplantation following triplet induction therapy].

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

Real-World Clinical Outcomes in Patients With Multiple Myeloma Administered With Elotuzumab-Based Treatment.

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.

[Updated treatment strategy for transplant-eligible multiple myeloma: current status and future perspectives].

Treatment outcomes of multiple myeloma (MM) have dramatically improved in the past 20 years. The IFM/DFCI group reported that triplet induction (bortezomib, lenalidomide, and dexamethasone), followed by up-front high-dose melphalan and autologous stem cell transplantation (HDM/ASCT) and maintenance therapy, demonstrated a median progression-free survival (PFS) of 50 months. Therefore, up-front HDM/ASCT is considered standard care even in the era of novel agents. Daratumumab, lenalidomide, and dexamethasone have also been reported to prolong PFS for newly diagnosed transplant-ineligible MM. Quadruplet induction, including anti-CD38 antibody, will be approved even for transplant-eligible MM soon. Conversely, the success of chimeric antigen receptor T-cell therapy revealed that cellular immunotherapy may play an important role in treating MM. This review discussed the current standard of care and future perspectives for transplant-eligible MM.

Real-world clinical outcomes in patients with relapsed and refractory multiple myeloma receiving VTD-PACE treatment in the era of monoclonal antibodies.

Bortezomib (Velcade), thalidomide, dexamethasone, platinum (cisplatin), adriamycin (doxorubicin), cyclophosphamide, and etoposide (VTD-PACE) are commonly used as salvage treatment for patients with relapsed/refractory multiple myeloma (RRMM). 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. The median follow-up period was 11.1 months, during which they received a median of two cycles of VTD-PACE. The overall response rate (ORR) was 66.7%; ORRs of 53.1 and 82.1% were noted in patients with ≥ 4 and ≤ 3 prior lines (P = 0.027), respectively. The median overall survival (OS) was 17 months, with a median progression-free survival (PFS) of 9.8 months. Using the 3-month time point after VTD-PACE treatment as a landmark, 54 patients were still alive. Landmark analysis was conducted for PFS and OS of patients who received or did not receive HSCT or CART after VTD-PACE treatment. Patients who underwent subsequent hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T-cell therapy (CART) following VTD-PACE showed a trend of longer PFS and OS than those who did not undergo subsequent HSCT or CART. The median OS in patients with and without renal dysfunction was 10.7 months and 21.5 months, respectively (P = 0.0091). Therefore, VTD-PACE is useful as a bridging therapy for HSCT or CART, as a response can be expected regardless of organ damage, disease risk, or history of anti-CD38 antibody use.

[Acute myeloid leukemia with t (8;21) translocation diagnosed at 21 weeks of gestation resulting in full-term delivery without chemotherapy].

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.

Clinical significance of late CMV disease in adult patients who underwent allogeneic stem cell transplant.

INTRODUCTION: Late cytomegalovirus (CMV) disease, which was defined as CMV disease occurring >100 days post-transplant, remains an important complication among allogeneic stem cell transplant recipients, even now that the prophylactic strategy using ganciclovir preemptive therapy has been established. Due to the recent expansion of donor sources and conditioning regimens, it is therefore appropriate to reevaluate the incidence, risk factors, and clinical impacts of late CMV disease. METHODS: This study included the 1295 adult patients, who underwent transplant for the first time from 2008 to 2015, without underlying disease relapse or CMV disease within 100 days post-transplant. There were no restrictions on underlying diseases or transplant procedures. RESULTS: During the median follow-up period of 48.4 months, 21 patients developed late CMV disease and the 5-year cumulative incidence of late CMV disease was 1.6%. By multivariate analysis, haploidentical related donor, adult T-cell leukemia lymphoma, and preemptive therapy before 100 days post-transplant were extracted as independent risk factors. Late CMV disease negatively affected transplant outcomes, and was identified as an independent risk factor for the non-relapse mortality rate (hazard ratio 3.83, p < 0.001) and overall survival rate (hazard ratio 4.01, p < 0.001). Although 17 of 21 patients with late CMV disease died, the main causes of death were not related to CMV, except in three patients with CMV pneumonia. CONCLUSIONS: Although the incidence of late CMV disease is low in transplant recipients, this complication negatively affects clinical courses. Therefore, transplant recipients with these risk factors should be more carefully managed.

