Chinese Multiple Myeloma Patients Research Articles

Safety and feasibility analysis of rapid daratumumab infusion in Chinese patients with multiple myeloma.

With the increasing use of daratumumab (DARA)-containing regimens for multiple myeloma (MM) patients in China, the standard infusion time of DARA is long, with the potential for infusion-related reactions (IRRs) and increased hospitalization and use of resources. Shortening the duration of DARA infusion helps to optimize the hospital stay and enhance the patient treatment experience. The current, commonly used 90-min rapid DARA infusion regimen may not be applicable to Chinese MM patients, and therefore, we explored a new 110-min rapid DARA infusion regimen aimed at reducing the treatment burden on patients to guarantee therapeutic safety. MM inpatients treated with the DARA regimen were divided into two groups according to the number of times the DARA regimen was used: a standard infusion regimen for patients treated with the first two doses of DARA and a 110-min rapid infusion regimen for patients treated with more than two doses of DARA. Anti-allergy medications were routinely administered prior to the start of DARA infusion, patient consent, and authorization was obtained for all treatments, and statistical evaluation of the results was conducted via descriptive analyses, one-way ANOVA and chi-square tests. A total of 129 patients were included in this study: 68 in the standard infusion group, with 121 DARA infusions, and 129 in the rapid infusion group (patients who participated in the standard infusion subsequently participated in the rapid infusion), with 738 DARA infusions. The incidence of IRRs was 27.27% (36/121) in the standard infusion group and 1.35% (10/738) in the rapid infusion group, which were significantly different (p < 0.001). The incidence of IRRs after rapid infusion in other studies was <6%. The incidence of grade 1 IRRs in the rapid infusion group was 0.81% (6/738), the incidence of grade 2 IRRs was 0.54% (4/738), and there were no IRRs above grade 3; age, sex, and underlying disease had no effect on the choice of infusion method (p > 0.05). The mean infusion time after the occurrence of IRRs was also shorter in the rapid infusion group than in the standard infusion group (F = 24.781, p < 0.001). The 110-min rapid infusion DARA regimen is feasible and safe for use in Chinese MM patients.

Evaluation of next-generation sequencing versus next-generation flow cytometry for minimal-residual-disease detection in Chinese patients with multiple myeloma

PurposeTo evaluate the efficacy of next-generation sequencing (NGS) in minimal-residual-disease (MRD) monitoring in Chinese patients with multiple myeloma (MM).MethodsThis study analyzed 60 Chinese MM patients. During MRD monitoring in these patients’ post-therapy, clonal immunoglobulin heavy chain (IGH) rearrangements were detected via NGS using LymphoTrack assays. MRD monitoring was performed using NGS or next-generation flow cytometry (NGF), and the results were compared. Additionally, the sensitivity and reproducibility of the NGS method were assessed.ResultsThe MRD detection range of the NGS method was 10–6–10–1, which suggested good linearity, with a Pearson correlation coefficient of 0.985 and a limit of detection of 10–6. Intra- and inter-assay reproducibility analyses showed that NGS exhibited 100% reproducibility with low variability in clonal cells. At diagnosis, unique clones were found in 42 patients (70.0%) with clonal IGH rearrangements, which were used as clonality markers for MRD monitoring post-therapy. Comparison of NGS and NGF for MRD monitoring showed 79.1% concordance. No samples that tested MRD-positive via NGF were found negative via NGS, indicating the higher sensitivity of NGS. MRD could be detected using NGS in 6 of 7 samples before autologous hematopoietic stem-cell transplantation, and 5 of them tested negative post-transplantation. In contrast, the NGF method could detect MRD in only 1 sample pre-transplantation.ConclusionCompared with NGF, NGS exhibits higher sensitivity and reproducibility in MRD detection and can be an effective strategy for MRD monitoring in Chinese MM patients.

Current status and challenges of immunotherapy for multiple myeloma

Multiple myeloma (MM) is the second most common hematologic malignancy and the incidence of MM in mainland China in 2016 was 1.15/100 000.With the development of China's aging society, the incidence of MM is expected to increase year by year. Immunotherapy for MM has become the fourth pillar of therapy after autologous hematopoietic stem cell transplantation, immunomodulators, and proteasome inhibitors, and is the most active area of MM treatment. Nine new drugs have been approved for multiple myeloma treatment in China, and three are expected to be approved in 2024, which will focus on immunotherapy. There are many ambiguities about the current status of research and utilization in this emerging field in China. Determining the optimal integration of these therapies into the treatment regimen for Chinese MM patients constitutes a critical challenge for clinicians. Immunotherapy for MM primarily encompasses two major categories: antibody-based drug therapy and cellular immunotherapy. Antibody-based medications primarily include monoclonal antibodies, T-cell engagers, IgG-like bispecific antibodies, and trispecific antibodies. Cellular immunotherapy mainly consists of chimeric antigen receptor T (CAR-T) cells, as well as other immune cells such as chimeric antigen receptor natural killer (CAR-NK) cells, dendritic cells, T cell receptor-engineered T cells, and peptide vaccines.This article mainly focuses on the current research status and existing issues of the aforementioned immunotherapy methods, with the aim of providing references for the treatment of MM.

