Myeloma bone disease: pathogenesis and management in the era of new anti-myeloma agents.

INTRODUCTION: Multiple myeloma (MM) is a malignancy of plasma cells with characteristic bone disease. Despite recent great strides achieved in MM treatment owing to the implementation of new anti-MM agents, MM is still incurable and bone destruction remains a serious unmet issue in patients with MM. APPROACH: In this review, we will summarize and discuss the mechanisms of the formation of bone disease in MM and the available preclinical and clinical evidence on the treatment for MM bone disease. CONCLUSIONS: MM cells produce a variety of cytokines to stimulate receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis and suppress osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. MM cells alter the microenvironment through bone destruction where they colonize, which in turn favors tumor growth and survival, thereby forming a vicious cycle between tumor progression and bone destruction. Denosumab or zoledronic acid is currently recommended to be administered at the start of treatment in newly diagnosed patients with MM with bone disease. Proteasome inhibitors and the anti-CD38 monoclonal antibody daratumumab have been demonstrated to exert bone-modifying activity in responders. Besides their anti-tumor activity, the effects of new anti-MM agents on bone metabolism should be more precisely analyzed in patients with MM. Because prognosis in patients with MM has been significantly improved owing to the implementation of new agents, the therapeutic impact of bone-modifying agents should be re-estimated in the era of these new agents.

[Adult T-cell leukemia/lymphoma with multiple intracranial masses and CMV and HHV-6 reactivation at initial presentation].

A 55-year-old male was referred to our hospital after complaining of a sore throat for a month. Physical examination revealed a disturbance in consciousness, nuchal rigidity, painful multiple ulcers in the oral cavity, and erythema, the size of rice grains on the body. Hematological examination showed the following results: white blood cells, 7,910/µl (abnormal lymphocytes 2%), LDH, 203 U/l, corrected calcium, 11.2 mg/dl, soluble IL-2 receptor, 11,800 U/ml, and cytomegalovirus antigenemia assay (C10, C11) 43/49. Abnormal lymphocytes (CD4+CD25+) were discovered in the peripheral blood, bone marrow, and skin samples. Southern blotting of peripheral blood revealed monoclonal integration of human T-cell leukemia virus type 1 (HTLV-1) provirus DNA; and consequently, he was diagnosed with adult T-cell leukemia/lymphoma (ATLL). Multiple tumors with ringed contrast effect were observed in the brain parenchyma using contrast-enhanced computed tomography. The cell number in the cerebrospinal fluid was 1,320/mm3 (ATLL cells were 79% in flow cytometry), and the protein level was 244 mg/dl; moreover, the examination revealed a positive result for human herpesvirus 6 DNA. Despite herpesvirus genus treatment and modified LSG15 therapy combined with intrathecal chemotherapy, the patient became comatose and died on day 21 of hospitalization. A better understanding of the pathogenesis of ATLL, and the involvement with the central nervous system is needed along with the development of standard treatment.

A machine learning model using SNPs obtained from a genome-wide association study predicts the onset of vincristine-induced peripheral neuropathy.

Vincristine treatment may cause peripheral neuropathy. In this study, we identified the genes associated with the development of peripheral neuropathy due to vincristine therapy using a genome-wide association study (GWAS) and constructed a predictive model for the development of peripheral neuropathy using genetic information-based machine learning. The study included 72 patients admitted to the Department of Hematology, Tokushima University Hospital, who received vincristine. Of these, 56 were genotyped using the Illumina Asian Screening Array-24 Kit, and a GWAS for the onset of peripheral neuropathy caused by vincristine was conducted. Using Sanger sequencing for 16 validation samples, the top three single nucleotide polymorphisms (SNPs) associated with the onset of peripheral neuropathy were determined. Machine learning was performed using the statistical software R package "caret". The 56 GWAS and 16 validation samples were used as the training and test sets, respectively. Predictive models were constructed using random forest, support vector machine, naive Bayes, and neural network algorithms. According to the GWAS, rs2110179, rs7126100, and rs2076549 were associated with the development of peripheral neuropathy on vincristine administration. Machine learning was performed using these three SNPs to construct a prediction model. A high accuracy of 93.8% was obtained with the support vector machine and neural network using rs2110179 and rs2076549. Thus, peripheral neuropathy development due to vincristine therapy can be effectively predicted by a machine learning prediction model using SNPs associated with it.

A Genome-Wide Association Study Predicts the Onset of Dysgeusia Due to Anti-cancer Drug Treatment.

