Complication Of Multiple Myeloma Research Articles

The Important Role of Egfr Change in Patients with Multiple Myeloma

Background. Renal impairment is a common complication in multiple myeloma (MM) patients and related to a higher mortality. However, whether the change of estimated glomerular filtration rate (eGFR) is associated with prognosis is not clear currently. Patients and Methods. A total of 1552 myeloma patients in West China Hospital from July 1, 2008 to September 1, 2022 were retrospectively included in this study, patients with dialysis or complicated with other malignancy were excluded. All patients had at least 3 measurements of creatinine and eGFR between 6 months and 2 years after baseline. The 1-year change in eGFR (slope) was calculated by linear regression, patients were divided into 3 groups by the eGFR slope (sustained group: eGFR slope was -5 ~ 5 ml/min per 1.73 m2 per year over 2 years; increased group: eGFR Slope > 5 ml/min per 1.73 m2 per year over 2 years; decreased group: eGFR Slope < -5 ml/min per 1.73 m2 per year over 2 years ), the Kaplan-Meier survival analysis, multiple Cox regression model and Restricted cubic spline (RCS) analysis were applied to explore the association of eGFR slope with the best efficacy and progression of myeloma patients. Results. After a median follow-up of 21 months, 977(62.95%) patients had reached VGPR or CR (the best efficacy), 24.1% patients experienced progression, the survival status is currently being followed up. The eGFR decline more than 5 ml/min per 1.73 m2 per year over 2 years (decreased group) was showed to have a higher risk of disease progression (P=0.01, Figure 1a) and to be an independent risk factor for disease progression, both in patients with (eGFR<60 ml/min per 1.73 m2) or without (eGFR>60 ml/min per 1.73 m2) renal failure (Table 1). The RCS analysis showed that the decline of eGFR within 2 years was positively related to the risk of disease progression, while the eGFR rise with a certain range could reduce the risk of progression (0-6.4 ml/min per 1.73 m2 per year) (Figure 1b). Inversely, the eGFR increased group showed a higher possibility of acquiring very good partial remission (VGPR) or complete remission (CR) (Figure 1c, P<0.001), and was a beneficial factor of reaching VGPR or CR for MM patients (HR 1.3, 95%CI 1.05-1.62, P=0.015, Table 1). The RCS analysis showed that eGFR slope was linearly correlated with patients' VGPR or CR rate (Figure 1d). Notably, in patients without renal insufficiency at baseline (eGFR>60 ml/min per 1.73 m2), eGFR improvement did not increase the rate of VGPR or CR (Table 1). Conclusions. eGFR decreasing >5 ml/min per 1.73 m2 per year over 2 years could increase the risk of disease progression in MM patients with or without renal impairment, while eGFR increasing at a certain range could reduce progression risk. For myeloma patients with renal impairment, eGFR increasing may improve the rate of VGRP or CR in MM patients.

Daratumumab, Bortezomib, and Dexamethasone for Treatment of Patients with Relapsed or Refractory Multiple Myeloma and Severe Renal Impairment: Results from the Phase 2 GMMG-DANTE Trial.

Renal function impairment (RI) is a common complication in multiple myeloma (MM). However, limited data exist on the safety and efficacy of anti-MM regimens in patients with severe RI, as these patients are frequently excluded from clinical trials. This investigator-initiated multicentric phase II GMMG-DANTE trial evaluated daratumumab, bortezomib, and dexamethasone (DVd) in relapsed or refractory (r/r) MM patients with severe RI. r/rMM patients with ≥1 prior treatment line and a GFR <30 mL/min/1.73 m2 or undergoing hemodialysis were eligible and received eight cycles of DVd followed by daratumumab maintenance. The trial closed prematurely after 22/36 planned patients. The primary endpoint was overall response rate (ORR). Median age of patients was 70 (range 55-89) years, with a median GFR of 20.1 mL/min/1.73 m2 (interquartile range, 9.4-27.3 mL/min/1.73 m2), and eight patients under hemodialysis. Median number of prior lines was two (range 1-10). The trial was successful, albeit with premature termination, as it met its primary endpoint, with an ORR of 67% (14/21). The rates of partial response, very good partial response, and complete response were 29%, 29%, and 10%, respectively (n = 6, 6, and 2). Fourteen patients (67%) achieved renal response. After median follow-up of 28 months, median progression-free survival was 10.4 months; median overall survival was not reached. Higher-grade toxicity was mainly hematologic, and non-hematologic toxicities ≥Grade 3 were mostly infections (24%). The prospective GMMG-DANTE trial investigating DVd exclusively in r/rMM patients with severe RI showed efficacy and safety to be comparable to data from patients without RI.