Validation of the IMPEDE VTE score for prediction of venous thromboembolism in Chinese patients with multiple myeloma: A single-center retrospective cohort study

Multiple myeloma (MM) significantly increases the risk of venous thromboembolism (VTE) within 6 months of treatment initiation. The IMPEDE VTE score is a VTE risk prediction model which is recently incorporated into the National Comprehensive Cancer Network (NCCN) guidelines, but it lacks validation among Asians, including Chinese MM patients. We performed a retrospective chart review of 405 Chinese with newly diagnosed MM who started therapy at Beijing Jishuitan Hospital between April 2013 to October 2022. The 6-month cumulative incidence of VTE was 3.8 % (95 % CI:1.6–7.6), 8.6 % (95 % CI: 5.3–21.9) and 40.5 % (95 % CI: 24.9–55.7) in the low-, intermediate- and high-risk groups (P < 0.001), respectively. The C-statistic of the IMPEDE VTE scores for predicting VTE within 6 months of treatment initiation was 0.74 (95 % CI: 0.65–0.83). Of note, in this single-center cohort study, we propose that the anticoagulant LMWH may be more effective than the antiplatelet aspirin in potentially preventing VTE in newly diagnosed MM patients. Our findings suggest that the IMPEDE VTE score is a valid evidence-based risk stratification tool in Chinese patients with newly diagnosed MM.

The development and validation of a liquid chromatography tandem mass spectrometry method for the quantification of selinexor and its application in Chinese multiple myeloma patients.

Selinexor is a nuclear exportin-1 (XPO1) inhibitor that has been approved for the treatment of multiple myeloma patients. However, sustained use of selinexor may result in some undesirable consequences. Furthermore, selinexor has moderate inter-patient variability. Herein, we developed an ultrahigh-performance liquid chromatography tandem mass spectrometry method for measuring selinexor levels in human plasma ranging from 1 to 1000 ng mL-1. Furthermore, the developed approach was validated in accordance with FDA criteria. The established approach demonstrated inter-day and intra-day precision, expressed as the relative standard deviation, of less than 8%, with accuracies of less than 6%, expressed as relative error. The results showed that the protein depletion was quite complete for selinexor extraction, with recoveries ranging from 85.89 to 108.38%. The validated method facilitates the quantitation of selinexor in multiple myeloma patients. The selinexor plasma concentration exhibits obvious inter-patient' variability after administration. Thus, it is necessary to make a personalized prescription through therapeutic drug monitoring. Furthermore, the change in platelet counts before and after selinexor treatment was shown to be related to the plasma concentration at 3 h after administration, which provides the basis for therapeutic drug monitoring sampling time points and a method for predicting the occurrence of thrombocytopenia. In conclusion, the developed method can be used for the quantification of the plasma concentration of selinexor, and it is of great significance to conduct therapeutic drug monitoring for patients taking selinexor in order to enhance therapeutic effects and prevent the occurrence of adverse reactions.

A genetic variant study of bortezomib-induced peripheral neuropathy in Chinese multiple myeloma patients.

Bortezomib results in peripheral neuropathy (PN) in approximately 50% of patients, during multiple myeloma (MM) treatment, a complication known as Bortezomib-induced peripheral neuropathy (BIPN). The drug response varies among individuals. Genetic factor may play an important role in BIPN. A next-generation sequencing (NGS) panel containing 1659 targets from 233 genes was used to identify risk variants for developing BIPN in 204 MM patients who received bortezomib therapy. mRNA expression of MTHFR and ALDH1A1 in 62 peripheral blood samples was detected by real-time quantitative PCR (RT-qPCR). Serum homocysteine (Hcy) levels were detected in 40 samples by chemiluminescent microparticle immunoassay (CMIA). Compared with the non-BIPN group (n = 89), a total of 8 significantly associated single nucleotide polymorphisms (SNPs) were identified in the BIPN group (n = 115): MTHFR (rs1801131, rs1801133, rs17421511), EPHX1 (rs1051740), MME (rs2016848), ALDH1A1 (rs6151031), HTR7 (rs1935349) and CYP2A6 (rs8192720). The mRNA expression level of MTHFR in newly diagnosed patients with peripheral neuritis after treatment (NP group) was lower than that of newly diagnosed patients without peripheral neuritis after treatment (NnP group) (1.70 ± 0.77 vs. 2.81 ± 0.97, p= 0.009). Serum Hcy levels were significantly higher in BIPN group than in non-BIPN group (11.66 ± 1.79 μmol/L vs. 8.52 ± 3.29 μmol/L, p= 0.016) and healthy controls (11.66 ± 1.79 μmol/L vs. 8.55 ± 2.13 μmol/L, p≤ 0.001). CYP2A6, EPHX1, MTHFR, ALDH1A1, HTR7, MME and BIPN are linked in Chinese MM patients. BIPN is more likely to occur in patients with lower MTHFR mRNA expression, which might result in higher serum Hcy levels.