Efficacy of Autologous Stem Cell Transplantation for Myeloma Patients with Suboptimal Response: A Multicenter Retrospective Analysis.

Autologous stem cell transplantation (ASCT) is the standard of care for myeloma patients who achieve partial response (PR) or better after induction therapy. However, its clinical significance in patients with suboptimal response (SR) before ASCT, including stable disease (SD) and progressive disease (PD), has not been established. Additionally, functional high-risk, including SR and early PD within 12 months, was a poor prognostic factor up to now. This study aimed to evaluate the efficacy of ASCT in myeloma patients with SR in the novel agent era. This multicenter retrospective study was conducted using the Transplant Registry Unified Management Program database of the Japanese Society of Transplantation and Cellular Therapy and included 3898 transplantation-eligible patients with newly diagnosed multiple myeloma who underwent ASCT between 2007 and 2020 and were followed up until 2021. The SR rate was 4.7%, including 1.7% with PD. In survival time analysis for overall cases, a significant difference in PFS between the very good partial response (VGPR) and PR groups was observed, whereas there was no significant difference in overall survival (OS) between the VGPR and PR groups. Additionally, there was no significant difference in OS or PFS between the PR and SD groups. Therefore, we focused on the PR, SD, and PD groups, as the purpose of this retrospective study was to investigate the clinical significance of ASCT in patients with SR compared with those with PR. The median patient age was 60 years (range, 30 to 77 years). In total, 1605 (97.4%) patients received bortezomib, 561 (38.2%) received an immunomodulatory drug (ImiD), and 512 (34.9%) received both bortezomib and an ImiD. A total of 558 patients (38.0%) received reinduction therapy. There were 229 patients (37.7%) with high-risk cytogenetics (HRCA). With a median follow-up of 31.7 months, there was a significant difference in 30-month OS rates among the PR, SD, and PD groups (86.3%, 78.5%, and 39.4%, respectively; P <.001). OS was significantly shorter in the SD group compared to the PR group among the patients with HRCA (P < .001) and patients treated with reinduction therapy (P = .013). In the PD group, the 30-month OS and PFS rates were 39.4% and 17.9%, respectively. Finally, early PD within 12 months after ASCT was predictive of short OS, whereas OS without early PD even in the PD group was similar to that in the SD and PR groups. In conclusion, OS in the SR group was not always short, but SR in the HRCA and the reinduction therapy groups was predictive of short OS, so that therapeutic alternatives to ASCT are needed. OS in the PD group was significantly short, but ASCT improved clinical outcomes when early PD did not occur even in the PD group.

Changing trends in the risk factors for second primary malignancies after autologous stem cell transplantation for multiple myeloma before and after the introduction of proteasome inhibitors and immunomodulatory drugs.

The incidence of second primary malignancies (SPM) in long-term survivors of multiple myeloma (MM) is increasing because of increased life expectancy. We retrospectively analyzed the risk factors for SPM in patients with MM after autologous stem cell transplantation (ASCT) before and after the introduction of proteasome inhibitors and immunomodulatory drugs (IMiDs). In total, 2,340 patients newly diagnosed with MM who underwent ASCT between 1995 and 2016 were enrolled in this study. Forty-three patients developed SPM (29 solid, 12 hematological, and 2 unknown tumors), with cumulative incidence rates of 0.8% and 2.5% at 24 and 60 months, respectively. The cumulative incidence rates of hematological and solid SPM at 60 months were 0.8% and 1.8%, respectively. The overall survival (OS) rate at 60 months after ASCT was 62.9% and the OS rates after the diagnosis of SPM at 24 months were 72.2% for hematological SPM and 70.9% for solid SPM. Multivariate analysis revealed that the use of IMiDs (P=0.024) and radiation (P=0.002) were significant independent risk factors for SPM. The probabilities of developing SPM and death due to other causes (mainly MM) at 60 months were 2.5% and 36.5%, respectively, indicating that the risk of SPM was lower than that of death from MM. Furthermore, SPM between the pre-novel and novel agent eras (ASCT between 2007 and 2016) groups significantly increased (1.9% vs. 4.3% at 60 months; P=0.022). The early occurrence of SPM after ASCT should be monitored cautiously.