MM-537 Impact of Melphalan Dose and CD34+ Cell Infusion on Engraftment and Post-Transplant Complications in Multiple Myeloma (MM) Patients

MM-537 Impact of Melphalan Dose and CD34+ Cell Infusion on Engraftment and Post-Transplant Complications in Multiple Myeloma (MM) Patients

POSTER: MM-537 Impact of Melphalan Dose and CD34+ Cell Infusion on Engraftment and Post-Transplant Complications in Multiple Myeloma (MM) Patients

POSTER: MM-537 Impact of Melphalan Dose and CD34+ Cell Infusion on Engraftment and Post-Transplant Complications in Multiple Myeloma (MM) Patients

#5831 LIGHT CHAIN REMOVAL IN MULTIPLE MYELOMA PATIENTS WITH HFR-SUPRA HEMODIALYSIS: OUR EXPERIENCE

Abstract Background and Aims Kidney injury is a common complication in multiple myeloma (MM) and it has a negative prognostic implication. Most common cause of Acute Kidney Injury (AKI) in these patients is Light chain Cast Nephropathy, where free light chains precipitate in the tubules and bind with uromodulin, turning into intratubular casts that obstruct the tubules and also promote local giant cell reaction and interstitial inflammation and fibrosis. Free light chains (FLCs) can also damage the kidneys due to direct tubular toxicity when excessive amounts are reabsorbed by the proximal tubules. Targeted therapy to reduce FLC load can help recover renal function. Both total reduction and reduction speed are relevant for prognosis. FLC removal through extracorporeal techniques can be used as an adjuvant therapy, having an important part on the evolution of the disease. We gathered data from our experience treating MM patients with AKI with HFR-supra hemodialysis (HD) and analized the evolution and possible influence of this technique on renal recovery. Method This is an observational retrospective study. We included all patients with a diagnosis of multiple myeloma and acute kidney injury who received HFR-Supra hemodialysis in between years 2016-2022 in Hospital Virgen Macarena (Seville). We initially performed 6-10 daily HFR-Supra HD sessions and then modulated the frequency based on renal response (if renal replacement therapy had to be continued they underwent a usual hemodialysis regime 3 days a week). We continued these sessions until renal recovery was achieved or free light chain levels were reduced in agreement with the Hematology team. Measurement of pre and post dialysis FLCs was made always at first and last session and at least once in between, depending on the total number of sessions. Results 12 patients, with mean age at diagnosis 63.6 (43-86) years, presented with AKI stage KDIGO 3. 1 of them was oliguric. Median serum creatinine at diagnosis was 4.4 mg/dL [2,2-17], mean proteinuria was 4,1g/24 h [0,7-8,7] and 66,7% had positive Bence Jones proteinuria (mean 2,3g/24 h). 2 of the patients had previous chronic kidney disease stage 3a. All of them were diagnosed with Light Chain Multiple Myeloma (75% kappa, mean 10346 mg/L; 25% lambda, mean 5990 mg/L). Mean clonal bone marrow plasma cell was 20,7% [2-55]. According to the Revised International Staging System (R-ISS), 25% were stage 2 and 75% were stage 3. Renal biopsy was performed in 4 patients, all showed evidence of Cast Nephropathy. The indication for starting HFR-Supra HD was FLC removal in 9 patients, need of renal replacement therapy in 1 and both in 2 patients. We have experience in our center with using this therapy as an adyuvant treatment and often we start the technique in patients who present with AKI but would not necessarily have immediate need for renal replacement therapy. The goal is to remove FLCs and avoid further damage to the kidney tissue. Out of the 12 patients, 9 were able so stop dialysis (75%). They received a mean number of 12,4 [3-41] sessions in 3,7 [0,2-25] months). Free light chain removal per session was 24% on average [5-43%]. All of them were started on bortezomib-dexamethasone regime as initial chemotherapy for MM. As per renal recovery, at 3 months 33,3% achieved complete response, 11,1% partial response and 55,6% minimal response. At 1 year, 42,9% achieved complete response, 14,3% partial response and 42,9% minimal response. One-year survival rate was 91,7% (1 patient died from respiratory sepsis less than 1 month after diagnosis). Conclusion HFR-Supra hemodialyisis achieved a 24% free light chain removal per session on average. After presenting severe AKI (KDIGO 3), almost 43% of patients who received this adyuvant therapy obtained full renal recovery at 1 year and in 75% of patients withdrawal from hemodialysis was possible. 1 year survival was 91,7%.