Treatment Patterns and Outcomes in Patients with Multiple Myeloma Who Received Ixazomib and in Patients with Triple-Class Refractory Multiple Myeloma: A Retrospective, Observational, Real-World Historical Database Analysis Study from China

Background: Multiple myeloma (MM) is a fatal, malignant disease of plasma cells characterized by an abnormal proliferation of monoclonal antibodies. China is estimated to have 22,450 newly diagnosed (ND) cases of MM and 17,360 related deaths in 2022. Emerging novel therapies have significantly improved survival in MM, and treatment guidelines have been updated to reflect these advances. Ninlaro® (ixazomib) is the first oral proteasome inhibitor (PI) approved by the US FDA in 2015 and by China's National Medical Products Administration in 2018 (conditionally) for MM patients receiving ≥1 prior therapy owing to its convincing efficacy and well-tolerated safety profile as seen in the landmark Phase III TOURMALINE-MM1 trial and the China Continuation Study. Novel drugs such as PIs, immunomodulatory drugs (IMDs), and anti-CD-38 monoclonal antibodies are the core component of MM treatment and have improved patient outcomes considerably. However, many patients remain refractory to these drugs (triple-class refractory, TCR) and have poor clinical outcomes. There is a lack of real-world evidence characterizing treatment patterns and outcomes of MM patients receiving ixazomib and TCR-MM patients, in China. The objective of this study is to bridge this data gap by providing vital information on the treatment patterns and outcomes, and healthcare resource utilization in Chinese MM patients receiving ixazomib and TCR-MM patients in real-world clinical practice. Study Design and Methods: This study is an ongoing, single-centre, non-interventional, retrospective database analysis study of MM patients identified from the Chinese National Longitudinal Cohort of Haematologic Diseases (NICHE)-MM registry, a historical and ongoing longitudinal data registry of the Institute of Haematology and Blood Diseases Hospital (IHBDH), and representing the top-tier MM care in China. The patients will be divided into two groups. Patients (aged ≥18 years) with a confirmed MM diagnosis receiving all ixazomib-based regimen as 2nd-line and above therapy (RR-MM), or as a 1st-line therapy (ND-MM) will form group one and TCR-MM patients' refractory to at least one IMiD (lenalidomide, pomalidomide or thalidomide), one PI (bortezomib, ixazomib, or carfilzomib) and one anti-CD-38 monoclonal antibody (daratumumab and isatuximab) will form group two. TCR-MM patients receiving ixazomib will be part of both groups. Patients enrolled in clinical trials will be excluded. The data for analysis will be collected from the ixazomib launch date in China (April 12, 2018) and/or the index date of the first patient enrolled in ixazomib Named Patient Program to September 2023 (tentative). Since 2000 till January 2023, the NICHE-MM registry has enrolled 3,329 MM patients of whom 156 patients have received ixazomib. This is the preliminary sample count and the final sample size will be calculated during data cleaning and analysis phases. The primary objective of this study will be to determine 1) treatment patterns and responses by lines of treatments and 2) time-to-event outcomes. The treatment patterns will include treatment name, dosage, type (induction, consolidation, or maintenance), number of cycles, duration and severe adverse event causing hospitalization. The treatment responses will include complete response (CR), stringent CR, partial response (PR), very good PR, minimal response, stable disease, and progressive disease as defined by the International Myeloma Working Group. The overall response rate of the last line of treatment for both study groups will be calculated as composite endpoint. Time-to-event outcomes will include progression-free survival, overall survival, duration of therapy, and time to next line of treatment in ND/RR-MM and TCR-MM patient groups. Secondary objectives will include assessment of patients' demographic, disease and clinical characteristics. Depending on data availability, the exploratory objective will be to determine the healthcare resource utilization and costs incurred by patients in both groups. Subgroup analysis between ND-MM vs. RR-MM or RR-MM patients receiving ixazomib in 2nd-line setting vs. TCR-MM patients receiving ixazomib in &amp;gt;3rd-line setting is also planned. Descriptive statistics will be used for the analyses. Our findings will also help clinicians in making strategic decision about more apt positioning of ixazomib in the treatment algorithm of MM.

