Progression-free Survival In Multiple Myeloma Patients Research Articles

The therapeutic effect and prognostic value of oligoclonal bands after autologous stem cell transplant in patients with multiple myeloma

Objective: To investigate the therapeutic effect and prognostic value of oligoclonal bands (OB) in multiple myeloma (MM) patients after autologous stem cell transplant (ASCT). Methods: The data of 156 patients with MM who underwent ASCT after inductive treatment in the Department of Hematology, Jiangsu Provincial People's Hospital from December 2013 to February 2022 were retrospectively analyzed, including 91 males and 65 females. The median age was 56 (26, 71) years. Patients were divided into two groups according to OB formation after ASCT treatment, including OB group (n=60) and non-OB group (n=96). The last follow-up date was August 31, 2023, and the follow-up period was 42 (18, 117) months. The clinical baseline characteristics and efficacy of the two groups were compared. Progression-free survival (PFS) and overall survival (OS) were compared between the two groups by Kaplan-Meier method. Cox risk regression modal was used to analyze the risk factors associated with prognosis. Results: There were no significant differences in age, type, stage, risk stratification, extramedullary disease (EMD), proportion of circulating plasma cells and induction therapy regimen between OB and non-OB groups (all P>0.05). The proportion of patients in OB group who achieved complete response (CR) or above after ASCT treatment was 93.3% (56/60), which was higher than that in non-OB group (80.2%, 77/96) (P=0.024). The negative rate of minimal residual disease (MRD) in OB group was 66.7% (40/60), which was higher than that in non-OB group (34.4%, 33/96) (P=0.001). The median PFS and OS in the OB group were not reached, and the median PFS and OS in the non-OB group were 28 (2, 80) months and 86 (2, 100) months, respectively. The PFS (P<0.001) and OS (P=0.017) of patients with OB were considerably longer. In the Cox multivariate analysis, OB was an independent prognostic factor for PFS in MM patients (HR=0.314, 95%CI: 0.153-0.644, P=0.002). Subgroup analysis showed that among high-risk patients with mSMART, the OS of patients in OB group was not reached, which was significantly better than that of non-OB group [71 (2, 90) months, P=0.046]. However, no significant difference was observed in the OS of patients with OB and those with non-OB in standard risk group (not reached vs not reached, P=0.103). In those with EMD at diagnosis, patients with OB had significantly better OS than those with non-OB [not reached vs 47 (6, 74) months, P=0.037]. However, no significant difference was observed in the OS of patients with OB and those with non-OB in those without EMD at diagnosis [not reached vs 86 (2, 100) months, P=0.130]. Conclusions: OB formation after ASCT treatment in MM patients is related to the efficacy and prognosis. OB formation can increase the negative MRD rate, prolong the OS and improve the prognosis, especially for newly diagnosed patients with extramedullary disease or patients with high-risk genetic characteristics.

Immunological Subgroups Predicting Efficacy of Elotuzumab in Multiple Myeloma Patients: Insights from the GMMG-HD6 Clinical Trial

Introduction: Elotuzumab, a monoclonal antibody targeting SLAM family member 7 protein (SLAMF7) on multiple myeloma (MM) cells, has shown promise in relapsed/refractory MM when combined with immunomodulatory agents. However, its effectiveness in newly diagnosed patients did not show improved progression-free survival (PFS) nor overall survival. In a previous study we demonstrated that elotuzumab specifically depleted high SLAMF7 expressing regulatory CD8 + T cells by macrophage induced antibody dependent phagocytosis. This study aimed to identify immunological predictive factors for elotuzumab efficacy, enabling improved risk stratification and personalized treatment decisions based on the detection and quantification of SLAMF7-positive T cell subsets. Patients and Methods: This pre-planned accompanying immunological research analyzed samples from the German-Speaking Myeloma Multicenter Group (GMMG) HD6 clinical trial (NCT02495922). The trial investigated elotuzumab in combination with lenalidomide/bortezomib/dexamethasone induction and consolidation, followed by lenalidomide maintenance in transplant-eligible newly diagnosed MM patients and found no progression-free or overall survival advantage with the addition of elotuzumab in any treatment sequence. Peripheral blood samples were collected at three time points: trial inclusion (T1), after induction therapy (T2), and during consolidation or maintenance therapy (T3). Flow cytometry was used to assess T cell subpopulations. Results: Elotuzumab during induction therapy significantly reduced the percentage of regulatory SLAMF7 high expressing CD8 + CD28 - ( p &amp;lt; 0.001) and effector CD8 + T cells ( p &amp;lt; 0.001) in MM patients after induction therapy and during maintenance therapy. A T2 landmark multivariate analysis (after induction therapy) revealed that a higher percentage of effector CD8 + T cells at T1 showed a borderline advantageous effect on the progression-free survival (PFS) ( HR = 0.98 [CI 95% 0.97; 1.00], p = 0.010) regardless of the study arm. Further, in a multivariate analysis a high regulatory CD8 + T cell level at T2 was associated with an adverse PFS in patients receiving elotuzumab in addition to lenalidomide during consolidation and maintenance (PFS from T2 for high vs. low regulatory CD8 + T cell levels at T2, HR = 3.64 [CI 95% 1.58; 8.36], p = 0.002 for patients that received elotuzumab during consolidation and maintenance only; regulatory CD8 + T cells at T2 [high versus low] HR = 5.93 [CI 95% 2.30; 15.26], p &amp;lt; 0.001 for patients that received elotuzumab during induction, consolidation and maintenance). Conclusion: The efficacy of elotuzumab in MM patients may be influenced by the frequency of regulatory CD8 + T cells after induction therapy. As high levels of regulatory CD8 + T cells showed adverse progression-free survival in MM patients, the assessment of the level of regulatory CD8 + SLAMF7 + T cells could be a prerequisite for MM patients' response to elotuzumab. This study highlights the importance of T cell level-driven immunological treatment approaches when utilizing elotuzumab.

