Deep hematologic response to RD treatment in patients with multiple myeloma is associated with overexpression of IL-17R in CD138+ plasma cells.

Lenalidomide (LEN) is widely used immunomodulatory drug (IMiD). Nonetheless, despite its efficacy, over time patients become resistant to LEN and relapse. Due to high clinical relevance, drug resistance in MM is being thoroughly investigated. However, less is known about predictors of good response to LEN-based treatment. The aim of this study was to identify molecular pathways associated with good and long response to LEN. The study included newly diagnosed MM patients (NDMM) and MM patients treated with first-line LEN and dexamethasone (RD) who achieved and least very good partial remission (VGPR). RNA was isolated from MM cells and new-generation sequencing was performed. Obtained results were validated with qRT-PCR. A global increase in gene expression was found in the RD group compared to NDMM, suggesting the involvement of epigenetic mechanisms. Moreover, upregulation of genes controlling the interaction within MM niche was detected. Next, genes controlling immune response were upregulated. In particular, the gene encoding the IL-17 receptor was overexpressed in the RD group which is a novel finding. This should be emphasized because IL-17-related signaling can potentially be targeted, providing the rationale for future research. Establishing the molecular background associated with long-lasting and profound response to LEN may improve LEN-based chemotherapy regimens and facilitate the development of adjuvant therapies to enhance its anti-MM activity.

[Caregiving Experience With a Young Father With Multiple Myeloma Undergoing Renal Dialysis and Autologous Stem Cell Transplantation].

This case report addresses the author's experience providing nursing care to a 37-year-old patient diagnosed with multiple myeloma requiring regular renal dialysis due to disease progression who received autologous stem cell transplantation. The patient was diagnosed with cancer in young adulthood and, as a father figure, faced various psychological issues associated with the unexpected challenges encountered during their treatment phase. Psychosocial health, which is closely associated with quality of life in patients with cancer, has gained increasing attention in recent years. The limited research published on the subject of fathers diagnosed with cancer encouraged the author to detail her experience with this case. The care period was from August 5th to August 19th, 2022. During the care period, the Gordons's 11 functional health assessment was applied, with potentially severe infections, coping disorders, anxiety, potential risk of injury existing or potential nutritional deficiencies, oral mucosal changes, and diarrhea identified as the primary health problems of concern. Nursing interventions applied included providing protective isolation measures to prevent post-transplant infection, helping the patient learn effective ways to cope with emotional distress, and providing comprehensive follow-up care information and health education to alleviate the anxiety associated with hospital discharge and life after discharge. The challenges of providing nursing care to adolescent and young adult patients differ significantly from those faced in the care of either elderly or pediatric patients. Furthermore, although extensive research has been conducted on mothers diagnosed with cancer, little research has addressed the impact on the paternal role when fathers are diagnosed with cancer, with limited information available regarding their psychological concerns and issues or the impact on family dynamics. The author hopes this case care experience offers an insightful reference and guide for nursing practice that contributes to a better understanding of the psychological aspects of young adult fathers diagnosed with cancer and facilitates more appropriate care in clinical settings.

Next-Generation Therapies for Multiple Myeloma.

Recent therapeutic advances have significantly improved the outcome for patients with multiple myeloma (MM). The backbone of successful standard therapy is the combination of Ikaros degraders, glucocorticoids, and proteasome inhibitors that interfere with the integrity of myeloma-specific superenhancers by directly or indirectly targeting enhancer-bound transcription factors and coactivators that control expression of MM dependency genes. T cell engagers and chimeric antigen receptor T cells redirect patients' own T cells onto defined tumor antigens to kill MM cells. They have induced complete remissions even in end-stage patients. Unfortunately, responses to both conventional therapy and immunotherapy are not durable, and tumor heterogeneity, antigen loss, and lack of T cell fitness lead to therapy resistance and relapse. Novel approaches are under development to target myeloma-specific vulnerabilities, as is the design of multimodality immunological approaches, including and beyond T cells, that simultaneously recognize multiple epitopes to prevent antigen escape and tumor relapse.

Isolated central nervous system (CNS) relapse of multiple myeloma 11 years after autologous stem cell transplantation: a case report.