Hepatitis B Virus Infection Status and Reactivation Analysis in Multiple Myeloma in China

Background: China is a highly endemic area for Hepatitis B virus (HBV) infection and HBV reactivation is an event of concern in treating patients with hematologic malignancy. However, there were very few reports regarding HBV reactivation in patients with multiple myeloma (MM) in China. Since the approval of novel agents, especially immunotherapy such as monoclonal antibody and chimeric antigen T cell immunotherapy, the risk of HBV reactivation has increased. Therefore, the study aimed to evaluate the HBV infection status in MM and explore the incidence and risk factors of HBV reactivation in MM patients in China. Methods: Newly diagnosed MM patients with available serologic assays for HBV infection were retrospectively enrolled between June 30, 2008 and December 30, 2022 in West China Hospital, Sichuan University. Demographic and clinical data were obtained from the “HemaTank” Chinese Multiple Myeloma Database (HCMMD). Meanwhile, patients diagnosed with Waldenstrom Macroglobulinemia (WM) at the same time were enrolled as the control group. HBV reactivation was defined as the occurrence of one of the following: ≥ 2 log increase in HBV-DNA levels from baseline level, detection of HBV-DNA with level &amp;gt; 100 IU/ml in a person with undetectable HBV DNA at baseline or HBsAg-negative becoming positive. The penalized maximum likelihood logistic regression for rare events was applied to identify independent risk factors related to HBV reactivation. Results: The study recruited 3040 MM patients with a median age of 62 (range 14~98) and 240 WM patients with a median age of 63 (range 25~92). The HBsAg-positive rates were similar between MM and WM (9.4% vs 10.8%, P=0.49), but both the HBcAb-positive rates and HBeAb-positive rates in WM were significantly higher than MM (76.3% vs 60.7%, P&amp;lt;0.001; 37.5% vs 25.1%, P&amp;lt;0.001). The analysis of co-expression of HBV markers shows that the prevalence of HBsAg-/Anti-HBs+/anti-HBC- in MM was significantly higher than WM (16.7% vs 8.3%, P&amp;lt;0.001) and HBsAg-/Anti-HBs-/anti-HBC+ in MM was significantly lower than WM (18.3% vs 27.1%, P&amp;lt;0.001). However, he prevalence of HBsAg+/ HBeAg+/anti-HBC+ and HBsAg+/ anti-HBeAb+/anti-HBC+ were similar between MM and WM (0.5% vs 1.3%, P=0.158; 8.6% vs 8.8%, P=0.503). The baseline characteristics of HBsAg-positive MM and HBsAg-negative MM were summarized in Table 1. The rates of HBsAg-positive MM were significantly increased in young male patients (P&amp;lt;0.05). The level of ALT and AST, and the incidence of HBV reactivation, liver cirrhosis and pulmonary disease were significantly higher in HBsAg-positive MM than in HBsAg-negative MM (P&amp;lt;0.05). Of the 2147 MM patients who have received at least one line of chemotherapy (Table 1), 924 (43%) MM patients received bortezomib-containing or lenalidomide-containing regimens as the frontline therapy, while only 21 (1.0%) received a daratumumab-containing regimen as the frontline therapy. During hospital-documented follow-up visits, 26 (1.21%) MM patients have experienced HBV reactivation. According to the multivariate analysis of risk factors for HBV reactivation in MM, liver cirrhosis (OR 8.63, 95%CI 2.95-25.24, P&amp;lt;0.001), autologous stem cell transplantation (OR 6.03, 95%CI 2.47-14.72, P&amp;lt;0.001) and HBsAg-positive (OR 14.45, 95%CI 6.50-32.14, P&amp;lt;0.001) were independent risk factors associated with high prevalence of HBV reactivation. The ROC curve of the model integrating the three factors is shown in Figure 1, and the AUC was 0.8584. Conclusions: Among Chinese MM patients with multiple myeloma, a high proportion of MM patients presented with resolved hepatitis B virus infection, whereas HBV reactivation was pretty rare. However, long-term HBV DNA levels monitoring is still needed for MM patients at high risk for HBV reactivation.

COVID-19 Vaccine Acceptance/Hesitancy and Influence on Infection in Patients with Multiple Myeloma: A National-Wide Multicenter Survey in China