Multiple Myeloma Prognosis From PET Images: Deep Survival Losses and Contrastive Pretraining

Objective: Diagnosis and follow-up of multiple myeloma (MM) patients involve analysing full-body Positron Emission Tomography (PET) images. Towards assisting the analysis, there has been an increased interest in machine learning methods linking PET radiomics with survival analysis. Despite deep-learning’s success in other fields, its adaptation to survival faces several challenges. Our goal is to design a deep-learning approach to predict the progression-free survival of MM patients from PET lesion images. Methods: We study three aspects of such deep-learning approach: i) the loss function: we review existing and propose new losses for survival analysis based on contrastive triplet learning, ii) Pre-training: We conceive two pre-training strategies to cope with the relatively small datasets, based on patch classification and triplet loss embedding. iii) the architecture: we study the contribution of spatial and channel attention modules. Results: Our approach is validated on data from two prospective clinical studies, improving the c-index over baseline methods, notably thanks to the channel attention module and the introduced pre-training methods. Conclusion and significance: We propose for the first time an end-to-end deep-learning approach, M2P2, to predict the progression-free survival of MM patients from PET lesion images. We introduce two contrastive learning approaches, never used before for survival analysis.

Expression of SIL-2R in Patients with Multiple Myeloma and Its Clinical Significance

To investigate the expression and clinical significance of soluble interleukin-2 receptor(sIL-2R) in patients with multiple myeloma(MM). 54 newly diagnosed MM patients in the Second Affiliated Hospital of Fujian Medical University from February 2020 to December 2021 were selected as the observation group, and 60 healthy people in our hospital in the same period were selected as the control group. The expression levels of sIL-2R in the serum of the two groups were detected by enzyme-linked immunosorbent assay. The differences of sIL-2R expression level among different clinical parameter groups in MM patients were compared. The clinical parameters include:gender, age, ISS stage, hemoglobin, albumin, serum creatinine, lactate dehydrogenase and β2-microglobulin, blood calcium, bone marrow plasma cell ratio and treatment response. The relationship between sIL-2R expression level and progression-free survival(PFS) and overall survival(OS) in MM patients were analyzed. The expression of serum SIL-2R in MM patients was significantly higher than that in healthy control group (P<0.05). The expression of sIL-2R in MM patients who did not achieve complete remission(CR) was significantly higher than those of CR patients (P=0.037). There was no significant difference in the expression of serum sIL-2R between the groups of different sex, age, ISS stage, hemoglobin concentration, albumin content, serum creatinine level, lactate dehydrogenase level, the content of β2-microglobulin, the concentration of blood calcium, and the proportion of bone marrow plasma cells(P>0.05). The PFS of sIL-2R high expression group(15 months) was shorter than that of sIL-2R low expression group (22 months), which was significant difference (P=0.041). But there was no significant difference in OS between sIL-2R high expression group and sIL-2R low expression group (P=0.124). Univariate analysis results showed that the high expression of serum sIL-2R was associated with poor PFS in MM patients. Multivariate analysis results showed that the high expression of serum sIL-2R was still an independent adverse prognostic factor for PFS in MM patients, However, the expression of serum sIL-2R was not statistically significant in evaluating OS in MM patients by univariate and multivariate analysis. The expression of serum sIL-2R in MM patients was significantly higher than that in healthy people. Serum sIL-2R is an independent prognostic factor of PFS in MM patients.

Aberrantly expressed long noncoding RNAs as potential prognostic biomarkers in newly diagnosed multiple myeloma: A systemic review and meta-analysis.

Numerous studies have manifested long noncoding RNAs (lncRNAs) as biomarkers to determine the prognosis of multiple myeloma (MM) patients. Nevertheless, the prognostic role of lncRNAs in MM is still ambiguous. Herein, we performed a meta-analysis to evaluate the predictive value of aberrantly expressed lncRNAs in MM. A systemic literature search was performed in PubMed, EMBASE, Cochrane, and Web of Science databases until October 9, 2021, and the protocol was registered in the PROSPERO database (CRD42021284364). Our study extracted the hazard ratios (HRs) and 95% confidence intervals (CIs) of overall survival (OS), progression-free survival (PFS), or event-free survival (EFS). Begg's and Egger's tests were employed to correct publication bias. Twenty-six individual studies containing 3501 MM patients were enrolled in this study. The results showed that aberrant expression of lncRNAs was associated with poor OS and PFS of MM patients. The pooled HRs for univariate OS and PFS were 1.48 (95% CI=1.17-1.88, p < 0.001) and 1.30 (95% CI=1.18-1.43, p< 0.001), respectively, whereas the pooled HRs for multivariate OS and PFS were 1.50 (95% CI=1.16-1.95, p < 0.001) and 1.59 (95% CI=1.22-2.07, p < 0.001), respectively. Subgroup analysis suggested that MALAT1, TCF7, NEAT1, and PVT1 upregulation were associated with poor OS (p< 0.05), PVT1, and TCF7 upregulation were implicated with worse PFS (p< 0.05), while only TCF7 overexpression was correlated with reduced EFS (p< 0.05). Moreover, the contour-enhanced funnel plot demonstrated the reliability of our current conclusion, which was not affected by publication bias. Aberrantly expressed particular lncRNAs are critical prognostic indicators in long-term survival as well as promising biomarkers in progression-free status. However, different cutoff values and dissimilar methods to assess lncRNA expression among studies may lead to heterogeneity.

