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.

Primary analysis of a prospective cohort study of Japanese patients with plasma cell neoplasms in the novel drug era (2016-2021).

The emergence of novel drugs has significantly improved outcomes of patients with plasma cell neoplasms (PCN). The Japanese Society of Hematology conducted a prospective observational study in newly diagnosed PCN patients between 2016 and 2021. The analysis focused on 1385 patients diagnosed with symptomatic PCN between 2016 and 2018. The primary endpoint was the 3-year overall survival (OS) rate among patients requiring treatment (n = 1284), which was 70.0% (95%CI 67.4-72.6%). Approximately 94% of these patients received novel drugs as frontline therapy. The 3-year OS rate was 90.3% (95%CI 86.6-93.1%) in the 25% of patients who received upfront autologous stem cell transplantation (ASCT), versus just 61.4% (95%CI 58.0-64.6%) in those who did not receive upfront ASCT. The only unfavorable prognostic factor that affected OS in ASCT recipients was an age of 65 or higher. For patients who did not receive ASCT, independent unfavorable prognostic factors included frontline treatment with conventional chemotherapies, international staging system score of 2/3, extramedullary tumors, and Freiberg comorbidity index of 2/3. This study unequivocally demonstrates that use of novel drugs improved OS in Japanese myeloma patients, and underscores the continued importance of upfront ASCT as the standard of care in the era of novel drugs.

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.

Tandem autologous stem cell transplantation in elderly patients with myeloma: A multicenter retrospective analysis.

Tandem autologous stem cell transplantation (ASCT) has been reconsidered for high-risk patients with myeloma, and the eligibility criteria for up-front ASCT have been updated to include more elderly patients. This study aimed to evaluate the efficacy and tolerability of tandem ASCT in elderly patients with myeloma compared to tandem ASCT in young patients and single ASCT in elderly patients. A retrospective study using the Transplant Registry Unified Management Program database of the Japanese Society for Transplantation and Cellular Therapy, which included 64 elderly and 613 young patients who received tandem ASCT, and 891 elderly patients who received single ASCT, was conducted. The median overall survival (OS) over 38.5 months in the elderly and young patients who received tandem ASCT, and elderly patients who received single ASCT was 78.9, 92.5, and 77.1 months, respectively; no significant difference in the median OS was observed. The cumulative incidence of transplantation-related mortality was similar in the elderly and young patients receiving tandem ASCT. High-risk cytogenetic abnormality was not identified as a poor prognostic factor for OS in elderly patients who received tandem ASCT but in those who received single ASCT. Thus, tandem ASCT was effective and tolerable in elderly patients with myeloma.

Improved survival of multiple myeloma patients treated with autologous transplantation in the modern era of new medicine.

New drugs for multiple myeloma (MM) have dramatically improved patients' overall survival (OS). Autologous stem cell transplantation (ASCT) remains the mainstay for transplant-eligible MM patients. To investigate whether the post-ASCT prognosis of MM patients has been improved by new drugs, we undertook a retrospective observational analysis using the Transplant Registry Unified Management Program database in Japan. We analyzed 7323 patients (4135 men and 3188 women; median age, 59 years; range 16-77 years) who underwent upfront ASCT between January 2007 and December 2018. We categorized them by when they underwent ASCT according to the drugs' introduction in Japan: group 1 (2007-2010), group 2 (2011-2016), and group 3 (2017-2018). We compared the groups' post-ASCT OS. The 2-year OS rates (95% confidence interval [CI]) of groups 1, 2, and 3 were 85.8% (84.1%-87.4%), 89.1% (88.0%-90.1%), and 92.3% (90.0%-94.2%) (P < .0001) and the 5-year OS (95% CI) rates were 64.9% (62.4%-67.3%), 71.6% (69.7%-73.3%), and not applicable, respectively (P < .0001). A multivariate analysis showed that the post-ASCT OS was superior with these factors: age less than 65 years, performance status 0/1, low International Staging System (ISS) stage, receiving SCT for 180 days or less post-diagnosis, better treatment response pre-ASCT, later year of ASCT, and receiving SCT twice. A subgroup analysis showed poor prognoses for the patients with unfavorable karyotype and poor treatment response post-ASCT. The post-ASCT OS has thus improved over time (group 1 < 2 < 3) with the introduction of new drugs for MM. As the prognosis of high-risk-karyotype patients with ISS stage III remains poor, their treatment requires improvement.

A nationwide survey on central nervous system multiple myeloma in Japan: analysis of prognostic and treatment factors that impact survival.