Background Patients with multiple myeloma (MM) are immunocompromised due to impaired humoral and cellular immunity in addition to immunosuppressive therapy. The situation and protective effects of severe coronavirus disease 2019 (COVID-19) vaccination in MM patients are not clarified. The study aimed to explore the reasons of COVID-19 vaccine hesitancy and its influence on severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection in MM patients during COVID-19 Omicron BA.4/5 subvariant outbreak in China. Methods An anonymous online questionnaire designed by our team was distributed to MM patients national-wide from December 26, 2022, to April 20, 2023. Then content of questionnaire included the contents of disease status, vaccination and SARS-COV-2 infection. Results A total of 508 valid questionnaires from 30 provinces were collected all over China. The vaccination rate of COVID-19 in MM patients was only 34.1% (n=173). The overall infection rate was 57.2%. Multivariate analysis showed that demographic characteristics were not factors affecting vaccination, while those accomplishing autologous stem cell transplantation (ASCT) presented a lower vaccination rate (20.2% vs. 48.4%, P&amp;lt;0.001). In the survey of vaccine acceptance/hesitancy, voluntary choice (49%), concerns to COVID-19 infection (35.1%), and trust of vaccine efficacy (26.5%) were the three main reasons for receiving vaccines. Physicians' suggestion (52.0%), conflicts of MM treatment (37.8%) and concerns about MM progression (31.3%) were the top three reasons for vaccine hesitancy. Adverse events (AEs) after vaccination were mainly myalgia or joint pain, fatigue and erythema or swelling at the site of injection. No MM disease-related adverse effects were reported. Among 104 vaccinated MM patients with SARS-COV-2 infection, the median time since last vaccines to infections was 304 days (range 4-593). The infection rates between the vaccinated population (n=173) versus non-vaccinated ones (n=335) were 60.1% vs. 55.8% respectively (P=0.35). In subgroup analyses, the infection rates in vaccinated patients were lower than those in unvaccinated ones including the elderly (49.3% vs. 55.2%), obese patients (BMI≥28) (50% vs. 63.3%), and R/RMM population (42.2% vs. 66.7%, P=0.005). The proportion of hospitalized patients due to SARS-COV-2 infection in vaccinated group was significantly lower than that in unvaccinated group (4.8% vs.12.3%, P=0.038). Conclusions Vaccine hesitation is common in Chinese MM patients although inactivated COVID-19 vaccine only causes mild AEs. Lower infection rate in MM patients is probably due to strict self-quarantine. COVID-19 vaccination is not translated into less SARS-COV-2 infections, but does protect the elderly, obese or R/RMM patients from severe infections. Clinicians are suggested to encourage MM patients to receive COVID-19 vaccines for the sake of reducing severe infections and related mortality. Keywords Questionnaire; Multiple Myeloma; vaccination; SARS-COV-2; outbreak infection

Development and validation of a new risk assessment model for immunomodulatory drug-associated venous thrombosis among Chinese patients with multiple myeloma

BackgroundIndividuals with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs) are at risk of developing venous thromboembolism (VTE), a serious complication. There is no established clinical model for predicting VTE in the Chinese population. We develop a new risk assessment model (RAM) for IMiD-associated VTE in Chinese MM patients.MethodsWe retrospectively selected 1334 consecutive MM patients receiving IMiDs from 16 medical centers in China and classified them randomly into the derivation and validation cohorts. A multivariate Cox regression model was used for analysis.ResultsThe overall incidence of IMiD-related VTE in Chinese MM patients was 6.1%. Independent predictive factors of VTE (diabetes, ECOG performance status, erythropoietin-stimulating agent use, dexamethasone use, and VTE history or family history of thrombosis) were identified and merged to develop the RAM. The model identified approximately 30% of the patients in each cohort at high risk for VTE. The hazard ratios (HRs) were 6.08 (P < 0.001) and 6.23 (P < 0.001) for the high-risk subcohort and the low-risk subcohort, respectively, within both the derivation and validation cohorts. The RAM achieved satisfactory discrimination with a C statistic of 0.64. The stratification approach of the IMWG guidelines yielded respective HRs of 1.77 (P = 0.053) and 1.81 (P = 0.063). The stratification approach of the SAVED score resulted in HRs of 3.23 (P = 0.248) and 1.65 (P = 0.622), respectively. The IMWG guideline and the SAVED score-based method yielded C statistics of 0.58 and 0.51, respectively.ConclusionsThe new RAM outperformed the IMWG guidelines and the SAVED score and could potentially guide the VTE prophylaxis strategy for Chinese MM patients.

The evolving diagnosis and treatment paradigms of multiple myeloma in China: 15 years' experience of 1256 patients in a national medical center.

Significant advances in multiple myeloma (MM) over the past 15 years led to exciting changes in the management of MM patients in China, which in turn brought about the early diagnoses, precise risk stratifications, and improved prognoses. We summarized the dynamic changes in the management of newly diagnosed (ND) MM in a national medical center, crossing the old and novel drug era. Demographics, clinical characteristics, first-line treatment, response rate, and survival were retrospectively collected among NDMMs diagnosed in Zhongshan Hospital Fudan University from January 2007 to October 2021. Of the 1256 individuals, median age was 64 (range 31-89) with 45.1% patients >65 years. About 63.5% were male, 43.1% were at ISS stage III and 9.9% had light-chain amyloidosis. Patients with abnormal ratio of free light chain (80.4%), extramedullary disease (EMD, 22.0%), and high-risk cytogenetic abnormalities (HRCA, 26.8%) were detected by novel detection techniques. The best confirmed ORR was 86.5%, including 39.4% with CR. Short- and long-term PFS and OS rates persistently increased each year along with increasing novel drug applications. Median PFS and OS were 30.9 and 64.7months. Advanced ISS stage, HRCA, light-chain amyloidosis and EMD independently predicted an inferior PFS. First-line ASCT indicated a superior PFS. Advanced ISS stage, elevated serum LDH, HRCA, light-chain amyloidosis, and receiving PI/IMiD-based regimen versus PI+IMiD-based regimen independently indicated a poorer OS. In brief, we illustrated a dynamic landscape of MM patients in a national medical center. Chinese MM patients evidently benefited from newly introduced techniques and drugs in this field.