Comparison of three risk assessment models for thromboembolism in multiple myeloma patients receiving immunomodulators: a Brazilian historical cohort.

Venous thromboembolism (VTE) is among the complications of Multiple Myeloma (MM) and may occur in up to 10% of this patient population. However, medications used in MM therapy such as immunomodulators (IMID) may raise these rates. Thus, risk prediction models have been developed to quantify the risk of VTE in MM patients. The aim of this study is to compare the performance of three risk assessment models for VTE in newly diagnosed MM (NDMM) patients using immunomodulatory agents. A historical cohort study during a 10-year period in a Brazilian metropolis with NDMM treated with IMID. Data were collected from patient's medical charts for the period of one year to calculate the scores using IMPEDE VTE, SAVED, and International Myeloma Working Group (IMWG) guidelines. The area under the curve (AUC) of the Receiver Operating Characteristic curve analysis was calculated to assess the discriminative power of three risk assessment models. We included 131 patients (9 in the VTE group versus 122 in the non VTE group). According to IMPEDE, 19.1, 62.6, and 18.3% of patients were considered low, intermediate, and high risk, respectively. SAVED classified 32.1% as high risk and 64.9% had ≥2 risk factors based on IMWG guidelines. The AUC of the IMPEDE VTE score was 0.80 (95% CI 0.66-0.95, p = 0.002), of the SAVED score was 0.69 (95% CI 0.49-0.89, p = 0.057), and of the IMWG risk score was 0.68 (95% CI 0.48-0.88, p = 0.075). IMPEDE VTE was the most accurate in predicting the development of VTE in Brazilian patients on IMID therapy. The SAVED score and the IMWG guidelines did not show discriminative ability in predicting VTE based on the population involved in this study.

Novel Local "Off-the-Shelf" Immunotherapy for the Treatment of Myeloma Bone Disease.

Myeloma bone disease (MBD) is one of the major complications in multiple myeloma (MM)-the second most frequent hematologic malignancy. It is characterized by the formation of bone lesions due to the local action of proliferating MM cells, and to date, no effective therapy has been developed. In this study, we propose a novel approach for the local treatment of MBD with a combination of natural killer cells (NKs) and mesenchymal stem cells (MSCs) within a fibrin scaffold, altogether known as FINM. The unique biological properties of the NKs and MSCs, joined to the injectable biocompatible fibrin, permitted to obtain an efficient "off-the-shelf" ready-to-use composite for the local treatment of MBD. Our in vitro analyses demonstrate that NKs within FINM exert a robust anti-tumor activity against MM cell lines and primary cells, with the capacity to suppress osteoclast activity (~60%) within in vitro 3D model of MBD. Furthermore, NKs' post-thawing cytotoxic activity is significantly enhanced (~75%) in the presence of MSCs, which circumvents the decrease of NKs cytotoxicity after thawing, a well-known issue in the cryopreservation of NKs. To reduce the tumor escape, we combined FINM with other therapeutic agents (bortezomib (BZ), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)), observing a clear therapeutic synergistic effect in vitro. Finally, the therapeutic efficacy of FINM in combination with BZ and TRAIL was assessed in a mouse model of MM, achieving 16-fold smaller tumors compared to the control group without treatment. These results suggest the potential of FINM to serve as an allogeneic "off-the-shelf" approach to improve the outcomes of patients suffering from MBD.