P1349: EFFECT OF TRANSPLANTED CD184-POSITIVE CELLS (WITH EXPRESSION CXCR4) FOR A LONG SURVIVAL AFTER AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA – ONE CENTER PROSPECTIVE STUDY.

Background: Autologous hematopoietic stem cell transplantation (AHSCT) remains the treatment of choice in multiple myeloma (MM) patients (pts). The role of chemokine CXCR4 knows also as CXCR4 in hematopoietic stem cell homing engraftment, and in hematopoietic recovery after AHSCT is still not fully understood as well. Aims: In this prospective study we would like to investigate the influence CD184+ cells for overall survival (OS) and progression free survival (PFS) after AHSCT in MM pts. Methods: Forty eight pts with MM with median age 56 (range 21-76) were undergoing AHSCT in our center in years 2011-2013. Conditioning regimen was Melphalan. Number of all CD184+ cells were measured in harvested material. Results: All pts successfully engrafted. The median follow-up was over 8 years. Currently 21 pts (44%) are alive, including 8 pts (17%) in disease’s remission, and 13 are treated for MM progression. Twenty-seven pts died including 19 pts due to disease progression. The median OS was 7.8 years. In the study group a statistically significant correlation was found between OS, PFS and the number of CD184+ cells. In the context of OS and PFS, number of CD184+ cells was found to have a negative impact (correlation coefficient R = -0.32, p=0.0261, and correlation coefficient R = -0.41, p=0.0039 for OS and PFS retrospectively). As OS and PFS increased, the number of CD184+ cells decreased. Summary/Conclusion: The number of CD184+ cells could have a negative effect on both OS and PFS in multiple myeloma patients.

Aiding early clinical drug development by elucidation of the relationship between tumor growth inhibition and survival in relapsed/refractory multiple myeloma patients.

Early prognosis of clinical efficacy is an urgent need for oncology drug development. Herein, we systemically examined the quantitative approach of tumor growth inhibition (TGI) and survival modeling in the space of relapsed and refractory multiple myeloma (MM), aiming to provide insights into clinical drug development. Longitudinal serum M‐protein and progression‐free survival (PFS) data from three phase III studies (N = 1367) across six treatment regimens and different patient populations were leveraged. The TGI model successfully described the longitudinal M‐protein data in patients with MM. The tumor inhibition and growth parameters were found to vary as per each study, likely due to the patient population and treatment regimen difference. Based on a parametric time‐to‐event model for PFS, M‐protein reduction at week 4 was identified as a significant prognostic factor for PFS across the three studies. Other factors, including Eastern Cooperative Oncology Group performance status, prior anti‐myeloma therapeutics, and baseline serum ß2‐microglobulin level, were correlated with PFS as well. In conclusion, patient disease characteristics (i.e., baseline tumor burden and treatment lines) were important determinants of tumor inhibition and PFS in MM patients. M‐protein change at week 4 was an early prognostic biomarker for PFS.

Pre-existing hypertension is associated with poor progression-free survival in newly diagnosed multiple myeloma patients.

Approximately 31% of patients diagnosed with multiple myeloma (MM) have pre-existing hypertension, but its effects on patient survival have not been investigated. We collected data from 228 newly diagnosed patients with MM and found that 71 (31.1%) had pre-existing hypertension. The impact of pre-existing hypertension on MM patients was determined by evaluating progression-free survival (PFS). Kaplan-Meier analyses revealed a significantly lower PFS in the pre-existing hypertension group than their non-hypertensive counterparts (median 22.6 vs 34.8months, respectively). The multivariable Cox proportional hazards model showed that pre-existing hypertension was an independent risk factor for PFS reduction in MM patients. Moreover, the risk of disease progression in MM patients with pre-existing hypertension was higher than in non-hypertension comparator patients (hazard ratio 1.735, 95% confidence interval 1.261-2.387). In MM patients with pre-existing hypertension, Kaplan-Meier analyses found that those with a higher risk of hypertension had a significantly shorter PFS than those with lower risk (median 19.3 vs 25.4months, respectively). However, multivariate Cox regression analysis showed that the risk stratification of hypertension was not an independent risk factor for poor PFS in MM patients with pre-existing hypertension. Our study demonstrates that pre-existing hypertension was significantly associated with a lower PFS in newly diagnosed MM patients.

The role of KIAA1191 in the necroptotic pathway of multiple myeloma.

Multiple myeloma (MM) is an incurable plasma cell malignancy, and International Staging System (ISS) is used to predict the outcomes of MM patients. However, ISS stage is imperfect, and there might exist other factors correlated with prognosis of MM patients. Expression profiles and clinical information of 340 newly diagnosed MM patients from GEO database and 105 newly diagnosed MM patients from our hospital were analyzed, and LASSO regression was used to screen genes associated with both overall survival and progression-free survival of MM patients. Nomogram was constructed to predict outcomes of MM patients. Then, CCK8 and transwell assays were used to evaluate the proliferation and migration ability of MM cells; flow cytometry was performed to verify whether MM cells underwent necroptosis. Quantitative real-time PCR and western blot were performed to evaluate gene expressions. We found that KIAA1191 was associated with both overall survival and progression-free survival of MM patients. Furthermore, KIAA1191 high expression suppressed the proliferation and migration of MM cells; upregulated the expression of RIP1, RIP3, and CYLD, and restored the TNF-α/z-VAD-induced necroptosis. Besides, KIAA1191 overexpression had a synergistic effect with bortezomib on the proliferation capability of MM cells.