Dysgeusia is a major side effect of anti-cancer drug treatment. Since dysgeusia significantly lowers the patient's QOL, predicting and avoiding its onset in advance is desirable. Accordingly, aims of the present study were to use a genome-wide association study (GWAS) to identify genes associated with the development of dysgeusia in patients taking anti-cancer drugs and to predict the development of dysgeusia using associated single nucleotide polymorphisms (SNPs). GWAS was conducted on 76 patients admitted to the Department of Hematology, Tokushima University Hospital. Using Sanger sequencing for 23 separately collected validation samples, the top two SNPs associated with the development of dysgeusia were determined. GWAS identified rs73049478 and rs41396146 SNPs on the retinoic acid receptor beta (RARB) gene associated with dysgeusia development due to the administration of anti-cancer drugs. Evaluation of the two SNPs using 23 validation samples indicated that the accuracy rate of rs73049478 was relatively high (87.0%). Thus, the findings of the present study suggest that the rs73049478 SNP of RARB can be used to predict the onset of dysgeusia caused by the administration of anti-cancer drugs.

First reported case of Lachnoanaerobaculum gingivalis bacteremia in an acute myeloid leukemia patient with oral mucositis during high dose chemotherapy.

CASE DESCRIPTION: Lachnoanaerobaculum gingivalis is an obligate anaerobe identified in a human dental plaque in 2019. Here, we report the first case of L. gingivalis bacteremia in a patient with oral mucositis during chemotherapy. L. gingivalis was confirmed by 16S rRNA gene analysis but not by MALDI-TOF-MS. CONCLUSION: During chemotherapy in patients with oral mucositis, we should consider the possibility of L. gingivalis bacteremia.

[Primary cutaneous anaplastic large cell lymphoma with systemic progression responding to low-dose methotrexate therapy].

The standard therapies for primary cutaneous anaplastic large cell lymphoma (pcALCL) in an advanced stage remain undefined. A 71-year-old man presented with multiple erythema and nodules. He was diagnosed with lymphomatoid papulosis (LyP) through a skin biopsy from the left postauricular area. All skin lesions achieved complete response by electron beam irradiation. However, nodular lesions appeared in both inner canthi 5 months later. Histopathological evaluation of the lesional biopsy revealed dominant infiltration of CD30-positive large cells. Positron emission tomography/computed tomography revealed fluorodeoxyglucose-positive cervical and inguinal lymph node swelling and right tonsillitis, followed by the diagnosis of pcALCL and TNM classification T3bN3M0. Since the patient had severe chronic obstructive pulmonary disease and recurrent pneumonia, he received low-dose methotrexate (MTX) (15 mg/week) therapy. Low-dose MTX effectively debulked the lymphadenopathies over time without particular adverse effects. Although the standard therapies for pcALCL are not established, low-dose MTX was effective and considered safe for patients with frailty and compromised respiratory function. Further study is warranted on the pathophysiology of pcALCL after the development of LyP and mechanisms of action of low-dose MTX against LyP and pcALCL.

TAK1 is a pivotal therapeutic target for tumor progression and bone destruction in myeloma.

Along with the tumor progression, the bone marrow microenvironment is skewed in multiple myeloma (MM), which underlies the unique pathophysiology of MM and confers aggressiveness and drug resistance in MM cells. TGF-ß-activated kinase-1 (TAK1) mediates a wide range of intracellular signaling pathways. We demonstrate here that TAK1 is constitutively overexpressed and phosphorylated in MM cells, and that TAK1 inhibition suppresses the activation of NF-κB, p38MAPK, ERK and STAT3 to decrease the expression of critical mediators for MM growth and survival, including PIM2, MYC, Mcl-1, IRF4, and Sp1, along with a substantial reduction in the angiogenic factor VEGF in MM cells. Intriguingly, TAK1 phosphorylation was also induced along with upregulation of vascular cell adhesion molecule-1 (VCAM-1) in bone marrow stromal cells (BMSCs) in cocultures with MM cells, which facilitated MM cell-BMSC adhesion while inducing IL-6 production and receptor activator of nuclear factor κ-Β ligand (RANKL) expression by BMSCs. TAK1 inhibition effectively impaired MM cell adhesion to BMSCs to disrupt the support of MM cell growth and survival by BMSCs. Furthermore, TAK1 inhibition suppressed osteoclastogenesis enhanced by RANKL in cocultures of bone marrow cells with MM cells, and restored osteoblastic differentiation suppressed by MM cells or inhibitory factors for osteoblastogenesis overproduced in MM. Finally, treatment with the TAK1 inhibitor LLZ1640-2 markedly suppressed MM tumor growth and prevented bone destruction and loss in mouse MM models. Therefore, TAK1 inhibition may be a promising therapeutic option targeting not only MM cells but also the skewed bone marrow microenvironment in MM.

