Serum-free light chains combined with the Revised International Staging System could further distinguish the superior and inferior clinical outcome of multiple myeloma patients.

The Revised International Staging System (R-ISS) was introduced as a powerful prognostic system to stratify patients with newly diagnosed multiple myeloma (NDMM). The serum-free light chain (sFLC) has been developed as a valuable marker to monitor multiple myeloma (MM) progression and response. Therefore, it is imperative to combine R-ISS and sFLC prognostic factors as modified R-ISS (MR-ISS) to better stratify patients into homogeneous survival subgroups, especially to further distinguish the high-risk MM patients who are likely to experience rapid progression or relapse. A total of 595 patients with NDMM were studied retrospectively. We performed the K-adaptive partitioning in 595 NDMM patients to define the MR-ISS classification: stage I includes R-ISS stage I and sFLC ratio < 80 (n = 66); stage III includes R-ISS stage III with sFLC ratio ≥ 80 (n = 87); stage II includes all the remaining conditions (n = 442). The median OS was not reached for MR-ISS stage I, 48.67 months for stage II, and 21.13 months for stage III. A significant OS difference of MR-ISS stage I and III patients has a particularly superior and inferior outcome compared with R-ISS stage I and III, respectively, which showed the similar results in PFS analysis. Validation of results was performed in an independent cohort. Our data indicate that the MR-ISS provides an improved prognostic power compared with R-ISS.

18F-FDG PET/CT is useful for determining survival outcomes of patients with multiple myeloma classified as stage II and III with the Revised International Staging System.

PURPOSE: This study evaluated the prognostic role of 18F-FDG PET/CT at baseline in patients with newly diagnosed multiple myeloa (MM) and evaluated the prognostic relevance of 18F-FDG PET/CT for each stage according to the Revised International Staging System (R-ISS). METHOD: We retrospectively analyzed the records of 167 patients with newly diagnosed MM. 18F-FDG PET/CT was performed prior to induction therapy in patients with newly diagnosed MM. RESULTS: In the total cohort, the presence of more than three hypermetabolic focal lesions (FLs) or extramedullary disease (EMD) on baseline PET/CT was associated with significantly inferior progression-free survival (PFS) and overall survival (OS) than other patients. Because most patients (91%) with EMD had more than three FLs, PET/CT positivity was defined as the presence of more than three FLs or the presence of EMD. In multivariate analyses, PET/CT positivity was an independent predictor of PFS and OS in all patients. Fifty-five patients (46.1%) with R-ISS II were PET/CT-positive at baseline and had significantly shorter PFS and OS. PET/CT positivity was also correlated with poor PFS and OS in patients with R-ISS III. CONCLUSION: 18F-FDG PET/CT was an independent predictor of survival outcomes in patients with newly diagnosed MM. In addition, performing 18F- FDG PET/CT at diagnosis may be useful for determining the survival outcomes of MM patients with R-ISS II and III.

Clinical characteristics and prognosis of immunoglobulin D myeloma in the novel agent era.

Immunoglobulin D (IgD) myeloma is a rare subtype that used to lead to a poor outcome. To investigate the current clinical features, cytogenetic changes and survival of patients with IgD myeloma under novel treatments, we analysed 47 patients with IgD myeloma, 31 men and 16 women, with a median age of 54.5 years. We found that IgD myeloma was associated with higher frequencies of anaemia, renal failure, and hypercalcemia and higher levels of serum LDH compared with non-IgD myeloma. More than 90% of patients with IgD myeloma had at least one cytogenetic abnormality demonstrated by fluorescence in situ hybridisation (FISH). IGH translocations were the most common abnormalities, which were mainly caused by t(11;14). Moreover, 36.2% of patients were at the Revised International Staging System (RISS) stage III when diagnosed. Those patients had significantly shorter PFS and OS compared with patients at RISS stages I and II. In conclusion, IgD myeloma has specific clinical characteristics. The RISS grade was shown to be a simple and effective method to predict the prognosis of patients with IgD myeloma.

Evaluation of the Revised International Staging System (R-ISS) in Japanese patients with multiple myeloma.