The Prognostic Impact of Abnormal Protein Bands in Multiple Myeloma: A Systematic Review and Meta-Analysis

Introduction: The detection of abnormal protein bands (APB) different from the original monoclonal protein in patients with multiple myeloma (MM) who underwent stem cell transplantation and/or chemotherapy has been reported. These atypical serum immunofixation patterns may be monoclonal (also termed secondary monoclonal gammopathy of undetermined significance) or oligoclonal bands (OB). The prognostic significance of this phenomenon remains controversial. This systematic review and meta-analysis aimed to summarize and analyze the evidence for the association between APB with survival in MM patients.Methods: A systematic search of PubMed, Cochrane, Google Scholar, Medline-Ovid, CINAHL, and ERIC, was conducted using relevant search terms. All studies were screened using predefined selection criteria and critically appraised for quality assessment following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. All studies that described the presence of APB, defined as monoclonal spike with heavy or light chain immunoglobulin distinct from the original paraprotein at initial diagnosis of MM, and its associations with survival were included. Studies that reported multivariate adjusted hazard ratios (HR) were further included for meta-analysis. Random-effects model was used to synthesize the pooled HR estimate for the association of APB with survival. Cochran's Q statistics and I2 tests were used to evaluate statistical heterogeneity.Results: A total of 24 out of 181 eligible studies were included for qualitative synthesis. Four studies (including 1115 patients) that reported HR estimates were included in the final meta-analysis. The random-effect summary HR for the progression-free survival among patients with APB was 0.44 (95% CI, 0.31-0.65) with no statistical heterogeneity (I2=0%, p=0.93). The pooled HR for the association with overall survival was 0.31 (95% CI, 0.14-0.66) with moderate statistical heterogeneity (I2=45%; p=0.16) for patients with APB. One study (Silva et al, 2017) only included patients with at least very good partial response while the other three studies reported similar findings of higher occurrence of APB with complete response (Tovar et al, 2013; Jo et al, 2014; Zou et al, 2014). These results are also consistent with the presumed association of APB with complete response as suggested in other studies included in qualitative review.Conclusions: This study indicated a potential prognostic value of APB for favorable outcomes in the context of both overall and progression-free survival in MM patients after treatment. Further research is needed to evaluate the prognostic impact of the sole emergence of APB irrespective of treatment response. [Display omitted] DisclosuresJamshed: Takeda: Honoraria.

The prognostic significance of [18F]FDG PET/CT in multiple myeloma according to novel interpretation criteria (IMPeTUs)

Purpose[18F]FDG PET/CT is the elective imaging modality for treatment monitoring in multiple myeloma (MM). However, MM is a heterogeneous disease from an imaging point of view, raising challenges in interpretation of PET/CT. We herein investigated the prognostic role of the novel Italian Myeloma criteria for PET Use (IMPeTUs) in MM patients undergoing high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT).MethodsForty-seven patients with newly diagnosed MM underwent [18F]FDG PET/CT before commencement of treatment (baseline PET/CT). Thirty-four of them (72.3%) were also examined after completion of ASCT (follow-up PET/CT). PET/CT analysis was based on the IMPeTUs criteria, which take into consideration—among others—the metabolic state of the bone marrow based on the 5-point Deauville score (DS), the number and metabolic state of focal [18F]FDG-avid lesions, as well as the presence of paramedullary disease (PMD) and extramedullary disease (EMD). We analyzed whether parameters from IMPeTUs correlate with clinically relevant parameters and patients’ outcome, as assessed by progression-free survival (PFS).ResultsMedian follow-up from baseline and follow-up PET/CT were 85.1 months and 76.7 months, respectively. The number of focal, [18F]FDG-avid lesions significantly correlated with the bone marrow infiltration rate and the R-ISS stage, while the presence of PMD was associated with LDH. After univariate survival analysis, the number of focal, [18F]FDG-avid lesions both before and after therapy as well as the presence of PMD and EMD before therapy adversely affected PFS. Multivariate survival analysis for baseline parameters confirmed that the number of focal, [18F]FDG-avid lesions and the presence of EMD are associated with adverse prognosis, irrespective of the ISS stage and/or the presence of high-risk cytogenetic abnormalities. The 5-point DS of [18F]FDG uptake in reference bone marrow and focal lesions showed a significant decrease as response to treatment, but it did not affect PFS.ConclusionSeveral parameters utilized in IMPeTUs predict PFS in MM patients, suggesting the potentially significant role of the new criteria in patient stratification and response assessment. Additional studies are warranted for the further evaluation of IMPeTUs in the direction of establishment of robust cut-off values with a prognostic significance in the disease.

Effect of Immunomodulatory Drugs (IMiDs) on Immune Effectors after Autologous Stem Cell Transplantation (ASCT) in Multiple Myeloma