Effect of serum concentration and concomitant drugs on vancomycin-induced acute kidney injury in haematologic patients: a single-centre retrospective study.

PURPOSE: Appropriate use of vancomycin (VCM) is important in preventing acute kidney injury (AKI). Because of the high frequency of VCM use for febrile neutropenia and concomitant use of other nephrotoxic drugs, haematologic patients have a different nephrotoxic background compared with patients with other diseases. Therefore, it is unclear whether the risk factors of VCM-induced AKI identified in other patient groups are also applicable to haematologic patients. Herein, we performed a single-centre retrospective analysis to identify the factors associated with VCM-induced AKI in haematologic patients. METHODS: We retrospectively analysed 150 haematologic patients to whom VCM was administered between April 2010 and March 2018 at Tokushima University Hospital. VCM-induced AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. Multivariate logistic regression analyses were performed to identify risk factors for VCM-induced AKI. RESULTS: Seventeen patients had VCM-induced AKI. Multivariate analysis revealed that the risk factors of VCM-induced AKI were an initial VCM trough concentration of > 15 mg/L and concomitant use of tazobactam/piperacillin (TAZ/PIPC) and liposomal amphotericin B (L-AMB). Patients with an initial VCM trough concentration of < 10 mg/L showed significantly lower efficacy in febrile neutropenia. Interestingly, concomitant L-AMB use increased the incidence of VCM-induced AKI in a VCM concentration-dependent manner, whereas concomitant TAZ/PIPC increased the incidence in a VCM concentration-independent manner. CONCLUSIONS: The optimal initial VCM trough concentration was 10-15 mg/L in haematologic patients, considering safety and effectiveness. There were differences in the effect of VCM-induced AKI between nephrotoxic drugs.

Unique anti-myeloma activity by thiazolidine-2,4-dione compounds with Pim inhibiting activity.

Proviral Integrations of Moloney virus 2 (PIM2) is overexpressed in multiple myeloma (MM) cells, and regarded as an important therapeutic target. Here, we aimed to validate the therapeutic efficacy of different types of PIM inhibitors against MM cells for their possible clinical application. Intriguingly, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a reduced PIM2 protein levels and impaired MM cell survival preferentially in acidic conditions, in contrast to other types of PIM inhibitors, including AZD1208, CX-6258 and PIM447. SMI-16a also suppressed the drug efflux function of breast cancer resistance protein, minimized the sizes of side populations and reduced in vitro colony-forming capacity and in vivo tumourigenic activity in MM cells, suggesting impairment of their clonogenic capacity. PIM2 is known to be subject to ubiquitination-independent proteasomal degradation. Consistent with this, the proteasome inhibitors bortezomib and carfilzomib increased PIM2 protein levels in MM cells without affecting its mRNA levels. However, SMI-16a mitigated the PIM2 protein increase and cooperatively enhanced anti-MM effects in combination with carfilzomib. Collectively, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a uniquely reduce PIM2 protein in MM cells, which may contribute to their profound efficacy in addition to their immediate kinase inhibition. Their combination with proteasome inhibitors is envisioned.

Cryptosporidiosis in a transplant recipient with severe intractable diarrhea: Detection of Cryptosporidium oocysts by intestinal biopsies.

Disseminated Cryptosporidium infection results in manifestations similar to those of graft-versus-host disease (GVHD), which hampers the detection of Cryptosporidium infection after allogeneic hematopoietic stem cell transplantation. Surveillance of oocysts on the surface of intestinal epithelial cells is needed for early and appropriate detection of Cryptosporidium infection in transplant recipients on immunosuppressants with severe intractable diarrhea. We present the first case of Cryptosporidium meleagridis infection in Japan after allogeneic cord blood transplantation.

Steroid pulse therapy in patients with encephalopathy associated with severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne infectious disease caused by the SFTS virus (SFTSV). Clinical symptoms of SFTS often involve encephalopathy and other central neurological symptoms, particularly in seriously ill patients; however, pathogenesis of encephalopathy by SFTSV is largely unknown. Herein, we present case reports of three patients with SFTS, complicated by encephalopathy, admitted to Tokushima University hospital: one patient was a 63-year-old man, while the other two were 83- and 86-year-old women. All of them developed disturbance of consciousness around the 7th day post onset of fever. After methylprednisolone pulse therapy of 500 mg/day, all of them recovered without any neurological sequelae. SFTSV genome was not detected in the cerebrospinal fluid of 2 out of the 3 patients that were available for examination. In these patients, disturbance of consciousness seemed to be an indirect effect of the cytokine storm triggered by SFTSV infection. We propose that short-term glucocorticoid therapy might be beneficial in the treatment of encephalopathy during early phase of SFTSV infection.