Adverse impact of delay of platelet recovery after autologous hematopoietic cell transplantation for aggressive non-Hodgkin lymphoma and multiple myeloma.

BACKGROUND AIMS: The prognostic impact of platelet recovery after autologous hematopoietic cell transplantation (AHCT) on clinical outcomes remains to be elucidated. We aimed to clarify the impact of platelet recovery on clinical outcomes, risk factors of delayed platelet recovery and the necessary dose of CD34+ cells for prompt platelet recovery in each patient. METHODS: Using a nationwide Japanese registry database, we retrospectively analyzed clinical outcomes of 5222 patients with aggressive non-Hodgkin lymphoma (NHL) or multiple myeloma (MM). RESULTS: At a landmark of 28 days after AHCT, a delay of platelet recovery was observed in 1102 patients (21.1%). Prompt platelet recovery was significantly associated with superior overall survival (hazard ratio [HR] 0.32, P < 0.001), progression-free survival (HR 0.48, P < 0.001) and decreased risks of disease progression (HR 0.66, P < 0.001) and non-relapse/non-progression mortality (HR 0.19, P < 0.001). The adverse impacts of a delay of platelet recovery seemed to be more apparent in NHL. In addition to the dose of CD34+ cells/kg, disease status, performance status and the hematopoietic cell transplant-specific comorbidity index in both diseases were associated with platelet recovery. We then stratified the patients into three risk groups according to these factors. For the purpose of achieving 70% platelet recovery by 28 days in NHL, the low-, intermediate- and high-risk groups needed more than 2.0, 3.0 and 4.0 × 106 CD34+ cells/kg, respectively. In MM, the low-risk group needed approximately 1.5 × 106 CD34+ cells/kg, whereas the intermediate- and high-risk groups required 2.0 and 2.5 × 106 CD34+ cells/kg to achieve about 80% platelet recovery by 28 days. CONCLUSIONS: A delay of platelet recovery after AHCT was associated with inferior survival outcomes.

Eosinophil-rich variant of nodal marginal zone lymphoma: a clinicopathological study of 11 cases.

AIMS: Tissue eosinophilia is commonly observed in T-cell and classic Hodgkin lymphomas, but rarely in B-cell lymphomas. Herein, we present the first report of a case series on nodal marginal zone lymphoma (NMZL) with tissue eosinophilia. METHODS AND RESULTS: All 11 patients in this study had nodal disease at primary presentation. The mean age at diagnosis was 64 years. The mean follow-up period was 39 months, and all patients were alive. Nine of the 11 patients (82%) showed no recurrence, but the other two patients experienced recurrence in the lymph nodes or skin. Marked eosinophilic infiltration was observed in all biopsied lymph nodes. Nine of the 11 patients had a preserved nodular architecture with expanded interfollicular areas. The other two patients showed diffuse lymphoma cell infiltration with effacement of nodal architecture. One of them was diagnosed as having diffuse large B-cell lymphoma transformed from NMZL because large cells accounted for >50% of the lymphoma cells and formed sheet-like patterns. Cells were positive for CD20 and BCL2 and negative for CD5, CD10, and BCL6. Some patients showed myeloid cell nuclear differentiation antigen (MNDA) positivity. All patients showed B-cell monoclonality via flow cytometry, southern blotting, and/or polymerase chain reaction (PCR). CONCLUSION: All patients showed distinctive morphological features and could be misdiagnosed with peripheral T-cell lymphoma due to their eosinophil-rich backgrounds. The predominance of B cells, absence of histiocytes, and high endothelial venules in the interfollicular areas are key factors for diagnosis. B-cell monoclonality is the most reliable evidence of differentiation. We designated this type of lymphoma as an eosinophil-rich variant of NMZL.

Real-world clinical outcomes in patients with multiple myeloma treated with isatuximab after daratumumab treatment.