INTRODUCTION: Patients with multiple myeloma have several phenotypic and functional immune aberrations that suppress host anti-myeloma immune responses. The degree and type of immune dysfunction can be targeted and reversed in many patients with active treatment. Therapies that result in deep and sustained remissions play a part in immunological control of disease in long-term responders. IMiD-mediated immunomodulatory effects conferring immune system reactivation have been reported in MM in the maintenance setting. We hypothesized that the circulating effector immune cell profile post-ASCT will be impacted by depth of response and IMiD based maintenance therapy.METHODS: Thirty multiple myeloma patients who underwent ASCT and IMiD based maintenance and consented for specimen collection protocol were included in this study. Blood and bone marrow samples were collected before starting IMiD based maintenance therapy on Day 60+ post ASCT (time point defined as baseline). Blood samples were then serially collected after 1 month (n=24), 3 months (n=26) and 6 months (n=19) of maintenance treatment. Multicolor flow cytometry was used for NK, NK-T and T cell distribution/activation immunotyping, and for measurement of bone marrow minimal residual disease (MRD) status. Threshold for MRD positivity was established as 1.5x10-5 abnormal/clonal plasma cells. Clinical response assessment was performed post-ASCT at baseline per IMWG guidelines. Welch's t-test was used to compare each immune variable between MRDpos and MRDneg groups and one-way ANOVA was used to analyze changes of each immune variable over time. The association of individual immune variable with progression free survival (PFS) was assessed by Cox regression analysis.RESULTS: In total, 16 patients achieved CR/sCR, 13 VGPR and 1 PR. MRD status was determined for 20 of 30 patients, 5 were MRDneg and 15 MRDpos. MRDpos patients had an immunotype characterized by higher expression of KIR2DS4 on NK (p=0.002) and NK-T cells (p=0.048) at baseline, compared with MRDneg patients. Twenty-six patients received single agent IMiD maintenance, 4 received IMiD/proteasome inhibitor combination. During IMiD maintenance therapy, NK and NK-T cell acquired phenotypes associated with greater effector functions as shown by increase in NK NKG2D+ (p=0.04), NK Tim3+ (p=0.049) and NK-T Tim3+ (p=0.01). T cells were marked by a NKG2D loss (p<0.001) and Tim3 gain (p<0.001) of expression. The median follow-up of the cohort was 19.3 months (IQR 14.8-21.3). Seven patients (5 MRDpos, 2 MRD status unknown) relapsed within 12 to 24 months post-ASCT. High KIR2DS4 (HR=1.072, 95% CI: 1.019-1.128; p=0.008), NKp46 (HR=1.05, 95% CI: 1.004-1.098; p=0.031) and NKG2A (HR=1.222, 95% CI: 1.018-1.466; p=0.032) expression by NK-T cells at baseline were associated with shorter PFS. NK and NK-T cells retained higher KIR2DS4 expression after 1, 3 and 6 months of IMiD maintenance therapy in relapsing patients compared with those in remission (Figure1).CONCLUSIONS: Our results demonstrate that KIR2DS4 expression by NK and NK-T cells is associated with MRD status post-transplant, as well as PFS in multiple myeloma patients treated with IMiD maintenance therapy. This simple blood-based immunotype, if validated in larger studies, could be used for longitudinal assessment to predict early on after starting IMiD maintenance treatment whether to continue this treatment or change to different treatment. Patients predicted to derive less clinical benefit from IMiDs could be offered alternative treatment regimens such as monoclonal antibodies, other immunotherapies or epigenetic therapy. [Display omitted] DisclosuresBhutani:Amgen: Speakers Bureau; Prothena Therapeutics: Research Funding; BMS: Speakers Bureau; Takeda Oncology: Speakers Bureau. Voorhees:Amgen: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy; Oncopeptides: Consultancy. Usmani:Array BioPharma: Honoraria, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

MicroRNAs in urine as diagnostic biomarkers for multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy. It is of great clinical significance to screen microRNAs (miRNAs) in urine as noninvasive diagnostic biomarkers for MM. Urinary miRNAs in MM were performed by Agilent Bioanalyzer 2100 and verified by quantitative real-time PCR (qRT-PCR). Receiver operator characteristic (ROC) was used to evaluate the diagnostic value of abnormal miRNAs for MM. Progression-free survival (PFS) of MM was calculated by Kaplan-Meier. In microarray analysis, twelve down-regulated miRNAs dysregulated in MM. The expression levels of miR-134-5p, miR-6500-5p, miR-548q, and miR-548y were validated. These miRNAs were significantly lower in MM (P<.05), but there was no significant difference between newly diagnosed, relapse, and remission group of MM (P>.05). ROC curve analysis showed that the sensitivity of miR-134-5p, miR-6500-5p, miR-548q, and miR-548y to MM was 91.7%, 100%, 100%, and 91.7%, and the specificity was 66.7%, 75.0%, 75.0%, and 100%, respectively. The four miRNAs were negatively correlated with the total urinary light chain (r=-0.427 P=.030, r=-0.461 P=.018, r=-0.469 P=.016, r=-0.493 P=.011). In addition, miR-134-5p, miR-6500-5p, and miR-548q were positively correlated with serum ALB (r=0.518 P=.006, r=0.400 P=.039,r=0.492 P=.009). The expression level of miRNAs had no significant influence on PFS in MM patients (P>.05). The results show that miR-134-5p, miR-6500-5p, miR-548q, and miR-548y are potential noninvasive diagnostic biomarkers for MM.

The paradoxical prognostic role of 1q21 Gain/Amplification in multiple myeloma: every coin has two sides

The prognostic value of 1q21 Gain/Amplification (1q21 Gain/Amp) in multiple myeloma (MM) has always been controversial. A total of 419 newly diagnosed MM patients were included in this retrospective study. The positive rate of 1q21 Gain/Amp was 48.6%. MM patients with 1q21 Gain/Amp were characterized as being in more advanced clinical stages and were more likely to be accompanied by del(13q14), t(4;14) or complex karyotypes (CKs) as well as with more severe anemia and worse renal function. In these patients, the percentage of complete remission (CR) or very good partial response (VGPR) was higher, however, in the early treatment period, the probability of progressive disease (PD) was also higher. No significant difference on progression free survival (PFS) and overall survival (OS) was showed between the group of 1q21Amp and 1q21Gain. The prognostic impact of 1q21 Gain/Amp on PFS of MM patients was heterogeneous and was in accordance with the accompanying parameters.

Correlation between Clinical Factors and Prognosis in Newly Diagnosed Multiple Myeloma.