Смешанный тип плазмоцитом с множественной миеломой: терапия и прогноз

Extramedullary and paraskeletal plasmacytomas are not common and are usually one of the possible complications of multiple myeloma. This variant of the disease is more aggressive, less responsive to therapy, and recurs more often than conventional multiple myeloma. In our work, we described two cases of aggressively ongoing multiple myeloma with a mixed plasmacytic variant diagnosed at the time of setting the diagnosis. In both cases, a rapid progressive course was observed despite the wide range of both the newest drugs and the classical chemotherapy drugs used during treatment. Thus, this variant of the disease remains most often resistant to the therapy, with an unfavorable prognosis, and requires further study and improvement of the treatment approach to improve outcomes.

Approach to Contemporary Risk Assessment, Prevention and Management of Thrombotic Complications in Multiple Myeloma.

Multiple myeloma (MM) is associated with an increased risk of thrombotic complications, which remains substantial despite the implementation of thromboprophylaxis. The procoagulant state that characterizes the disease is multifactorial, and a greater understanding of the underlying pathophysiology is required to inform appropriate thrombosis prevention. Currently, there is a shift towards using direct oral anticoagulants (DOACs) in this setting; head-to-head comparisons in the context of controlled clinical trials between class agents are still missing. MM-specific VTE risk assessment scores have been developed to optimize management and minimize the associated mortality/morbidity. Their clinical utility remains to be evaluated. The value of adding biomarkers to clinical scores to optimize their performance and increase their discriminatory power is also under assessment.

PB2029: MULTIPLE MYELOMA AND SPINAL CORD COMPRESSION: THE EXPERIENCE OF THE HEMATOLOGY DEPARTMENT OF SFAX

Background: Spinal cord compression (SCC) is the most serious complication in Multiple myeloma (MM). An emergency that must be diagnosed and treated promptly to preserve neurological functions and save the patient’s live. Aims: We studied the clinical, biological, and radiological features of patients with MM from southern Tunisia complicated by SCC and the different modalities of treatment. Methods: It is a retrospective study over 18 years (2003-2020) which included young patients (pts) (<65years old) with MM presented SCC and treated at the hematology department of Hedi Chaker Hospital Sfax, Tunisia. Here we are interested in studying the characteristics (clinical, biological, and radiological) of affected pts, the various revealing symptoms of SCC, the possible therapeutic modalities and the outcome of patients. Results: Among 173 young pts followed with MM, 18 had SCC (10%) which was inaugural in 5 pts (27% of cases). The average age was 53 years (36- 63 years) and the sex ratio M/F= 10/8. The MM immunoglobulin type was IgG in 6 cases, IgA in 7 cases, Ig D in 1 cases and light chains in 4 cases. Symptoms of SCC included pain, motor defects, sensory deficits and bowel and bladder dysfunction in respectively 72, 11,100 and 2% of cases. While in 2 cases the SCC was asymptomatic (11%). The spinal MRI showed a cervical compression in 2 cases (11%), a dorsal compression in 8 cases (44.5%) and lumbar compression in 8 cases (44.5%). In 17 cases, lesions were first treated by radiotherapy (which did not produce regression of the compression). Decompressive laminectomy was carried out one time. All patients underwent high doses of corticosteroids. Pts were subsequently treated by different regimens of systemic therapy (DT in 12 cases, MPT in 3 cases and VTD in 3 cases). In 17 cases a definite and steady regression of the neurological symptoms was achieved. Median overall survival was 34 months after identification of SCC. At the date of last news, around 66% of the pts were dead. Summary/Conclusion: The frequency of different localizations of compression in our studies are comparable to the literature, however, the SCC rate in our series is higher than those described in the other series in literature (10% vs 5%) the same for the rate of different symptoms at diagnosis (in literature more of asymptomatic form) which could be explained by the delay in the diagnosis of MM and by the neglect of minimal symptoms by patients and their consultation only after the installation of deficient signs.