Background: Multiple myeloma (MM) relapse in the central nervous system (CNS) confers an adverse prognosis, usually occurring in a short period after stem cell transplant and with a short overall survival. Isolated CNS relapse is so rare that there is no current standard treatment. Case Description: We present a 59-year-old male with an isolated CNS MM relapse, who had received autologous stem-cell transplant (ASCT) and thalidomide maintenance 11 years prior. He returned to our clinic with cauda equina syndrome and a nuclear magnetic resonance (NMR) identified a spinal lesion, a lumbar puncture was performed and plasma cells were identified in his cerebrospinal fluid (CSF). He was initially treated with intrathecal (IT) chemotherapy with methotrexate and steroid + radiotherapy and plasma cells disappeared after a few bi-weekly doses. Later on, treatment with pomalidomide/dexamethasone was given for 12 cycles with good clinical response with 80% recovery of his motor function. Conclusions: In this rare case of a very late CNS MM relapse, we demonstrate that IT chemotherapy complemented with a systemic pomalidomide-based treatment is safe and effective. This is particularly important in contexts where newer therapies such as bispecifics, chimeric antigen receptor-T (CAR-T) cells or even daratumumab or selinexor are not widely available. Further clinical experience in this particular scenario will be required to confirm this observation and define overall the best strategy for this rare group of patients.

Recent advances in targeted drug delivery systems for multiple myeloma.

Despite significant therapeutic advances, multiple myeloma (MM) remains a challenging, incurable, hematological malignancy. The efficacy of traditional chemotherapy and currently available anti-MM agents is in part limited by their adverse effects, which restrict their therapeutic potential. Nanotherapeutics is an emerging field of cancer therapy that can overcome the biological and chemical barriers of existing anticancer drugs. This review presents an overview of recent advancements in nanoparticle- and immunotherapy-based drug delivery systems for MM treatment. It further delves into the targeting strategies, mechanism of controlled drug release, and challenges associated with the development of drug delivery systems for the treatment of MM.

Case Report: Application of 18F-FDG PET/CT in identifying plasmacytoma in monoclonal gammopathy associated peripheral neuropathy.

Peripheral neuropathy is a prevalent complication in plasma cell disorders, posing significant diagnostic and therapeutic challenges. This study presents three cases initially diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP). Despite initial symptom regression post-immunomodulatory treatment, the patients exhibited progressive neurological deficits. Advanced laboratory evaluation confirmed monoclonal protein presence, yet traditional diagnostic methods, including bone marrow biopsy and flow cytometry, yielded normal results. Utilizing 18F-FDG PET/CT, we identified multiple hypermetabolic vertebral lesions, which upon biopsy, confirmed the diagnosis of plasmacytoma. Our findings underscore the utility of PET/CT as a reliable diagnostic tool for monoclonal gammopathy associated neuropathy, advocating for its consideration in cases with equivocal diagnosis. When the diagnosis is in doubt, biopsy of a lesion may facilitate early and accurate diagnosis, potentially influencing treatment strategies and patient outcomes.

Identifying immune checkpoints on dysregulated T-cells as prognostic biomarkers for multiple myeloma patients with COVID-19.

Background: Broad T cell phenotypic alterations and potential dysfunctions were prominent in COVID-19. There are few and inconclusive data about the role of immune checkpoints for T cell exhaustion/activation during SARS-CoV-2 infection in multiple myeloma (MM) patients. Methods: We tested T cell subsets and immune checkpoints in 177 MM patients with COVID-19, as well as in 32 healthy infected controls and 42 uninfected MM patients. The percentage of CD4+ and CD8+ subpopulation and immune checkpoints (PD-1, TIGIT, TIM-3, LAG-3, CTLA-4, OX40, and 4-1BB) were evaluated by flow cytometry. Results: We have found that pronounced lymphopenia and inverted CD4/CD8 ratio in severe COVID-19 patients were especially developed within the first month after infection. And T cell subset dysregulation was persistent in severe patients recovering from SARS-CoV-2 infection. Immune checkpoints on CD4+ T cells were variable and uncorrelated with the level of adaptive immunity, while the proportion of CD4+ T cells was positively correlated with humoral immune response. PD-1 and TIGIT on CD8+ T cells were significantly elevated in severe patients and sustained for more than 2 months, which was associated with impaired cellular immune function. Moreover, exhausted molecules PD-1 and TIGIT on T cells were reduced in immunotherapy patients. Conclusion: The prolonged T cell dysregulation after severe SARS-CoV-2 infection highlights the close surveillance from reinfection in MM patients even during convalescence. PD-1 and TIGIT on CD8+ T cells could be important prognostic factors to stratify prognosis in MM patients with COVID-19. Moreover, immunotherapy may downregulate the expression of exhausted checkpoints PD-1 and TIGIT, leading to T cell overactivation and severe COVID-19.