To explore the correlation between clinical factors and the prognosis of multiple myeloma (MM). A cohort study. At the Third Affiliated Hospital of Inner Mongolia Medical University, Mongolia from January 2014 to December 2018. The clinical data of 81 patients with newly diagnosed MM were collected retrospectively. The correlation of prognosis with immunophenotype and (FISH) Fluorescence in situ hybridization was subjected to univariate and multivariate analyses. Overall and progression-free survival was determined. The overall survival (OS) and progression-free survival (PFS) of patients with CD200+, CD81+, and CD27- were significantly shortened. CD200+ and CD27- were independent prognostic factors for OS and PFS in MM patients. The prognosis-related abnormal genes were analyzed, and univariate analysis revealed that OS and PFS were significantly shortened in patients with RB-1 deletion, CDKN2C deletion, and IGH rearrangement. CDKN2C deletion was an independent prognostic factor for OS and PFS in MM patients. CDKN2C deletion is an independent prognostic factor of MM. CD200+ is an independent risk factor for poor prognosis of MM. Key Words: Multiple myeloma, Prognostic analysis, Fluorescence in situ hybridization, Immunity, Immunophenotype.

Frequency of Marrow Infiltrating PD-1 Expressing CD4 Effectors Following Autologous Stem Cell Transplant (ASCT) for Multiple Myeloma Is Prognostic for Clinical Outcome

Introduction: High dose therapy and autologous stem cell transplant (ASCT) remain standard first line therapy for young fit patients with multiple myeloma (MM). Beyond cytoreduction, ASCT may also alter the bone marrow (BM) immune environment to augment anti-tumour immune responses. A more precise understanding of the immune microenvironment post ASCT and its relationship with clinical outcomes may identify biomarkers to refine prognostication and provide opportunity for therapeutic intervention. Aim: We aimed to define T cell subsets and expression of co-activating and co-inhibitory proteins in the BM early post ASCT, and explore associations with clinical outcomes. Methods: BM samples were obtained at 100 days (D100) post ASCT from 61 MM patients, and 15 healthy donors (HD). BM mononuclear cells (MNCs) were stained for surface (CD3, CD4, CD8, PD-1, LAG-3, and ICOS) and intracellular markers (GzmB, Ki-67, CTLA-4, and FoxP3). Data were acquired on a BD LSR Fortessa and analysed using FlowJo. Progression free survival (PFS) was defined from ASCT as per IMWG criteria, and patient groups were compared using Mann-Whitney U test. Adverse risk genetics was defined as t(4;14), t(14;16) or del(17p). Results: Median age of patients at ASCT was 58yrs (36-71), 70.5% were male. Median follow up was 17 months (3-54). At diagnosis, 36.1% were ISS stage I, 8.2% had extramedullary disease, and 14.7% had adverse risk genetics. As induction therapy, 96.7% received a proteasome inhibitor, 45.9% an immunomodulatory drug, 54.1% both, and 21.3% received post ASCT maintenance/consolidation. Median PFS was 24 months. At D100, 24.6% had achieved CR, 47.5% VGPR, 21.3% PR, 4.9% SD and none had PD. Improved PFS was found in patients with deeper response (CR/VGPR vs. rest, p=0.003), and with ISS stage I vs II/III (p=0.013). There was a trend for improved PFS with standard risk genetics (p=0.088 cf high risk). MM BM contained lower frequencies of CD3 and CD4 T cells compared to HD (CD3, 28% of live MNCs, vs 41.2%, p=0.012; CD4, 4.1% vs 14.0%, p&lt;0.0001), while CD8 frequency was similar. The frequency of regulatory T cells (CD4+FoxP3+, Tregs) was higher in MM patients compared to HD (0.23% of live MNCs vs 0.07%, p=0.02; 4.2% of CD4+ vs 1.2%, p&lt;0.0001). Thus CD4 effector (CD4+FoxP3-, CD4eff):Treg ratio was lower in MM patients (16.8 vs 140.2, p&lt;0.00001). There was no difference in CD8:Treg ratio. Immune checkpoint proteins were highly expressed on BM T cell subsets in post ASCT compared to HD. CD4eff in MM patients expressed higher frequency of PD-1, LAG-3, ICOS, CTLA-4, GzmB, and Ki-67 (p&lt;0.0001, p=0.0016, p=0.0018, p=0.003, p&lt;0.0001, and p&lt;0.0001, respectively). CD8 T cells in MM patients expressed higher frequency of LAG-3, GzmB and Ki-67 (p=0.0003, p&lt;0.0001, and p&lt;0.0001 respectively). We observed higher frequencies of ICOS and CTLA-4 on Tregs in MM patients (vs HD p=0.0025 for both) indicating Treg activation and enhanced suppressive function. There were considerable correlations between the frequency of LAG-3 on different T cell subsets; (CD4eff LAG-3+ vs CD8 LAG-3+ r=0.82, p&lt;0.0001; CD4eff LAG-3+ vs Tregs LAG-3+, r=0.56, p&lt;0.0001; Tregs LAG-3 vs CD8 LAG-3, r=0.5, P&lt;0.0001). Clinical outcomes were not influenced by T cell subsets (CD3, CD4eff, CD8, and Treg) but there was an inverse association with co-inhibitory receptor expression. High frequency (&gt;median) of LAG-3 on CD4eff and CD8, and Tregs was associated with shorter PFS (median 18mo vs 53, p=0.0028; 20mo vs 53, p=0.0057; 20mo vs 53, p=0.046 respectively). Further, patients with high frequency of PD-1 on CD4eff and Ki-67 on CD8 T cells had shorter PFS (median 18mo vs 36, p=0.042 and 18mo vs unreached, p=0.019 respectively). A multivariate Cox regression model was built to include ISS stage, depth of response at D100, and the immune phenotypes identified to correlate with PFS. In this model, high frequency of PD-1 on CD4eff retained independent prognostic value, along with ISS stage and CD8 Ki67+ T cells. Conclusion: We present data indicating that high frequency of PD-1+ CD4eff and Ki67+ CD8 T cells post ASCT associate with shorter PFS in MM patients. Pending confirmation in larger cohorts, these data reveal potential immune biomarkers for poor outcomes, and prompt deeper phenotypic analysis and mechanistic studies to uncover the immune drivers of sustained remissions post ASCT. Disclosures Lee: Autolus Therapeutics: Equity Ownership, Research Funding. Yong:Takeda: Research Funding, Speakers Bureau; Autolus: Consultancy; Amgen: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Sanofi: Speakers Bureau.