Development and validation of a chemotherapy tolerance prediction model for Chinese multiple myeloma patients: The TM frailty score.

The physical fitness of older individuals is heterogeneous, making it difficult to know their chemotherapy tolerance. The toxicities may offset the benefits of anti-myeloma therapy in frail patients. The accurate evaluation of frailty status before chemotherapy is essential. We aimed to explore the applicability of the IMWG GA and develop a new frailty screening tool more suitable for Chinese MM patients. We performed the IMWG GA and the full CGA in 167 MM patients and validated the applicability of the IMWG GA to chemotherapy and prognosis. The CGA domains were screened for their predictive value to improve IMWG GA and develop new frailty screening tools. The results showed that the IMWG GA had limitations in distinguishing the risk of grade ≥3 adverse events (AEs) between fit and int-fit patients. Of the CGA domains, TUG and MNA-SF were independent prognostic factors for grade ≥3 AEs and OS and further stratified the risk of grade ≥3 AEs in the IMWG GA int-fit subgroup (P< 0.05). We combined TUG and MNA-SF to construct the TM frailty score. The frail subgroup had a higher proportion of adverse outcomes, a higher hazard ratio (HR) in Cox regression and a higher Harrell's C-index for distinguishing the risk of grade ≥3 AEs and OS than the IMWG GA frail subgroup. The TM frailty score is more suitable than the IMWG GA for evaluating chemotherapy tolerance and prognosis in the Chinese population.

A Phase IV, Multicenter, Open-Label, Safety, and Efficacy Study of High-Dose, Propylene Glycol-Free Melphalan Hydrochloride for Injection (EVOMELA) As a Myeloablative Conditioning Regimen in Chinese Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation

A Phase IV, Multicenter, Open-Label, Safety, and Efficacy Study of High-Dose, Propylene Glycol-Free Melphalan Hydrochloride for Injection (EVOMELA) As a Myeloablative Conditioning Regimen in Chinese Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation

Pomalidomide, Bortezomib, and Dexamethasone (PVd) for Chinese Multiple Myeloma Patients at First Relapse

Background:The phase 3 OPTIMISMM（NCT01734928） trial done at 133 hospitals and research centres in 21 countries but no Chinese site involved in this study. In the OPTIMISMM study ,pomalidomide, bortezomib, and dexamethasone (PVd) demonstrated excellent efficacy in patients at first relapse, including immediately after upfront lenalidomide treatment failure and other common first-line treatments, the mPFS was 20.73 months, the ORR was 90.1%, and no new safety signals were observed. Building on these promising results, we decided to explore PVd in Chinese patients at first relapse.Study Design/Methods:This is a multicenter, prospective, single-arm phase 2 study designed to evaluate the efficacy and safety of PVd in Chinese patients at first relapse.Eligible patients were aged ≥18 years and had a diagnosis of multiple myeloma, measurable disease, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were required to have had only 1 prior antimyeloma regimen. Key exclusion criteria included creatinine clearance<30 mL/min requiring dialysis, grade ≥3 peripheral neuropathy, or grade 2 peripheral neuropathy with pain. Patients with prior exposure to bortezomib were eligible, provided they were not refractory to a bortezomib-containing regimen dosed at 1.3 mg/m 2 twice weekly.Patient（n=62,Figure 1）will receive pomalidomide 4 mg on days 1-14 of each cycle. Bortezomib 1.3 mg/m 2 on days 1, 4, 8, and 11 of cycles 1-8 and on days 1 and 8 of cycles 9 and beyond. Dexamethasone was given on days 1, 2, 4, 5, 8, 9, 11, and 12 of cycles 1-8 and on days 1, 2, 8, and 9 of cycles 9 and beyond; patients received 20 mg of dexamethasone if aged ≤75 years and 10 mg otherwise.The primary endpoint is ORR, the secondary endpoints are≥VGPR, MRD(-) rate, PFS, OS and safety. ORR will be assessed by the International Myeloma Working Group criteria after each cycle until PD. The Kaplan-Meier method will be used to estimate PFS and OS. Safety analysis will be conducted in the safety population, which are composed of all patients who received ≥1 dose of study medication. The trial is currently enrolling and will be open in 7 sites of China.Disclosures:Research Sponsor: CHIATAI TIANQING PHARMACEUTICAL GROUP. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