[Analysis of long-term survivors with cardiac AL amyloidosis].

Cardiac AL amyloidosis (CA) is generally known as a severe disease with very poor prognosis. Here we retrospectively examined seven patients with CA in our cohort who achieved long-term survival. All six patients who underwent high-dose melphalan and autologous stem cell transplantation (ASCT) survived for >3 years, whereas four patients survived for >5 years. Patients who underwent ASCT had prompt hematological responses, and five patients showed organ responses. ASCT helps to achieve a quick and deep hematological response required for long-term survival in patients with CA. New agents have been implemented for the treatment of CA. However, the risks and benefits of each treatment modality should be considered according to patient condition, thus making the best use of ASCT in combination with new agents for the treatment of CA.

Clinical Evaluation of Pharmacist Interventions in Patients Treated with Anti-methicillin-Resistant Staphylococcus aureus Agents in a Hematological Ward.

The therapeutic effects of anti-methicillin-resistant Staphylococcus aureus (MRSA) agents, vancomycin (VCM), teicoplanin (TEIC), and arbekacin (ABK), depend on their concentrations in blood. Therefore, therapeutic drug monitoring (TDM) is important when these antibiotics are used. In the hematological ward at Tokushima University Hospital, pharmacists have ordered the measurement of blood VCM, TEIC, and ABK concentrations to promote the use of TDM in accordance with an agreed protocol since 2013. Moreover, the infection control team includes several medical disciplines and has advised on the optimal treatment using VCM, TEIC, and ABK since 2013. This study aimed to investigate the clinical effectiveness of these pharmacist interventions. We retrospectively studied 145 cases in which patients were treated with VCM, TEIC, or ABK between January 2012 and December 2013 in the hematological ward at Tokushima University Hospital. The patients were divided into a control group (71 cases) and an intervention group (74 cases), and their clinical outcomes were compared. The rate of achievement of effective drug concentrations significantly increased in the intervention group (74%), compared to the rate in the control group (55%). Moreover, univariate and multivariate Cox proportional hazard regression revealed that pharmacist intervention and appropriate concentrations of anti-MRSA agents were independent factors associated with reduced hospitalization periods in patients with lymphoma. Our study revealed that proactive pharmacist intervention may improve the therapeutic effect of anti-MRSA agents in hematology ward patients.

[Multiple myeloma].

Owing to the positive clinical benefits obtained with new agents, complete remission (CR) can be used as a surrogate for overall survival, and should be achieved. Although multiple myeloma is a heterogeneous disease in terms of myeloma cell- and patient-related risk factors, patients should receive the most effective combination therapy based on proteasome inhibitors and/or immunomodulatory drugs (IMiDs) as backbone medication irrespective of the risks encountered in the setting of induction therapy ("one-size-fits-all" therapy), followed by consolidation/maintenance therapy to achieve CR with the ultimate goal of extended survival. Myeloma-defining biomarkers have been established to identify high-risk smoldering myeloma requiring treatment. The development of salvage treatments yielding better outcomes for relapsed/refractory myeloma is urgently needed. Upcoming novel molecular targeting agents with different modes of action and immunotherapeutic agents will be integrated into myeloma treatment regimens with a great therapeutic impact, and further evolution of the treatment paradigm for multiple myeloma is eagerly anticipated.

[Management of bone disease in myeloma patients: zoledronic acid or denosumab?].

With improvement of survival owing to the recent implementation of new anti-myeloma (MM) agents, bone management will become more important for maintaining the quality of life (QoL) of patients. Bisphosphonates are currently the standard of care for MM-related bone disease. Zoledronic acid is recommended for newly diagnosed MM patients receiving front-line anti-MM treatment regardless of existing detectable bone lesions. Intriguingly, an overall survival benefit has been observed with zoledronic acid in patients on anti-MM treatment with documented bone disease at baseline. Denosumab, a human monoclonal antibody against RANKL, has been demonstrated to reduce bone-related events in patients with MM as effectively as zoledronic acid. Hypocalcemia is generally accepted as occurring more frequently and more severely with denosumab than with zoledronic acid, especially in patients with renal insufficiency. Bisphosphonates but not denosumab deposit in bone with a long half-life, which may make a difference in long-term efficacy as well as adverse effects. Clinical benefits of long-term anti-resorptive therapies after achieving a good response should be clarified, in order to avoid the emergence of severe complications. Impacts of new agents in combination with these anti-resorptive agents on bone metabolism have yet to be studied.