PB2098 IDENTIFICATION OF NOVEL REGULATORS OF PLASMA CELLS MIGRATION IN MULTIPLE MYELOMA PATIENTS

Background:High number of peripheral blood circulating aberrant plasma cells in the patients with multiple myeloma (MM) correlates with worse survival prognosis and likely contributes to the development of extramedullary lesions. Molecular mechanisms responsible for egress of tumor cells from the supportive bone marrow niche into the blood stream are largely unknown. In the presented study we focus on deubiquitinating enzymes (DUBs), a group of hydrolytic proteases removing ubiquitin modifications from proteins. DUBs are involved in numerous cellular processes and as such provide very promising drug targets.Aims:Through analysis of expression datasets and progression free survival (PFS) we seek to identify DUBs deregulated specifically in MM, highlight those with relevance to plasma cells migration and finally uncover the responsible molecular mechanisms.MethodsThe GSE2658 dataset was used to analyse PFS of MM patients and other hematological malignancies (GSE12417, GSE10846, GSE16131, GSE22762, GSE2350, GSE4475) in relation to expression levels of all and selected human DUBs, respectively. Pathological bone marrow residing plasma cells from 14 newly diagnosed MM patients identified by the expression pattern of following antigens (CD19, CD56, CD45, CD38) were sorted and total mRNA was isolated for gene‐specific qPCR analysis. In parallel, percentages of aberrant plasma cells circulating in the peripheral blood were determined by flow cytometry. Co‐immunoprecipitation of OTUD1 and Filamin A was performed using HEK293 T cells and specific antibodies. For the gene set enrichment analysis (GSEA) the GSE4581 dataset was used.Results:In the pilot analysis we compared PFS of a large cohort of MM patients (n = 559) in relation to expression levels of all currently annotated human DUBs (n = 100). We have indentified 10 DUBs whose expression significantly affected PFS of MM patients (p &lt; 0,05). Low expression levels of 6 DUBs (USP22, USP48, USP49, YOD1, OTUD6B, FAM105A) correlated with good PFS, while low expression of another 4 DUBs (USP3, USP30, USP35, OTUD1) correlated with significantly worse prognosis. Only 4 of the indentified DUBs (USP22, USP30, USP35 and OTUD1) were affecting PFS exclusively in MM patients and not in other hematological malignancies (AML, CLL, DLBCL, FCL, BL). We focused specifically on OTUD1 as it is the only DUBs from our list that was previously implicated to suppress migration and metastasis (Zhang, 2017). Quantitative PCR revealed that low expression of OTUD1 in bone marrow plasma cells (in 14 newly diagnosed MM patients) correlates with significantly higher number of plasma cells in peripheral blood. We have also identified actin crosslinking protein Filamin A as a novel OTUD1 binding partner. Additionally, GSEA of the GSE4581 dataset reveled that low expression of OTUD1 is associated with induction of genes related to actin polymerization and ER stress response.Summary/Conclusion:Database analysis, patient and cell lines derived data indicate that downregulation of OTUD1 is associated with higher number of peripheral blood circulating plasma cells and significantly worse PFS in a large subset of MM patients. Mechanistical investigation unveils Filamin A as direct OTUD1 binding partner and highlights involvement OTUD1 in actin cytoskeleton remodeling and ER stress response.

PB2175 LONG TERM FOLLOW‐UP OF MAINTENANCE THERAPY WITH INTEREFRON ALPHA AFTER AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANT IN MULTIPLE MYELOMA PATIENTS–SINGLE CENTER EXPERIENCE

Background:Maintenance therapy after autologous hematopoietic stem cell transplantation (AHSCT) in multiple myeloma (MM) patients was a matter of debate until recently, when lenalidomide in this setting proved to increase overall survival (OS). Before lenalidomide interferon alpha (IFN) was standard maintenance therapy.Aims:The aim of this analysis was to determine the impact of maintenance therapy after AHSCT on progression free survival (PFS) and OS in MM patients treated at our institution between 1993 and 2014.MethodsWe performed a retrospective analysis of outcomes of MM patients autografted at our institution between 1993 and 2014. We identified 274 pts. who had PFS at least 6 months posttransplant; median age was 57, range 28‐71, 48% were male. 124 of them received tandem and 150 single AHSCT. Median follow‐up was 62 mo. Posttransplant 200 patients received IFN, 44 thalidomide and 30 no maintenance according to physicians’ choice.Results:Patients receiving IFN had longer 5‐year PFS compared to patients receiving thalidomide or no maintenance (52% vs. 34% vs. 31%, respectively, p &lt; 0.001). OS was best in the IFN group, intermediate in the thalidomide and worst in the no maintenance group (67% vs. 59% vs. 32%, respectively, p &lt; 0.001). The difference was limited to patients receiving tandem transplants. In this group 5‐year PFS was 61% vs. 35% vs 0% (p &lt; 0.001) and OS 85% vs. 67% vs. 65% (p = 0.003) in the IFN, thalidomide and no maintenance group respectively. In patients that received a single transplant 5‐year PFS was 43% vs. 33% vs 36% (p = 0.157) and 5‐year OS 70% vs. 75% vs. 54% (p = 0.06) in the IFN, thalidomide and no maintenance group respectively.Summary/Conclusion:Our results indicate that maintenance therapy has beneficial effects on OS and PFS in MM patients treated with tandem, but not single AHSCT. IFN is superior in this setting to thalidomide and could be considered as a treatment option when lenalidomide is not available.