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% (18 patients). The 1-year overall survival was 53.9%, with a median progression-free survival of 5.6 months. The median progression-free survival in patients with high and normal lactate dehydrogenase levels was 4.5 and 9.6 months, respectively (P = 0.004). The median progression-free survival in patients with and without triple-class refractory disease was 5.1 months and not reached, respectively (P = 0.001). The median overall survival in patients with high and normal lactate dehydrogenase levels was not reached and 9.3 months, respectively (P = 0.001). The median overall survival in patients with and without triple-class refractory disease was 9.9 months and not reached, respectively (P = 0.038). Our findings provide insight into the optimal use and timing of anti-CD38 antibody therapy.

Severe short-term adverse events in related bone marrow or peripheral blood stem cell donors.

The incidence of severe adverse events (SAEs) and associated risk factors in hematopoietic cell transplantation donors needs to be clarified for related donors (relatives of the transplant recipient), whose criteria for donation are more lenient than for unrelated donors. Data from related donors registered in the Japanese national data registry database between 2005 and 2021 were evaluated to determine the association of short-term SAE incidence with donor characteristics at registration.Fourteen of 4339 bone marrow (BM) donors (0.32%) and 54 of 10,684 peripheral blood stem cell (PBSC) donors (0.51%) experienced confirmed SAEs during the short donation period. No deaths were observed. Past medical history was a common risk factor for SAEs in both BM and PBSC donors. Age of 60 years or older and female sex were identified as risk factors for SAEs in PBSC donors. Female sex was also a risk factor for poor mobilization, which resulted in discontinuation of PBSC collection.Although donors should be selected carefully, a certain level of safety is ensured for related donors in Japan. Donor safety should be further increased by improving the selection method for related donors and extending the follow-up period.

Outcomes of poor peripheral blood stem cell mobilizers with multiple myeloma at the first mobilization: A multicenter retrospective study in Japan.

Autologous stem cell transplantation (ASCT) remains an important therapeutic strategy for multiple myeloma; however, a proportion of patients fail to mobilize a sufficient number of peripheral blood stem cells (PBSCs) to proceed to ASCT. In the present study, we aimed to clarify the characteristics and outcomes of poor mobilizers. Clinical data on poorly mobilized patients who underwent PBSC harvest for almost 10 years were retrospectively collected from 44 institutions in the Japanese Society of Myeloma (JSM). Poor mobilizers were defined as patients with less than 2 × 106/kg of CD34+ cells harvested at the first mobilization. The proportion of poor mobilization was 15.1%. A sufficient dataset including overall survival (OS) was evaluable in 258 poor mobilizers. Overall, 92 out of 258 (35.7%) poor mobilizers did not subsequently undergo ASCT, mainly due to an insufficient number of PBSCs. Median OS from apheresis was longer for poor mobilizers who underwent ASCT than for those who did not (86.0 vs. 61.9 mon., p = 0.02). OS from the diagnosis of poor mobilizers who underwent ASCT in our cohort was similar to those who underwent ASCT in the JSM database (3y OS rate, 86.8% vs. 85.9%). In this cohort, one-third of poor mobilizers who did not undergo ASCT had relatively poor survival. In contrast, the OS improved in poor mobilizers who underwent ASCT. However, the OS of extremely poor mobilizers was short irrespective of ASCT.

The safety and efficacy of hematopoietic stem cell mobilization using biosimilar filgrastim in related donors.

In April 2014, the Japan Society for Hematopoietic Cell Transplantation started a prospective observational study entitled "A short-term follow-up investigation of related hematopoietic stem cell donors receiving biosimilar G-CSF to mobilize peripheral blood stem cells." A total of 106 donors were registered from 25 transplant facilities through the end of March 2017. The study cohort consisted of 47 men and 58 women, and their median age was 38.5 years (range 15-65 years). The mean total count of collected CD34-positive cells/recipient body weight for all 106 donors was 4.40 ± 2.38 × 10 6/kg. The yield of CD34-positive cells was weakly correlated with donor age was observed. However, gender, WBC count on day 4, G-CSF dose reduction, type of apheresis device, collection speed, and treated blood volume had no significant impact on the collection efficacy of CD34-positive cells. The safety profile of biosimilar G-CSF was also acceptable: 126 adverse events in 73 donors were reported, but none was serious. The most common adverse events were low back pain, headache, and bone pain. This prospective study confirmed that biosimilar G-CSF had comparable efficacy and safety to reference G-CSF for CD34-positive cell mobilization in healthy related donors.