This nationwide multicentre retrospective study was performed to analyze clinical features that predict the prognosis of central nervous system invasion in multiple myeloma (CNS-MM, approximately 1% of MM). Overall, of the 77 adult patients with CNS-MM identified between 2005 and 2016, those diagnosed at MM diagnosis (n = 3) had longer overall survival (OS) than those diagnosed at relapse (n = 74; median: 48·5 vs 2·7 months). Therefore, we compared the relapsed MM with CNS-MM in patients with any treatment (n = 60). Multivariate analyses revealed that lenalidomide treatment [hazard ratio (HR) 0·27, P = 0·003], intrathecal chemotherapy (IT; HR 0·54, P = 0·05), and radiation therapy (RTx; HR 0·33, P < 0·001) for CNS-MM had a positive effect on longer OS. These factors were used to develop a scoring system combining the number of treatments with lenalidomide, IT, and RTx (0, 1, 2, 3). The OS of CNS-MM patients was stratified based on these factors, with a median OS of 1·1, 4·5, and 7·5 months for patients with zero, one, two to three favourable features, respectively (0 vs 1, P = 0·0002; 1 vs 2-3, P = 0·08). Multimodal treatment including lenalidomide in addition to conventional IT and RTx can improve OS.

Evaluation of the Revised International Staging System (R-ISS) in Japanese patients with multiple myeloma.

In spite of recent development in the treatment armamentarium for multiple myeloma, overall survival (OS) still depends on risk status and sensitivity to treatment of each patient. We have evaluated the clinical relevance of the Revised International Staging System (R-ISS) by comparing it with the original ISS in 718 Japanese patients. The distribution of patients according to response was similar between the ISS and R-ISS stages. Treatment response was greatly influenced by initial treatment modalities and deeper response was observed more frequently in transplanted patients. The R-ISS discriminated the difference in OS between the stages more distinctly than the ISS (p = 9.0 × 10-15 and p = 4.0 × 10-10, respectively). Differences in OS were clarified by both R-ISS and ISS in non-transplanted patients (p = 2.4 × 10-12 and p = 1.4 × 10-8, respectively), but the ISS failed to distinguish the difference between the stages in transplanted patients (p = 0.13). In contrast, the R-ISS could at least discriminate the excellent prognosis of stage I patients whereas the distinction between stage II and III was not that clear (p = 0.033). The R-ISS stage II encompassed a large number of patients, and the prognosis was heterogeneous depending on the fulfillment of prognostic factors such as LDH and adverse cytogenetics. These results suggest that treatment factors and prognostic factors greatly affect the therapeutic response and outcome, and the R-ISS is superior to ISS in prognostication of both transplant-eligible and -ineligible patients in our current clinical practice.

Unsuppressed serum albumin levels may jeopardize the clinical relevance of the international staging system to patients with light chain myeloma.

The international staging system (ISS) is the most commonly used risk-stratification system for patients with multiple myeloma (MM) and is determined by serum albumin and ß2-microglobulin levels. In the two determinants, ß2-microglobulin levels are frequently observed to be elevated in patients with myeloma, particularly in those with renal impairment. In comparison with patients with intact immunoglobulin myeloma, patients with LC myeloma do not necessarily show decreased levels of serum albumin. The clinical impact of ISS in patients with LCMM, in particular the distinction between ISS I and II, may be complicated due to non-decreased levels of serum albumin in both stages. Accordingly, we have attempted to assess clinical relevance of the ISS in patients with LC myeloma. The clinical data of 1899 patients with MM diagnosed between January 2001 and December 2012 were collected from 38 affiliated hospitals of the Japanese Society of Myeloma. Significant difference was not found between stage I (n = 72) and stage II (n = 92) in LC myeloma patients (n = 307). The mean serum albumin concentration of patients with LC myeloma was within the reference range but higher than that of patients with IgG + IgA myeloma (n = 1501), which complicates the distinction between ISS stage I and II myeloma. Patients with LC myeloma had low frequencies of t(4; 14) and high frequency of elevated lactate dehydrogenase, and despite a relevant amount of missing data in our registry (R-ISS stage I; n = 11, stage II; n = 32, and stage III: n = 18), the information included in the R-ISS scoring system seems to be more accurate than ISS to obtain a reliable risk stratification approach in non-ISS stage III LC myeloma patients.

[Acute leukemia recurring as extramedullary tumors of the ovary following allogeneic hematopoietic stem cell transplantation].