Bone marrow MRI after autologous transplantation and the effect of residual tumor on progression-free survival of multiple myeloma patients

Background . The study of influence of residual tumor mass, determined by magnetic resonance imaging (MRI), on the progression-free survival (PFS) remains an actual problem. Since the visual assessment of tumor bone marrow lesion can be one of the criteria for the subsequent personalized treatment choice in multiple myeloma patients.The objective of study was to determine the effect of bone marrow lesions detected by MRI after autologous hematopoietic stem cells transplantation (auto-HSCT) on PFS in multiple myeloma patients.Materials and methods . The prospective study included 60 patients who underwent spine and pelvic bones MRI on the 100 th day after autoHSCT.Results . Focal bone marrow changes were found in 47 of them – from 1 to 56 lesions (mean 6 ± 9). Significant (p = 0.01) differences of PFS in multiple myeloma patients depending on the presence or absence of tumor mass on 100 th day after auto-HSCT were revealed: with MRI negative status, 2-year PFS was 89 % versus 50 % in a group of patients with residual tumor mass.Conclusion . MRI-negative status after auto-HSCT is a favorable prognostic factor contributing to prolonged disease-free survival.

Impact of Newer Agents on Progression Free Survival of Multiple Myeloma in the 2nd 3rd and 4th Line Setting- a Systematic Review

Background: Multiple Myeloma (MM) remains incurable. Majority of the patients ultimately relapse with a lower median event free survival after each successive line of therapy. For newly diagnosed MM patients, the median progression free survival (PFS) has improved drastically with the advent of novel agents. Aim of our review is to discuss median PFSnwith novel agents in the 2nd 3rd and 4th line of treatment in MM.Methods: A comprehensive literature search was done in accordance with the PRISMA guidelines from Jan 1st 2010 to May 30th 2018 using the following 4 databases: PubMed/ Medline, Elsevier/Embase, Wiley/Cochrane and clinicaltrials.gov. Inclusion criteria consisted of all prospective clinical trials that a) included patients with 1-3 prior lines of therapies b) received novel therapeutic agents as an intervention c) outcome was reported as median PFS. We excluded case series, retrospective/observational studies, systematic reviews/meta-analysis. We identified 4777 records through initial database search. After removing duplicates and further screening, 59 full-text articles were assessed for eligibility. 50 articles were subsequently excluded with reason and 9 articles constituting 4937 patients were selected for data extraction and final analysis.Result In a randomized clinical trial (RCT) by Dimopolous et al (2017), 396 patients (median age: 64) in the carfilzomib, lenalidomide and dexamethasone (KRD) arm had median PFS of 26.3 m. In comparison, 396 patients in the control group (median age: 65) that received RD regimen had a median PFS of 17.6 m. Percentage of patients with prior bone marrow transplant (BMT) and high-risk (HR) cytogenetics was 54.8% and 12.1% respectively in the KRD regimen and 57.8% and 13.1% respectively in the RD regimen. The median prior number of therapies was 2 in each group. In the trial by Avet-Loiseau et al 2017, patients in the Ixazomib-RD arm (n=360; HR cytogenetics=21%) had a median PFS of 20.6m as compared to 14.7 m in the control group (RD) arm (n=362; HR cytogenetics=17%). Median prior number of therapies was 2 in each group and 59% and 57% of the patients had prior BMT respectively. Lonial et al (2015) showed that the group (n=321; median age 67) that received elotuzumab-RD regimen had median PFS of 19.4m compared to 14.5m in the control group (n=325; median age 66) that received RD regimen. Prior median therapies were 2 in each arm and BMT was done in 52% and 57% of the patients respectively. A RCT of two drug regimen by Chang et al (2017) showed that patients (n= 464) who received KD had a higher median PFS (18.7m) as compared to patients (n= 465) who received bortezomib(V)-D (9.4 m). KD arm had 37.2% patients with prior BMT as compared to 49.6% in the VD arm whereas the median prior number of therapies was 2 in each arm. HR cytogenetics were present in 21% and 24% respectively. In the trial by Orlowski et al (2015), there was no improvement in the median PFS with the addition of Siltuximab to V as compared to V alone. Similarly, no significant improvement in median PFS was noted by Dimopolus et al (2017) in the combination regimen of Vorinostat-V as compared to placebo-V. In the trial by white et al (2017), the median PFS was 6.2 with bevacizumab-V as compared to 5.1m with placebo-V. In a trial by Richardson et al (2016), Panobinostat-VD had a median PFS of 11.99 which was higher than 8.08 with placebo-VD.Conclusion: Regimen consisting of KRD has the highest median PFS in MM patients with multiple prior lines of therapy followed by IRD based regimen. Limitations of our analysis include a heterogeneous patient population and exclusion of data with daratumumab based regimen because of unavailability of median PFS specifically in the 2nd 3rd and 4th line setting in the published clinical trials. DisclosuresNo relevant conflicts of interest to declare.