Immunoglobulin D-Lambda Multiple Myeloma Initially Presenting in the Sphenoid Sinus, Orbital Apex, and Skull Base: A Systematic Review with a Case Report.

Objectives Multiple myeloma (MM) with initial manifestations in the sphenoid sinus, orbital apex, and skull base is exceedingly rare. A systematic review was conducted to investigate the epidemiology and advancements . Methods Relevant cases were identified by searching CNKI, WanFang Data, CQVIP databases, PubMed, Embase, and Web of Science. Additionally, we present a case of IgD-λ (immunoglobulin D-lambda) MM with initial symptoms of dizziness, unilateral pain, blindness, and ophthalmoplegia, leading to a 4-month overall survival. Strictly based on PRISMA standards, we included and summarized existing cases and reflected our case. Results Our systematic review includes 34 case reports, revealing 67.6% of patients initially presented with diplopia and 44.1% underwent endoscopic procedures, notably with only two cases of IgD-λ subtype. In our case, we performed an endoscopic wide trans-ethmoidal sphenoidotomy and biopsy of the skull base and orbital apex lesion. Postoperative pathology confirmed a highly active plasmacytoma, clinically diagnosed as IgD-λ MM with a TP53 deletion mutation and multiple extramedullary metastases. A range of diagnostic tools was employed, including hemoglobin, immunoglobulin, urinary protein analysis, positron emission tomography-computed tomography (CT), bone marrow cytology, and gene detection. Conclusion The subtle clinical manifestations of IgD-λ MM in the paranasal sinuses and skull base hinder early diagnosis. There is a paucity of literature describing MM initially presenting in these locations. CT/magnetic resonance scans are necessary to identify characteristic bone destruction. An endoscopic approach is popular for tissue biopsy. Bone marrow biopsy with a smear, serum or urine protein electrophoresis, and immunofixation electrophoresis are crucial upon the appearance of target organ damage.

Galectin-9 - ligand axis: an emerging therapeutic target for multiple myeloma.

Galectin-9 (Gal-9) is a tandem-repeat galectin with diverse roles in immune homeostasis, inflammation, malignancy, and autoimmune diseases. In cancer, Gal-9 displays variable expression patterns across different tumor types. Its interactions with multiple binding partners, both intracellularly and extracellularly, influence key cellular processes, including immune cell modulation and tumor microenvironment dynamics. Notably, Gal-9 binding to cell-specific glycoconjugate ligands has been implicated in both promoting and suppressing tumor progression. Here, we provide insights into Gal-9 and its involvement in immune homeostasis and cancer biology with an emphasis on multiple myeloma (MM) pathophysiology, highlighting its complex and context-dependent dual functions as a pro- and anti-tumorigenic molecule and its potential implications for therapy in MM patients.

Gaucher-like crystal-storing histiocytosis associated with kappa chain myeloma: A case report with next generation sequencing study.