In spite of recent development in the treatment armamentarium for multiple myeloma, overall survival (OS) still depends on risk status and sensitivity to treatment of each patient. We have evaluated the clinical relevance of the Revised International Staging System (R-ISS) by comparing it with the original ISS in 718 Japanese patients. The distribution of patients according to response was similar between the ISS and R-ISS stages. Treatment response was greatly influenced by initial treatment modalities and deeper response was observed more frequently in transplanted patients. The R-ISS discriminated the difference in OS between the stages more distinctly than the ISS (p = 9.0 × 10-15 and p = 4.0 × 10-10, respectively). Differences in OS were clarified by both R-ISS and ISS in non-transplanted patients (p = 2.4 × 10-12 and p = 1.4 × 10-8, respectively), but the ISS failed to distinguish the difference between the stages in transplanted patients (p = 0.13). In contrast, the R-ISS could at least discriminate the excellent prognosis of stage I patients whereas the distinction between stage II and III was not that clear (p = 0.033). The R-ISS stage II encompassed a large number of patients, and the prognosis was heterogeneous depending on the fulfillment of prognostic factors such as LDH and adverse cytogenetics. These results suggest that treatment factors and prognostic factors greatly affect the therapeutic response and outcome, and the R-ISS is superior to ISS in prognostication of both transplant-eligible and -ineligible patients in our current clinical practice.

Staging Systems for Newly Diagnosed Myeloma Patients Undergoing Autologous Hematopoietic Cell Transplantation: The Revised International Staging System Shows the Most Differentiation between Groups.

The Revised International Staging System (R-ISS) and the International Myeloma Working Group 2014 (IMWG 2014) are newer staging systems used to prognosticate multiple myeloma (MM) outcomes. We hypothesized that these would provide better prognostic differentiation for newly diagnosed multiple myeloma (MM) compared with ISS. We analyzed the Center for International Blood and Marrow Transplant Research database from 2008 to 2014 to compare the 3 systems (N = 628) among newly diagnosed MM patients undergoing upfront autologous hematopoietic cell transplantation (AHCT). The median follow-up of survivors was 48 (range, 3 to 99) months. The R-ISS provided the greatest differentiation between survival curves for each stage (for overall survival [OS], the differentiation was 1.74 using the R-ISS, 1.58 using ISS, and 1.60 using the IMWG 2014) . Univariate analyses at 3 years for OS showed R-ISS I at 88% (95% confidence interval [CI], 83% to 93%), II at 75% (95% CI, 70% to 80%), and III at 56% (95% CI, 3% to 69%; P < .001). An integrated Brier score function demonstrated the R-ISS had the best prediction for PFS, though all systems had similar prediction for OS. Among available systems, the R-ISS is the most optimal among available prognostic tools for newly diagnosed MM undergoing AHCT. We recommend that serum lactate dehydrogenase and cytogenetic data be performed on every MM patient at diagnosis to allow accurate prognostication.

Prognostic significance of ß2-microglobulin decline index in multiple myeloma.

Purpose: To assess the prognostic significance of ß2-microglobulin decline index (ß2M DI) in multiple myeloma (MM). Methods: 150 MM patients diagnosed with MM were enrolled in this study. Cox proportional hazards model was used to analyze the uni- and multivariate prognosis in training cohort (n=105). A new combined prognostic model containing ß2M DI was built up based on the data in training cohort. The validation group was used to verify the model. Results: ß2M DI showed significant correlation with prognosis in both uni- and multivariate analyses and had a good correlation with complete response (CR) rate and deep remission rate. The ROC and calibration curves in validation cohort (n=45) indicated a good predictive performance of the new model. Based on the median risk score of the training group, we classified patients into high- and low- risk groups. In both training and validation groups, patients in the low-risk group had longer overall survival (OS) time than that in the high-risk group (p<0.05). Conclusion: ß2M DI is a good predictive index for predicting treatment response and survival time in MM patients. The prognostic model added with ß2M DI showed a better correlation with OS.

Semi-quantitative FDG parameters predict survival in multiple myeloma patients without autologous stem cell transplantation.

BACKGROUND: F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is useful in multiple myeloma (MM) for initial workup and treatment response evaluation. Herein, we evaluated the prognostic value of semi-quantitative FDG parameters for predicting the overall survival (OS) of MM patients with or without autologous stem cell transplantation (ASCT). METHODS: Study subjects comprised 227 MM patients who underwent baseline FDG PET/CT. Therein, 123 underwent ASCT while 104 did not. Volumes of interest (VOIs) of bones were drawn on CT images using a threshold of 150 Hounsfield units. FDG parameters of maximum standardized uptake value (SUVmax), mean SUV (SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and number of focal lesions (FLs) were measured. Kaplan-Meier survival analysis with log-rank tests and Cox proportional hazards regression analyses were performed for overall survival (OS). RESULTS: In the ASCT cohort, R-ISS stage, MTV, and TLG were associated with survival. In the non-ASCT cohort, however, R-ISS stage was not associated with patient outcomes. In contrast, high SUVmax, SUVmean, MTV, TLG, and FL could predict worse OS (hazard ratio [HR] = 2.569, 2.649, 2.506, 2.839, and 1.988, respectively). Importantly, combining FDG parameters with R-ISS stage provided a new risk classification system that discriminated worse OS in the non-ASCT cohort significantly better than did R-ISS stage alone. CONCLUSIONS: In the non-ASCT cohort, semi-quantitative FDG parameters were significant predictors of worse OS. Furthermore, combining FDG parameters with R-ISS stage may provide a new risk staging system that can better stratify the survival of MM patients without ASCT.