Metformin Inhibits Multiple Myeloma Serum-induced Endothelial Cell Thrombosis by Down-Regulating miR-532

Thrombotic complications in multiple myeloma (MM) impairs the quality of life in patients. Metformin has a certain effect on anti-thrombosis, but its role and mechanism in MM-induced thrombosis are still uncovered. Therefore, this study evaluated the effect of metformin on MM-induced thrombosis. Human umbilical vein endothelial cells (HUVECs) were exposed to normal serum (15%), MM serum (15%), metformin (0.01mmol/L), or MM serum, and metformin simultaneously. The expression of tissue factor (TF) in HUVECs was detected by flow cytometry and quantitative real-time polymerase chain reaction PCR (qRT-PCR). QRT-PCR was also used to determine the expressions of endothelial protein C receptor (EPCR) and miR-532. The generation of thrombin and activated protein C was measured by thrombin generation and protein C activation assays. EPCR, extracellular signal-regulated kinase (ERK) 1/2, p38 mitogen activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathway related protein expressions were detected by western blot. MM serum increased the expressions of TF and miR-532, induced thrombin generation, inhibited EPCR and protein C activation in HUVECs. And metformin could reverse the effectsof MM serum on the expressions of TF, EPCR and miR-532, thrombin generation, protein C activation in HUVECs. However, miR-532 mimic reversed the effects of metformin and promoted the levels of thrombosis-related indicators in HUVECs. Moreover, metformin activated the ERK 1/2, p38 MAPK, and NF-κB pathways but miR-532 mimic suppressed the pathway activation. Metformin played an inhibitory effect on MM serum-induced HUVEC thrombosis, suggesting that metformin could serve as a novel antithrombotic approach for MM patients.

POS-266 SPECTRUM OF GLOMERULAR LESIONS IN MULTIPLE MYELOMA: A RETROSPECTIVE STUDY OF 53 PATIENTS

Renal involvement is a major complication in multiple myeloma (MM) and it is related to higher mortality. In this study, we examined glomerular lesions found at kidney biopsy in patients with MM and renal impairment.

POS-037 MULTIPLE MYELOMA AND RENAL IMPAIREMENT: DESCRIPTIVE STUDY ABOUT 53 CASES IN NEPHROLOGY DEPARTEMENT

Multiple myeloma disease is a malignant proliferation of monoclonal plasma cells producing inadequately animmunoglobulin or its fragments. It represents 1% of cancers and 10% of malignant hemopathies. Renal impairmentis a frequent and severe complication in multiple myeloma (MM); it remains a poor prognostic factor and associatedwith a significant impact in survival.

Incidence of Arrhythmias and Their Prognostic Value in Patients With Multiple Myeloma.