PCN161 REAL-WORLD EVIDENCE ON ECONOMIC BURDEN OF MULTIPLE MYELOMA IN CHINA: A RETROSPECTIVE STUDY OF CLAIMS DATA

The development of novel agents for multiple myeloma (MM) was rapid in past decade but MM remains an incurable disease with an important shortening of life expectancy. Whereas the clinical burden of MM was recognized, studies assessing the economic burden of MM patients in China were limited. This study aims to estimate the all-cause direct medical costs and the cost composition of MM patients from disease onset to progression using real-world data. A retrospective cost-of-illness cohort study was conducted using reimbursement claims database of a tier 2 city in China. Newly diagnosed patients with at least one inpatient or two outpatient claims of MM between 1 January 2012 and 31 December 2015 were followed until inpatient death or end of data. The date of the first MM diagnosis was set as index date. Patients were excluded if they had any claim for MM in the 12-month period prior to the index date. Healthcare resource utilization and costs per patient per year (PPPY) in the post index period were estimated. A total of 307 patients were included in the study (mean age: 65 years, 59% male). Of 270 treated patients, 48% received conventional chemotherapy, 42% received thalidomide-based regimens and only 10% received bortezomib-based regimens. Average total all-cause PPPY costs in the first year after diagnosis for 2012-2015 MM patients were RMB 57,867, RMB 66,968, RMB 56,904 and RMB 103,184 respectively. Anti-MM drug costs represented more than 60% of total all-cause costs PPPY. Analyses of real-world claims data showed that during 2012-2015, novel agents such as bortezomib has not been generally used for the treatment of MM in tier 2 cities in China. However, the direct-medical costs of MM patients were high. The study results suggested that before 2015, Chinese MM patients had limited treatment options and experienced a significant economic burden.

Fecal Microbiota Taxonomic Shifts in Chinese Multiple Myeloma Patients Analyzed by Quantitative Polimerase Chain Reaction (QPCR) and 16S rRNA High-Throughput Sequencing.

BackgroundIncreasing evidence has suggested that gut flora play an important role in tumor progression and prognosis. However, the relationship between fecal microbiota and hematologic malignancy requires further investigation. This study aimed to characterize the relationship of the fecal microbial community in multiple myeloma (MM) patients.Material/MethodsA total of 40 MM patients and healthy controls (n=17) were retrospectively collected from the First Affiliated Hospital of Sun Yat-sen University between October 2018 and May 2019. The fecal samples were collected for 16S rRNA high-throughput sequencing for the fecal microbial community, as well as diversity and correlation analysis. Furthermore, 21 MM patients and their family members were selected for the matched pair analysis to confirm the fecal microbiota taxonomic changes by qRT-PCR assay.ResultsDiversity analysis showed that diversity measured by Shannon index was lower in MM patients compared with healthy controls. At the phylum level, higher abundances of Proteobacteria but lower abundances of Actinobacteria were identified in the MM group in comparison with the healthy control group. At the genus level, the proportion of Bacteroides, Faecalibacterium, and Roseburia was significantly higher in the MM group. The matched pair analysis showed that Pseudomonas aeruginosa and Faecalibacterium were significantly more abundant in the MM group. Further analysis on prognostic risk factors revealed that the Faecalibacterium prausnitzii level was significantly correlated with ISS stage.ConclusionsOur study highlights the imbalanced composition and diversity of the gastrointestinal microbiome in MM patients, which could be further used as a potential biomarker for MM risk screening, therapeutic strategies, and prognostic prediction.

Mutations In Thirty Hotspot Genes In Newly Diagnosed Chinese Multiple Myeloma Patients.

ObjectiveIn recent years, whole-genome sequencing and whole-exon sequencing have revealed the spectrum of gene mutations in multiple myeloma (MM). Gene mutations may play an important role in the pathogenesis, progression, and prognosis of this disease. On the basis of these studies, we established a box of mutations in 30 hotspot genes and analyzed the characteristics in newly diagnosed MM patients in China.MethodsBone marrow samples were collected. Mononuclear cells were isolated and plasma cells were separated using CD138 magnetic beads. Gene mutations were detected by PCR and Sanger sequencing. Fluorescence in situ hybridization (FISH) was used to analyze 1q21, 17p13.1, 14q32/16q23, 14q32/4p16, and 14q32/11q13.3. In the first part of this study, characterization of 30 genes and FISH analysis were performed in 40 patients. For economic reasons, in the second part of this study, 12 of 30 genes were characterized in another 46 patients.ResultsIn the 40 patients of the first part of this study, single nucleotide polymorphisms (SNPs) were detected in 7 genes (CRBN, ATM, FAT4, FAM46C, RB1, NR3C1, and SPEN), while 16 genes were mutated (ATM, CUL4B, IRF4, CCND1, KRAS, DIS3, CRBN, TP53, FAT4, NR3C1, VCAN, RB1, SP140, NRAS, EGR1, and BRAF). Overall, 83 mutations of 30 genes were identified, including 54 intronic mutations, 18 missense mutations, 6 synonymous mutations, 3 5′/3′-UTR mutations, and 2 deletions mutations. Cytogenetic abnormalities were also screened in the 40 patients assayed, with 50% of the patients having 1q21+, 12.5% having 17p−, 15% having t(4;14), and 17.5% having t(11;14). DIS3 was mutated in 4/40, three of which involved t(4;14) or t(11;14). TP53 was mutated in two non-17p− patients, one of whom survived only 7 months, while the other survived 13 months. Three genes (ATM, CUL4B, and IRF4) with a high mutation rate were analyzed for an association with survival. There was no statistically significant difference in 2-year PFS (progress free survival) and 2-year OS (overall survival) between patients with or without ATM or CUL4B mutation (P>0.05). This finding was also obtained for IFR4 mutation, but patients with IFR4 mutation did show trends for longer PFS and OS.ConclusionSNPs and other types of gene mutations are common in newly diagnosed Chinese multiple myeloma patients. The genes most commonly featuring SNPs are CRBN, ATM, FAT4, and FAM46C, while the genes most commonly featuring other mutation types are ATM, CUL4B, and IRF4. There were differences in the profiles of genes affected by SNPs and by other mutation types. Intronic mutations were the most common mutation type. Gene mutations may differ among patients with different cytogenetic abnormalities. Genetic mutations may be associated with prognosis.