Acute suppression of translation by hyperthermia enhances anti-myeloma activity of carfilzomib.

Hyperthermia is a unique treatment option for cancers. Multiple myeloma (MM) remains incurable and innovative therapeutic options are needed. We investigated the efficacy of hyperthermia and carfilzomib in combination against MM cells. Although MM cell lines exhibited different susceptibilities to pulsatile carfilzomib treatment, mild hyperthermia at 43℃ induced MM cell death in all cell lines in a time-dependent manner. Hyperthermia and carfilzomib cooperatively induced MM cell death even under suboptimal conditions. The pro-survival mediators PIM2 and NRF2 accumulated in MM cells due to inhibition of their proteasomal degradation by carfilzomib; however, hyperthermia acutely suppressed translation in parallel with phosphorylation of eIF2α to reduce these proteins in MM cells. Recovery of ß5 subunit enzymatic activity from its immediate inhibition by carfilzomib was observed at 24 h in carfilzomib-insusceptible KMS-11, OPM-2, and RPMI8226 cells, but not in carfilzomib-sensitive MM.1S cells. However, heat treatment suppressed the recovery of ß5 subunit activity in these carfilzomib-insusceptible cells. Therefore, hyperthermia re-sensitized MM cells to carfilzomib. Our results support the treatment of MM with hyperthermia in combination with carfilzomib. Further research is warranted on hyperthermia for drug-resistant extramedullary plasmacytoma.

Ex vivo expansion and activation of Vγ9Vδ2 T cells by CELMoDs in combination with zoledronic acid.

As multiple myeloma (MM) progresses, immune effector cells decrease in number and function and become exhausted. This remains an insurmountable clinical issue that must be addressed by development of novel modalities to revitalize anti-MM immunity. Human Vγ9Vδ2 T (Vδ2+ γδ T) cells serve as the first line of defense against pathogens as well as tumors and can be expanded ex vivo from peripheral blood mononuclear cells (PBMCs) upon treatment with amino-bisphosphonates in combination with IL-2. Here, we demonstrated that next-generation immunomodulators called cereblon E3 ligase modulators (CELMoDs), as well as lenalidomide and pomalidomide, expanded Th1-like Vδ2+ γδ T cells from PBMCs in the presence of zoledronic acid (ZA). However, the expansion of Th1-like Vδ2+ γδ T cells by these immunomodulatory drugs was abolished under IL-2 blockade, although IL-2 production was induced in PBMCs. BTN3A1 triggers phosphoantigen presentation to γδ T-cell receptors and is required for γδ T-cell expansion and activation. ZA but not these immunomodulatory drugs upregulated BTN3A1 in monocytes. These results suggest that immunomodulatory drugs and ZA have cooperative roles in expansion of Th1-like Vδ2+ γδ T cells, and provide the important knowledge for clinical application of human Vδ2+ γδ T cells as effector cells.

Skeletal muscle mass during chemotherapy for haematological malignancies: a retrospective study.

OBJECTIVE: This study investigated whether baseline or alteration in muscle mass affects complications during chemotherapy or overall survival (OS) in haematological malignancies. METHODS: Skeletal Muscle Index (SMI) was evaluated by bioimpedance analysis before and after chemotherapy in patients with haematological malignancies, and the association between muscle mass and clinical data was retrospectively analysed. RESULTS: Exactly 104 patients were enrolled, with a mean age of 62.2 years. SMI was 7.85 and 6.08 in male and female patients under 65 years and 7.10 and 5.92 over 65 years, before chemotherapy, respectively. Lower baseline SMI was not correlated with worse OS in total patients (p=0.915). After a median measurement interval of 30 days after chemotherapy (n=67), body weight and SMI decreased by 2.73% and 2.87% (mean), respectively. The decrease in body weight correlated with the loss of trunk muscle mass (R2=0.2107) but was more strongly associated with the loss of lower limbs muscle mass (R2=0.3985). The muscle mass of lower limbs significantly decreased in lymphoma patients who experienced febrile neutropenia (-0.42% vs -6.04%, p=0.040). OS significantly decreased in lymphoma patients with loss of lower limbs muscle ≥2.8% (p=0.0327). CONCLUSIONS: Muscle loss occurred following anticancer treatments, significantly contributing to worse outcomes. Body composition assessment and relevant multimodal prevention of muscle loss may be vital for patients receiving chemotherapy for haematological malignancies.