Background: Arrhythmias are common cardiovascular complications in multiple myeloma (MM) patients and are related to a poor prognosis.Objective: This study aimed to assess the burden of arrhythmias and their prognostic value in patients with MM.Methods: This was a retrospective study of patients with MM between January 2015 and April 2020 at the First Affiliated Hospital of Xi'an Jiaotong University. The incidence of arrhythmia and associated risk factors were evaluated. The relationship between the type of arrhythmia and survival was analyzed.Results: A total of 319 patients with MM were identified, and 48.0% (153/319) had arrhythmias. The most common type of arrhythmia was sinus tachycardia (ST) (15.0%, 48/319), followed by sinus bradycardia (SB) (14.4%, 46/319), premature atrial contractions (PACs) (6.3%, 20/319), conduction disorders (CDs) (6.0%, 19/319), atrial fibrillation (AF) (6.0%, 19/319), premature ventricular contractions (PVCs) (4.4%, 14/319) and paroxysmal supraventricular tachycardia (PSVT) (0.6%, 2/319). The patients with arrhythmias had higher levels of log NT-proBNP and creatinine, greater bortezomib use, and a higher incidence of diabetes than those without arrhythmias (P < 0.05). The all-cause mortality rates of patients without arrhythmias and those with AF, ST, PACs, CDs, SB, and PVCs were 50.6% (84/166), 73.7% (14/19), 60.4% (29/48), 60.0% (12/20), 52.6% (10/19), 34.8% (16/46), and 28.6% (4/14), respectively. In a subgroup analysis of patients experiencing different types of arrhythmias, patients with SB had lower all-cause mortality than patients with AF (P < 0.01). Univariate and multivariate Cox analyses showed that there was a positive statistically significant association between SB and survival (HR: 0.592 [0.352–0.998], P = 0.049) in a subgroup analysis of different arrhythmias.Conclusions: Patients with MM had a heavy arrhythmia burden, and in this study, approximately half of MM patients had arrhythmias. MM patients with SB were associated with lower all-cause mortality than those with AF. SB might be an independent positive factor for prognosis.

Advances in the Treatment of Relapsed and Refractory Multiple Myeloma in Patients with Renal Insufficiency: Novel Agents, Immunotherapies and Beyond.

Simple SummaryThe treatment of patients with relapsed/refractory multiple myeloma has advanced considerably in recent years, irrespective of whether they are younger or older patients. Treating patients with relapsed/refractory multiple myeloma and renal impairment is far more complicated than treating patients with normal renal function due to the frequent dose adjustments that are necessary and the resulting loss in effectiveness.Background: Renal insufficiency is one of the most frequent complications in multiple myeloma. The incidence of renal insufficiency in patients with multiple myeloma ranges from 20% to 50%. Renal impairment in patients with multiple myeloma results primarily from the toxic effects of monoclonal light chains on the kidneys. Dehydration, hypercalcemia, hyperuricemia, the application of nephrotoxic NSARs, antibiotics, contrast agents, etc., all play a major role in the deterioration of renal function in patients with multiple myeloma. The diagnosis and treatment of these patients use an interdisciplinary approach in consultation with hematologist–oncologists, radiologists, nephrologists and intensive care specialists. Using new drugs in the treatment of patients with refractory/relapsed multiple myeloma and renal insufficiency markedly improves progression-free survival and overall survival in these patients. Conclusions: New drugs have helped to widen the treatment options available for patients with renal impairment and refractory/relapsed multiple myeloma, since dose adjustments are unnecessary with carfilzomib as well as with panobinostat, elotuzumab, pomalidomide or daratumumab in patients with renal impairment. Several new substances for the treatment of refractory/relapsed multiple myeloma have been approved in the meantime, including belantamab mafodotin, selinexor, melflufen, venetoclax, CAR T-cell therapy and checkpoint inhibitors. Ongoing studies are investigating their administration in patients with renal impairment.

The role of cystatin C in multiple myeloma.