The poor prognosis of extramedullary recurrence of acute leukemia following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a therapeutic challenge, and thus far no effective treatment method has been established. Here, we report two patients who presented with relapsed leukemia as extramedullary tumor in the ovary following allo-HSCT. Case 1: A 23-year-old female underwent unrelated allogeneic bone marrow transplantation during the second remission of acute myeloid leukemia. After 706 days post-transplant, bilateral ovarian tumors were detected during the pelvic ultrasound, and extramedullary recurrence in the bilateral ovaries was subsequently established on right salpingo-oophorectomy and biopsy of the left ovary. Following completed systemic chemotherapy and total body irradiation, the patient underwent unrelated cord blood transplantation (CBT) and remission was maintained without recurrence for 7 years after second transplantation. Case 2: A 49-year-old female underwent unrelated CBT during the second remission of acute lymphocytic leukemia. At 372 days post-transplant, a pelvic tumor was detected by FDG-PET/CT, and extramedullary recurrence in the right ovary was diagnosed on examination of the resected pelvic mass. Chemotherapy and radiation were performed, but the tumor recurred on day 1,027 and the patient died on day 1,603. Extramedullary recurrence of adult acute leukemia as a mass in the ovary following allo-HSCT has been rarely reported. Therefore, further accumulation of related case reports is desired.

[Philadelphia chromosome-positive acute lymphoblastic leukemia complicated by concomitant Achromobacter xylosoxidans and Corynebacterium striatum bacteremia following allogeneic hematopoietic stem cell transplantation].

A 54-year-old woman with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) underwent hematopoietic stem cell transplantation from an HLA-matched sibling. Subsequently, she suffered from chronic graft versus host disease (GvHD) and received medical treatment. Fever developed on day 697 and resulted in a shock state at 10 h after the visit. Achromobacter xylosoxidans was detected in the initial blood culture on day 699. General conditions exacerbated even after the start of meropenem hydrate (MEPM, Meropen®) administration, with Corynebacterium striatum detected as an additional species in the initial blood culture on day 701. Although vancomycin hydrochloride (VCM, Vancomycin®) was administered, the conditions did not improve. She died on day 702. Between January 2012 and December 2016, A. xylosoxidans was detected only in nine cases in our hospital, which included five with hematological malignancies and only one (present) with sepsis. At the same time, Corynebacterium species were detected in blood cultures from 39 cases in our hospital, which included 31 with hematological malignancies. Some reports on drug-resistant A. xylosoxidans and C. striatum have been published. Infections with these species may become fatal when complicated by sepsis in immunocompromised patients with hematological malignancies. More cases should be accumulated for detailed investigation.

Successful haploidentical stem cell transplantation with prophylactic administration of liposomal amphotericin B after invasive pulmonary zygomycosis.

A 54-year-old woman with acute myeloid leukemia (AML) achieved complete remission by induction chemotherapy, but developed zygomycosis after consolidation therapy. As zygomycosis could not be cured by liposomal amphotericin B and micafungin, left lower lobectomy was performed. As AML relapsed 7 months after onset, she received haploidentical stem cell transplantation under administration of liposomal amphotericin B. Despite experiencing severe acute graft-versus-host disease, she remains alive with no relapse of either zygomycosis or AML.

Post-allogeneic stem cell transplant extramedullary relapse of acute megakaryoblastic leukemia initially detected by elevated WT1 mRNA levels in peripheral blood.

An 18-year-old male was admitted to our hospital for fever, and was diagnosed with acute megakaryoblastic leukemia (AML M7) based on the presence of CD42a and CD61 positive myeloblasts in peripheral blood (PB). Induction chemotherapy at our hospital resulted in complete remission (CR). Subsequently, he underwent unrelated HLA-DR one locus-mismatched allogeneic bone marrow (BM) transplantation. Although CR was maintained without development of graft-versus-host disease (GvHD), the WT1 mRNA level in PB was elevated on post-transplant day 134. As BM aspiration performed 1 week later confirmed maintenance of CR, and because the WT1 mRNA level in BM was not high in comparison with PB, we suspected extramedullary relapse. PET-CT demonstrated a thymic tumor and a gastric tumor with abnormal accumulation of FDG, and biopsy confirmed both to be extramedullary relapse of AML M7. Induction chemotherapy following local radiation therapy achieved a second CR, following which he received HLA haploidentical peripheral blood stem cell transplantation on day 256 after the first transplant. The patient is currently surviving free from both relapse and GvHD. High WT1 mRNA levels in PB as compared with BM should raise suspicion of extramedullary relapse, and PET-CT is very useful for whole body evaluation in such cases.