Crystal-storing histiocytosis is a rare entity due to tumorous deposits of histiocytes containing crystalline inclusions, which in a majority of cases are made of immunoglobulins associated with lymphoproliferative disorders, although association with non-neoplastic disorders has also been reported. The histiocytes may be so abundant to obscure the underlying lymphoplasmacytic neoplasm. On the other hand, the Gaucher-like histiocytes might lead to a misinterpretation of granulomatous inflammation or storage disease. Herein, this case study reported clinical, pathological and next generation sequencing (NGS) features of a case of kappa chain myeloma with Gaucher-like crystal-storing histiocytosis in the bone marrow (BM). The methodology included BM aspiration and biopsy, immunohistochemistry, electron microscopy and NGS study by TruSight Oncology 500. Morphologically, the BM smear showed dense infiltration of sea blue histiocytes and atypical plasma cells with rhomboid crystals in cytoplasm. The BM biopsy showed excessive plasmacytic aggregates and dense histiocytic infiltrates with wrinkled paper-like or needle shaped cytoplasm. These plasma cells were positive for CD138 and showed lambda chain restriction. Electron microscopy highlighted the long rhomboid crystals with distinct periodicity consistent with crystalline immunoglobulins in the histiocytes. In addition, the NGS study from the BM aspiration specimen revealed PARP1, MSH6, KDR, CCND3 and STK11 mutations, which might be associated with inferior survival of myeloma patients. Accordingly, this case died of pneumonia with septic shock during treatment. Our findings suggest that the presence of rhomboid crystals in bone marrow smears may alert pathologists to look for the possibility of crystal-storing histiocytosis and the prognosis of patients with multiple myeloma may depend on the genetic features of tumor cells rather than the association with crystal-storing histiocytosis.

[Role of CAR-T in multiple myeloma and coordination between referring and treating centers].

Immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 antibodies have been the three mainstays of myeloma treatment. B-cell maturation antigen (BCMA)-targeted immunotherapy, including chimeric antigen receptor T-cell therapy (CAR-T) and bispecific antibodies (BsAbs), is emerging as another important class of treatment. Two BCMA-targeting CAR-T products, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel, are approved in Japan, but only ide-cel is available for clinical use. Recently, a randomized phase III study comparing ide-cel with standard therapy in patients with refractory myeloma who had received 2 to 4 prior lines of therapy showed that ide-cel was superior in terms of both response rate and PFS. Based on these results, ide-cel was approved as a third-line therapy. The new availability of bispecific antibodies has also raised new clinical questions regarding how to use CAR-T and BsAbs for each patient, and in what order. Limited data have suggested that favorable responses can be achieved when BsAbs are administered after CAR-T, but responses are suboptimal when CAR-T is administered after BsAbs. Finally, it is important to note that coordination between referring centers and treating centers, including aspects such as timing of patient referral, bridging therapy, and long-term follow-up after CAR-T, is critical to optimization of CAR-T.

[Development and prospects of bispecific antibodies for multiple myeloma].

Patients with triple-class refractory multiple myeloma once had a poor prognosis, but recently developed bispecific antibodies (bsAbs) targeting B-cell maturation antigen (BCMA), G protein-coupled receptor 5D (GPRC5D), and Fc receptor-homolog 5 (FcRH5) have shown significant clinical activity in these patients. However, responses to bsAbs are not universal, and resistance often develops during therapy. Mechanisms that mediate resistance may be tumor-intrinsic or immune-dependent. Tumor-intrinsic factors include antigen loss (biallelic or functional) due to deletion or mutation of target genes, increased soluble BCMA (for BCMA targeting bsAbs), high tumor burden, and extramedullary disease. Immune-mediated resistance highly depends on T cell fitness and the resistant immune environment. This article describes bispecific antibodies against multiple myeloma that are currently being developed.

[Current state of genetic analysis in multiple myeloma and future perspectives].

Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells. Recent advances in next-generation sequencing technologies have facilitated in-depth genetic exploration of MM, unveiling a more comprehensive genomic landscape that extends beyond classical chromosomal alterations, such as IGH translocations and hyperdiploidy. These studies have elucidated recurrent mutations across various functional pathways including those involving MAPK, NF-κB, cell cycle regulation, and epigenetic modulation. With respect to clinical utility, studies have shown that the number of genetic alterations and biallelic events in TP53 are associated with worse prognosis, and CRBN mutations with resistance to immunomodulatory drugs. We recently analyzed the full landscape of genetic alterations in relapsed and refractory MM using circulating tumor DNA (ctDNA), revealing TP53 mutations as the most frequent driver mutation. Notably, more than half of TP53 mutations were present in only ctDNA, suggesting a subclonal origin. Mutations in six genes, including KRAS and TP53, were associated with poor progression-free survival. In addition, the number of ctDNA mutations was identified as a prognostic factor independent of IGH translocations and clinical factors. Here we summarize recent progress in genetic analysis of MM, focusing on clinical relevance.

[Immune microenvironment and immunotherapy resistance in multiple myeloma].