Renal insufficiency is one of the common complications in multiple myeloma (MM) and an independent factor indicating a poor prognosis. Cystatin C (Cys C) is considered to be expected to replace creatinine to calculate glomerular filtration rate due to its own characteristics. Gene expression analysis suggested that cystatin C is up-regulated nearly 50-fold in patients with multiple myeloma. To further clarify the role of cystatin C in multiple myeloma, we retrospectively evaluated pretreatment cystatin C levels in 195 newly diagnosed patients through statistical analysis. The elevation of serum cystatin C was positively related to the elevation of serum creatinine (P<.001), LDH (P=.006), β2-microglobulin (P<.001), bone marrow plasma cell proportion (P=.005) and the reduction of hemoglobin levels (P<.001). Patients with serum cystatin C levels >1.6mg/L had a significantly shorter progression-free survival (PFS) or overall survival (OS) than patients with serum cystatin C levels <1.6mg/L (median PFS: median unreached vs 16.7months, P<.001; median OS: 68months vs 42months, P=.014). Although serum cystatin C is not an independent prognostic factor of OS and PFS in patients with multiple myeloma, serum cystatin C can be considered as a sensitive indicator to differentiate well OS and PFS in the group of ISS II patients. Serum cystatin C is associated with tumor burden of multiple myeloma and cystatin C can further differentiate the prognosis of ISS II patients. More prospective studies are required to explore the role of serum cystatin C in multiple myeloma.

Four and a Half LIM Domains Protein 2 Mediates Bortezomib-Induced Osteogenic Differentiation of Mesenchymal Stem Cells in Multiple Myeloma Through p53 Signaling and β-Catenin Nuclear Enrichment.

Myeloma bone disease (MBD), caused by the inhibition of osteoblast activity and the activation of osteoclast in the bone marrow environment, is the most frequent and life-threatening complication in multiple myeloma (MM) patients. Bortezomib (Bzb) was shown to promote MM-derived mesenchymal stem cells (MM-MSCs) differentiation to osteoblast in vitro and in animal models, promoting the bone formation and regeneration, may be mediated via β-catenin/T-cell factor (TCF) pathway. Further defining molecular mechanism of Bzb-enhanced bone formation in MM will be beneficial for the treatment of myeloma patients. The present study has identified for the first time four and a half LIM domains protein 2 (FHL2), a tissue-specific coregulator that interacts with many osteogenic marker molecules, as a therapeutic target to ameliorate MM bone disease. First, increased messenger RNA (mRNA) and protein levels of FHL2, and the mRNA level of main osteoblast markers (including Runx2, ALP, and Col1A1), were found in MM-patients-derived MSCs after Bzb treatment. FHL2 KD with short hairpin RNA (shRNA) reduced the expression of osteoblast marker genes and blocked the osteogenic differentiation of MM-MSCs regardless of the presence or absence of Bzb, implying that FHL2 is an important activator of the osteogenic differentiation of human MSCs under a proteasome inhibition condition. Molecular analysis showed that the enhanced expression of FHL2 was associated with the Bzb-induced upregulation of p53. No significant change at protein level of total β-catenin was observed with or without Bzb treatment. However, it was mostly enriched to nuclei in MSCs after Bzb treatment. Moreover, β-catenin was restricted to the perinuclear region in FHL2 KD cells. These data provide evidence that FHL2 is essential for promoting β-catenin nuclear enrichment in MM-MSCs. In conclusion, FHL2 is critical for Bzb-induced osteoblast differentiation of MM-MSCs and promotes the osteogenesis, through p53 signaling and β-catenin activation. Targeting FHL2 in MM may provide a new therapeutic strategy for treating MBD.

Melphalan flufenamide inhibits osteoclastogenesis by suppressing proliferation of monocytes

Myeloma bone disease is a major complication in multiple myeloma affecting quality of life and survival. It is characterized by increased activity of osteoclasts, bone resorbing cells. Myeloma microenvironment promotes excessive osteoclastogenesis, a process of production of osteoclasts from their precursors, monocytes. The effects of two anti-myeloma drugs, melphalan flufenamide (melflufen) and melphalan, on the activity and proliferation of osteoclasts and their progenitors, monocytes, were assessed in this study. In line with previous research, differentiation of monocytes was associated with increased expression of genes encoding DNA damage repair proteins. Hence monocytes were more sensitive to DNA damage-causing alkylating agents than their differentiated progeny, osteoclasts. In addition, differentiated progeny of monocytes showed increased gene expression of immune checkpoint ligands which may potentially create an immunosuppressive microenvironment. Melflufen was ten-fold more active than melphalan in inhibiting proliferation of osteoclast progenitors. Furthermore, melflufen was also superior to melphalan in inhibition of osteoclastogenesis and bone resorption. These results demonstrate that melflufen may exert beneficial effects in patients with multiple myeloma such as reducing bone resorption and immunosuppressive milieu by inhibiting osteoclastogenesis.