Survival of multiple myeloma patients aged 65-70 years in the era of novel agents and autologous stem cell transplantation. A multicenter retrospective collaborative study of the Japanese Society of Myeloma and the European Myeloma Network.

Novel agents such as thalidomide, lenalidomide and bortezomib have dramatically changed the treatment paradigm of multiple myeloma (MM). However, it is not clear whether these agents improve the prognosis of elderly patients who have undergone autologous stem cell transplantation (auto-SCT). We retrospectively analyzed the outcome of 318 newly diagnosed patients aged 65­70 years who were treated between January 1, 2004, and December 31, 2009. As initial therapy, 192 patients were treated with conventional chemotherapy,88 with novel agent-containing regimens, 21 with conventional chemotherapy plus auto-SCT and the remaining 17 with novel agents plus auto-SCT. The median progression-free survival was 19.1, 24.5, 26.8 and 35.2 months, respectively, and the 5-year overall survival (OS) was 40, 62, 63 and 87%, respectively. Initial therapy with novel agents (p < 0.001) or auto-SCT (p < 0.02) significantly improved OS compared with the group without these treatment modalities. Salvage therapy with novel agents also significantly improved survival after relapse compared with conventional chemotherapy alone (p < 0.04). In a multivariate analysis, the use of novel agents was an independent prognostic factor significantly associated with extended OS(p < 0.003). These results indicate that novel agents and auto-SCT had a major impact on OS in eligible patients in this subgroup of MM.

Genomic vulnerability to LINE-1 hypomethylation is a potential determinant of the clinicogenetic features of multiple myeloma.

BACKGROUND: The aim of this study was to clarify the role of global hypomethylation of repetitive elements in determining the genetic and clinical features of multiple myeloma (MM). METHODS: We assessed global methylation levels using four repetitive elements (long interspersed nuclear element-1 (LINE-1), Alu Ya5, Alu Yb8, and Satellite-α) in clinical samples comprising 74 MM samples and 11 benign control samples (7 cases of monoclonal gammopathy of undetermined significance (MGUS) and 4 samples of normal plasma cells (NPC)). We also evaluated copy-number alterations using array-based comparative genomic hybridization, and performed methyl-CpG binding domain sequencing (MBD-seq). RESULTS: Global levels of the repetitive-element methylation declined with the degree of malignancy of plasma cells (NPC>MGUS>MM), and there was a significant inverse correlation between the degree of genomic loss and the LINE-1 methylation levels. We identified 80 genomic loci as common breakpoints (CBPs) around commonly lost regions, which were significantly associated with increased LINE-1 densities. MBD-seq analysis revealed that average DNA-methylation levels at the CBP loci and relative methylation levels in regions with higher LINE-1 densities also declined during the development of MM. We confirmed that levels of methylation of the 5' untranslated region of respective LINE-1 loci correlated strongly with global LINE-1 methylation levels. Finally, there was a significant association between LINE-1 hypomethylation and poorer overall survival (hazard ratio 2.8, P = 0.015). CONCLUSION: Global hypomethylation of LINE-1 is associated with the progression of and poorer prognosis for MM, possibly due to frequent copy-number loss.

Establishment of an HS23 stromal cell-dependent myeloma cell line: fibronectin and IL-6 are critical.

A multiple myeloma (MM) cell line, MSG1, which depends on HS23 stromal cells for its survival, was established from the pleural effusion of a patient with MM who expressed the M-protein of IgA-λ in his serum. During the first 2 months of culture, the myeloma cells survived on adhesive cells from the pleural effusion and, subsequently, they continued to proliferate on HS23 stromal cells. The phenotype of the established MSG1 cell line was: CD138(+), CD38(++), CD19⁻, CD56⁻, VLA-4(+), VEGFR1(+) and VEGFR2(+). Immunohistochemical staining also demonstrated expression of the IgA and λ chain in MSG1 cytoplasm. Karyotype analysis indicated complex chromosomal abnormalities; hypertriploidy, including the deletion of chromosomes 13 and 17, and c-myc translocation. MSG1 cells continued to proliferate, not only when co-cultured with HS23 cells, but also when cultured only on fibronectin-coated plates with the supernatant of HS23 cells or with control medium containing IL-6. Tocilizumab, an anti-IL-6 receptor antibody, inhibited MSG1 survival under these conditions. Therefore, MSG1 may be a unique myeloma cell line that is useful for the study of cell adhesion-mediated drug resistance induced by adhesion molecules and IL-6 stimulation of myeloma cells.