Multiple myeloma (MM) is currently treated with combined immunotherapies targeting the immune microenvironment surrounding MM cells. Although novel immunotherapeutic agents for MM have improved complete response rates and survival time, some patients experience repeated relapses and die of MM because its progression is strongly influenced by the immune microenvironment as well as cytogenetic abnormalities of MM cells. Various studies have elucidated the mechanisms underlying the immunosuppressive immune microenvironment of MM. Recently, single-cell RNA sequencing and cytometry by time-of-flight analysis have revealed spatiotemporal crosstalk between MM and immune cells in the bone marrow of patients with MM. These studies showed that immunosuppression appears in the early stages of MM and becomes stronger as the disease progresses, leading to immunotherapy resistance. Understanding the state of the immune microenvironment in patients with MM is important for developing immunotherapeutic strategies for long-term complete response and cure.

[Practical guidance for CAR T-cell therapy in adults].

Chimeric antigen receptor (CAR) T-cell therapy is an innovative treatment for B-cell malignancies and multiple myeloma. CAR T-cell therapy is now approved in Japan and has become one of the essential therapeutic options for chemotherapy-resistant disease. It has many unique features that distinguish it from conventional chemotherapies, including the limitations imposed by the production of CAR-T cells from autologous T cells, and the limited availability and mandatory waiting period for treatment. Importantly, each patient has only one opportunity to receive CAR T-cell therapy. To achieve the maximum therapeutic benefit from CAR T-cell therapy, it is necessary to understand all aspects of CAR T-cell therapy, including factors that influence its efficacy. The design of the entire treatment sequence, including before and after CAR T-cell therapy, is also important to optimize clinical outcomes. In addition, since this treatment is only available at a limited number of facilities, effective coordination between local hospitals and treatment centers is also important. This educational session will focus on the practical aspects of CAR T-cell therapy in adults and will provide indispensable knowledge for providing CAR T-cell therapy to patients with B-cell lymphoma and multiple myeloma.

[Cost-effectiveness analysis in the treatment of hematologic malignancies].

Recent advancements in treatment have improved the prognosis of hematologic malignancies. However, the increasing cost of therapeutic drugs has become an urgent issue. Cost-effectiveness analysis is performed using the incremental cost-effective ratio (ICER), a value calculated by dividing the incremental cost by the incremental quality-adjusted life year (QALY). The ICER must be compared with the willingness-to-pay (WTP) threshold, which differs between countries. Since the analysis should be made over a long time horizon, it is necessary to model and extrapolate the long-term outcomes of clinical trials to calculate cumulative costs and QALYs. This article discusses several approaches to cost-effectiveness analysis for chronic myelogenous leukemia, multiple myeloma, and CAR-T therapy. As even expensive treatments could be cost-effective if they provide long treatment-free survival, it is essential to judge cost-effectiveness by an appropriate method, rather than price alone.

T(11;14) with multiple myeloma: Standard risk survival but slow and poor response.

We described 790 patients with newly diagnosed multiple myeloma, including 224 (28.4%) standard risk (SR) patients without t(11;14), 99 (12.5%) patients with t(11;14)alone, 58 (7.3%) with t(11;14) + HR, and 409 (51.8%) in the high-risk cytogenetic abnormality (HRCA) group including t(4;14), t(14;16), t(14;20), C1A1 and/or del(17p) but without t(11;14), to evaluate the impact of t(11;14) in NDMM patients on response rate, response kinetics and survival. Our study showed that NDMM patients in the t(11;14)alone group had similar PFS (49.3 vs. 50.7 months; P = 0.392) and OS (112.4 vs. NR months; P = 0.982) as those in the SR group. However, the t(11;14)alone group exhibited a significantly poorer depth of response compared to the SR group, particularly with a lower MRD negativity rate (60.0% vs. 76.0%, P = 0.009). In the t(11;14)alone group, MRD status did not significantly impact PFS or OS, which was in contrast to the other groups. Response kinetics analyses showed that the t(11;14)alone group had a slower response rate than the other subgroups (t(11;14)alone vs. SR vs. HRCA: median time to MRD negativity = 9.19 vs. 4.25 vs. 4.27 months; P < 0.001). Our study showed that t(11;14)alone was characterized by survival comparable to standard risk cytogenetics despite exhibiting the slowest timing of response onset and lowest plateau of remission, which suggested a relatively indolent clinical course.