Prevalence and Clinicopathologic Significance of BRAF V600E Mutation in Chinese Multiple Myeloma Patients

BackgroundPrevious studies in Western countries demonstrated BRAF V600E mutation only in a small subset of multiple myeloma (MM) patients. However, the prevalence and clinicopathologic significances of this mutation remain unclear in Chinese MM patients. Patients and MethodsWe studied diagnostic bone marrow samples from 205 Chinese MM patients by allele-specific PCR to detect BRAF V600E mutation and by high-resolution melting assay to detect KRAS and NRAS mutations. The mutations were confirmed by independent assays. ResultsBRAF V600E mutation was found in 9.3% of the cases, the highest prevalence hitherto reported. In addition, the mutation was significantly associated with hypercalcemia and a male predominance but not with aggressive extramedullary diseases or a high serum creatinine level as reported in Western studies. Importantly, BRAF V600E mutation was an adverse prognostic factor for overall survival in younger MM patients by subgroup analysis. Concurrent analysis of RAS mutations highlighted differential alteration spectrum of RAS signaling between Chinese and Western MM, which may suggest a unique myeloma-related genetic profile in Chinese patients. ConclusionOur study revealed a higher prevalence of BRAF V600E mutation in Chinese MM patients. The associated prognostic impacts on younger patients could be beneficial to risk stratification and potential application of BRAF-targeted therapies in Chinese MM management. This is the first large-scale study revealing the prevalence and clinicopathologic significances of BRAF V600E mutation in Chinese myeloma.

MDR1 polymorphisms affect the outcome of Chinese multiple myeloma patients

ObjectiveTo illustrate the association of MDR1 (Multidrug Resistance 1) polymorphisms at loci 1236, 2677, 3435 and the prognosis of multiple myeloma (MM) in Jiangsu population. MethodsA total of 129 MM patients were recruited from Jiangsu Province, China. The DNA was extracted from white blood cells (WBC) of peripheral blood and was amplified by polymerase chain reaction-allele specific primers (PCR-ASP). MDR1 polymorphisms at 3 loci were analyzed by electrophoresis followed by photograph or DNA direct sequencing. The association between the MDR1 and clinical outcomes were calculated by Graphpad and SPSS. ResultsMDR1 alleles at locus C1236T with T had significant lower calcium level in MM patients compared with C. The genotype CT had a significantly prolonged progress free survival (PFS) compared genotype CC at locus C1236T (median time: 48 months vs. 28 months, respectively; p=0.0062; HR=0.21; 95%CI0.061–0.715) while patients carrying T allele (CT and TT) at locus C3435T had a longer PFS than patients without T allele (CC) (median time: 60 months vs. 29 months, respectively; p=0.038; HR=0.508; 95%CI 0.264–0.978). And a borderline significance was found in haplotype at loci 2677-3435 and PFS. No significant findings were revealed between OS and MDR1 polymorphisms. ConclusionMDR1 polymorphisms could affect the prognosis of multiple myeloma whereas more samples and a longer follow-up are also needed.

The Applicability of the International Staging System in Chinese Patients with Multiple Myeloma Receiving Bortezomib or Thalidomide-Based Regimens as Induction Therapy: A Multicenter Analysis.

The International Staging System (ISS) is the most important prognostic system for multiple myeloma (MM). It was identified in the era of conventional agents. The outcome of MM has significantly changed by novel agents. Thus the applicability of ISS system in the era of novel agents in Chinese patients needs to be demonstrated. We retrospectively analyzed the clinical outcomes and prognostic significance of ISS system in 1016 patients with newly diagnosed multiple myeloma in Chinese patients between 2008 and 2012, who received bortezomib- or thalidomide-based regimens as first-line therapy. The median overall survival (OS) of patients for ISS stages I/II/III was not reached/55.4 months/41.7 months (p < 0.001), and the median progression-free survival (PFS) was 30/29.5/25 months (p = 0.072), respectively. Statistically significant difference in survival was confirmed among three ISS stages in thalidomide-based group, but not between ISS stages I and II in bortezomib-based group. These findings suggest that ISS system can predict the survival in the era of novel agents in Chinese MM patients, and bortezomib may have the potential to partially overcome adverse effect of risk factors on survival, especially in higher stage of ISS system.