Exploring the R-ISS stage-specific regular networks in the progression of multiple myeloma at single-cell resolution.

The Revised International Staging System (R-ISS) is a simple and powerful prognostic tool for multiple myeloma (MM). However, heterogeneity in R-ISS stage is still poorly characterised, hampering improvement of treatments. We used single-cell RNA-seq to examine novel cellular heterogeneity and regular networks in nine MM patients stratified by R-ISS. Plasma cells were clustered into nine groups (P1-P9) based on gene expression, where P1-P5 were almost enriched in stage III.PDIA6 was significantly upregulated in P3 and LETM1 was enriched in P1, and they were validated to be upregulated in the MM cell line and in 22 other patients' myeloma cells. Furthermore, in progression, PDIA6 was newly found and verified to be activated by UQCRB through oxidative phosphorylation, while LETM1 was activated by STAT1 via the C-type lectin receptor-signalling pathway. Finally, a subcluster of monocytes was exclusively found in stage III specifically expressed chemokines modulated by ATF3. A few ligand-receptor pairs (CCL3/CCL5/CCL3L1-CCR1) were obviously active in monocyte-plasma communications in stage III. Herein, this study identified novel molecules, networks and crosstalk pairs in different R-ISS stages of MM, providing significant insight for its prognosis and treatment.

Propensity-score matched analysis of the efficacy of maintenance/continuous therapy in newly diagnosed patients with multiple myeloma: a multicenter retrospective collaborative study of the Japanese Society of Myeloma.

BACKGROUND: Maintenance ± consolidation or continuous therapy is considered a standard of care for both transplant-eligible and -ineligible patients with multiple myeloma (MM). However, long-term benefits of such therapy have not yet been clarified in the context of clinical practice. PURPOSE: To clarify the efficacy of maintenance/continuous approach, we retrospectively analyzed the cohort data of newly diagnosed MM patients by propensity-score matching based on age, gender, revised International Staging System (R-ISS) stage, and implementation of transplantation to reduce the bias due to confounding variables. FINDINGS: Among 720 patients, 161 were identified for each of the maintenance and no maintenance groups. Maintenance/continuous therapy employed immunomodulatory drugs (n = 83), proteasome inhibitors (n = 48), combination of both (n = 29), or dexamethasone alone (n = 1). Progression-free survival (PFS) was significantly prolonged in the maintenance group compared with the no maintenance group (median 37.7 and 21.9 months, p = 0.0002, respectively). Prolongation of PFS was observed in both transplanted and non-transplanted patients (p = 0.017 and p = 0.0008, respectively), with standard risk (p < 0.00001), R-ISS stage I (p = 0.037) and stage II (p = 0.00094), and those without obtaining complete response (p = 0.0018). There was no significant benefit in overall survival (OS), but it tended to be better in the maintenance group in non-transplanted patients. Regarding the treatment pattern, the substitution or addition of drugs different from the induction therapy and the combination with immunomodulatory drugs and proteasome inhibitors appeared to be more beneficial for PFS but not OS. CONCLUSION: These results support the benefit of current maintenance/continuous approach in routine clinical practice in the management of MM.

Revised International Staging System (R-ISS) stage-dependent analysis uncovers oncogenes and potential immunotherapeutic targets in multiple myeloma (MM).