Optimizing multiple Myeloma clinical trials: research direction, addressing limitations, and strategies for improvement.

Despite significant advancements in multiple myeloma (MM) treatment, including novel therapies and combination strategies, the translation of findings from randomized controlled trials (RCTs) into real-world clinical practice has been associated with several challenges. Specifically, the principles and criterion that shape the current design of MM RCTs have left out a sizable portion of patients that would particularly benefit from trial inclusion. In addition, RCTs may use primary outcomes which only partially cover patient-relevant endpoints important for evaluating treatment efficacy and quality of life. In this review, we explore the current MM RCT landscape and suggest possible solutions to improve generalizability of trial results, mitigate logistical pitfalls, and integrate real-world evidence into trials. Together, these strategies are designed to refine MM treatment guidelines and improve outcomes for all patient populations.

Differences in survival of patients with multiple myeloma in rural versus metropolitan regions: Analysis of population data of an Australian local health district.

OBJECTIVE: The objective of this study is to determine if there are differences in outcome for patients diagnosed with multiple myeloma in a rural setting compared to a metropolitan setting and which factors influence these outcomes. DESIGN: Retrospective cohort study. SETTING: Illawarra Shoalhaven Local Health District. PARTICIPANTS: A total of 391 patients diagnosed with multiple myeloma between 2000 and 2022. MAIN OUTCOME MEASURES: Treatment and survival outcomes of these patients. RESULTS: Patients being treated in a rural cancer care centre had lower overall survival compared to those treated at a metropolitan cancer care centre (median OS = 44.4 months vs. 80.2 months, p = 0.002), despite access to similar treatments by the same group of haematologists. There was a significantly higher rate of upfront autologous transplantation (38% vs. 20%, p = 0.001) and higher rate of inclusion in clinical trials (16% vs. 7%, p = 0.021) in patients treated at a metropolitan cancer care centre compared to the rural cancer care centre. CONCLUSIONS: Multiple myeloma patients treated at a rural centre had shorter survival compared to patients treated at a metropolitan centre, and this may be related to lower rates of autologous transplantation and inclusion in clinical trials.

Dynamics of minimal residual disease and its clinical implications in multiple myeloma: A retrospective real-life analysis.

BACKGROUND: Minimal residual disease (MRD) testing is a promising approach to tailor the treatment of multiple myeloma (MM). However, several major concerns remain to be addressed before moving it into daily practice, most of which stem from the dynamic natures of the MRD status. Thus, it is crucial to understand the MRD dynamics and propose its clinical implications. METHODS: We retrospectively analysed the data of patients with newly diagnosed MM (NDMM) who had flow cytometry-based MRD test at multiple time points after initiation of therapy. The impact of undetectable MRD (including attainment, duration, and loss) on clinical outcomes was analysed. RESULTS: In a cohort of 220 patients with newly diagnosed MM, attainment of MRD- offered favourable outcomes (P < 0.0001 for both PFS and OS), regardless of baseline risk factors. Notably, the MRD- duration ≥12 months was associated with an 83% (95% CI, 0.09-0.34; P < 0.0001) or 69% (95% CI, 0.13-0.76; P = 0.0098) reduction in risk of progression/death or death, while the longer MRD- was sustained, the better the outcome was. Loss of MRD- led to poor PFS (HR 0.01, 95% CI 0-0.06, P < 0.0001) and OS (HR 0.03, 95% CI 0-0.24, P = 0.0008). Most patients (70%) who lost the MRD- status carried high-risk cytogenetic abnormalities (HRCAs). While MRD- was temporally inconsistent with conventional therapeutic responses (e.g., ≥CR or VGPR), it predicted disease progression or recurrence more robustly than the latter. Last, the predictive value of the MRD status was independent of the baseline risk factors (e.g., HRCA, ISS, or R-ISS staging). CONCLUSIONS: Longitudinal assessment of MRD during the treatment course and follow-up is required for monitoring disease progression or relapse to guide treatment decisions. Accordingly, a prospective study is currently ongoing to investigate the feasibility and benefit of the MRD-tailored therapy according to the longitudinal changes of the MRD status.