Crystalcryoglobulinemia as a manifestation of monoclonal gammopathy of renal significance in a patient with renal cell carcinoma

Crystalcryoglobulinemia refers to the extracellular deposition of crystals in the systemic vasculature, leading to vascular injury, thrombosis, and occlusion. This entity is usually described as a complication of multiple myeloma, although it can also occur in the setting of a monoclonal gammopathy of renal significance. Synchronous presentation of a monoclonal gammopathy and renal cell carcinoma is rare. Hypothetically, as both neoplasms’ growth depends on certain cytokines such as interleukin-6, it is possible that cytokine production from one neoplasm may stimulate the growth of the other. In this report, we describe a case of crystalcryoglobulinemia in a patient with a monoclonal gammopathy of renal significance and concomitant renal cell carcinoma. Additionally, we performed a systematic review of the literature and analyzed data of 61 reported cases of crystalcryoglobulinemia and of 40 reported cases describing the association between multiple myeloma and renal cell carcinoma.

Role of adjunct plasma exchange or high cut-off hemodialysis in the management of myeloma cast nephropathy: A systematic review.

e20032 Background: Renal impairment by cast nephropathy is a common complication in multiple myeloma. Tubulointerstitial injury results from precipitation of filtered free light chains (FLC) with Uromodulin in the distal convoluted tubules. Rapid reduction in serum FLC levels has shown to improve renal function in modeling studies. Extracorporeal light chain removal techniques such as plasma exchange (PEX) and high cut-off hemodialysis (HCO-HD) have been explored as potential adjunct treatment options for cast nephropathy in various clinical trials. Methods: PubMed, Cochrane library, and Clinicaltrials.gov were searched systematically for the use of plasma exchange and/or hemodialysis with chemotherapy in the treatment of myeloma cast nephropathy using their MeSH words and keywords. PRISMA guidelines were followed for screening and 5 out of 866 studies were finalized (N = 342). Results: Zucchelli et al. 1988 (n = 29) reported a dramatic reduction in Bence Jones protein (BJP) levels of 0.81 ± 0.46 g/day (P value &lt; 0.01) and 1-year survival rate of 66% in the PEX group and decrease in BJP of 3.25 +/- 0.21 g/day (P-value &lt; 0.05) with a survival rate of 28% in the control group. Clark et al. 2005 (n = 104) reported a primary composite response (patient alive at 6 months + dialysis independence + serum creatinine improvement of 50% at 6 months) in 57.9% of patients in the PEX group and 69.2% in the control group [95% CI, -8.3% to 29.1%]; P = 0.36. Johnson et al. 1990 (n = 21) reported a mean change of 880 μmol /L ± 260(SD) in serum creatinine in the PEX group and 570 μmol /L +/-240 in the control group. HD independence at 3 months was reported as 41.3% (n = 19) in the HCO-HD group and 33.3% (n = 16) in the conventional HD group (95% CI -12%–27.9%; P = 0.42) in the MYRE trial 2017 (n = 98). The EuLITE trial 2019 (n = 90) compared the efficacy of the high cut-off vs high flux hemodialysis (HF-HD) technique and concluded that there was no clinical benefit of one over the other. Independence from HD was achieved in 56% (n = 24) in the HCO-HD cohort vs 51% (n = 24) in HF-HD cohort (relative risk [RR] 1.09, 95% CI 0.74–1.61; P = 0.81). Conclusions: The use of high cut-off hemodialysis and plasma exchange as adjunct therapy did not show any significant survival benefit or improvement in clinical outcome. The role of routine use of PEX/HCO-HD in the management of cast nephropathy is still unclear and the decision to use these modalities should be made on an individual basis.