Multiple myeloma (MM) accounts for ~10% of all haematologic malignancies. Little is known about high intratumour heterogeneities in patients stratified by the Revised International Staging System (R-ISS). Herein, we constructed a single-cell transcriptome atlas to compare differential expression patterns among stages. We found that a novel cytotoxic plasma cell (PC) population exhibited with NKG7 positive was obviously enriched in stage II patients. Additionally, a malignant PC population with significantly elevated expression of MKI67 and PCNA was associated with unfavourable prognosis and Epstein-Barr virus (EBV) infection in our collected samples. Moreover, ribonucleotide reductase regulatory subunit M2 (RRM2) was found and verified to promote proliferation of MM cell lines, suggesting RRM2 may serve as a detrimental marker in MM. The percentages of CD8+ T cells and NKT cells decreased along with R-ISS stages, reflecting the plasticity of the tumour immune microenvironment. Importantly, their crosstalks with myeloid cells and PC identified several potential immunotargets such as SIRPA-CD47 and CD74-MIF, respectively. Collectively, this study provided an R-ISS-related single-cell MM atlas and revealed the clinical significance of novel PC clusters, as well as potential immunotargets in MM progression.

Multiple myeloma is a type of bone cancer. It affects the immune cells that make antibodies, known as plasma cells. These immune cells live in the bone marrow. As with many types of cancer, the chance of survival is highest when multiple myeloma is diagnosed early. It has three stages, labelled I, II, and III. People with stage I or II disease have better outcomes than those with stage III, but the exact reasons are unclear. Bone marrow contains lots of different types of cells, which can affect the growth of a tumour. These include cancer-targeting cells, called killer T-cells, and cancer-supporting cells called myeloid cells. Understanding these cells and how they interact could shed light on the different stages of multiple myeloma. One way to do this is to use single cell sequencing, which looks at the genes in use inside each cell at any one time. Zhong, Hao, Zhang, Jiang et al. examined the bone marrow of two healthy donors and nine people with different stages of multiple myeloma. This revealed two new groups of plasma cells. One group, highest in stage II patients, was protective, with the potential to kill cancer cells. The other, highest in people with more aggressive disease, was harmful, with the potential to divide rapidly. The sequencing also identified molecules that might be useful drug targets for the future. These included a gene that drove growth in the dangerous plasma cells, and several that might help tumours escape from the immune system. It is becoming increasingly clear that the environment around a tumour has a huge role to play in its progression. Understanding how this environment changes over time could aid in the development of more targeted treatments. The next step is to find out more about the molecules identified here.

BoBafit : A copy number clustering tool designed to refit and recalibrate the baseline region of tumors' profiles.

Human cancer arises from a population of cells that have acquired a wide range of genetic alterations, most of which are targets of therapeutic treatments or are used as prognostic factors for patient's risk stratification. Among these, copy number alterations (CNAs) are quite frequent. Currently, several molecular biology technologies, such as microarrays, NGS and single-cell approaches are used to define the genomic profile of tumor samples. Output data need to be analyzed with bioinformatic approaches and particularly by employing computational algorithms. Molecular biology tools estimate the baseline region by comparing either the mean probe signals, or the number of reads to the reference genome. However, when tumors display complex karyotypes, this type of approach could fail the baseline region estimation and consequently cause errors in the CNAs call. To overcome this issue, we designed an R-package, BoBafit , able to check and, eventually, to adjust the baseline region, according to both the tumor-specific alterations' context and the sample-specific clustered genomic lesions. Several databases have been chosen to set up and validate the designed package, thus demonstrating the potential of BoBafit to adjust copy number (CN) data from different tumors and analysis techniques. Relevantly, the analysis highlighted that up to 25% of samples need a baseline region adjustment and a redefinition of CNAs calls, thus causing a change in the prognostic risk classification of the patients. We support the implementation of BoBafit within CN analysis bioinformatics pipelines to ensure a correct patient's stratification in risk categories, regardless of the tumor type.

Cytogenetics and Revised International Staging System (R-ISS): Risk Stratification in Multiple myeloma - A Retrospective Study in Indian Population.

BACKGROUND & OBJECTIVE: Cytogenetic abnormalities in Multiple myeloma (MM) has emerged as the most important factor that determine the prognosis and survival. Fluorescence in situ hybridization (FISH) can detect a greater number of cytogenetic abnormalities as compared to conventional karyotyping and hence has become the standard test in determining genetic abnormalities in MM. The present study was planned as there is an unmet need to find out various cytogenetic abnormalities and to implement them in prognostic stratification by Revised International Staging System (R-ISS) among Indian population. METHODS: A single institution retrospective study was conducted among a total of 117 patients newly diagnosed as Multiple Myeloma. They were analyzed for various cytogenetic abnormalities by using interphase FISH (iFISH) and were staged according to Revised International Staging System (R- ISS). RESULTS: Out of the 117 patients studied, deletion 17p13 (p53) was present in 16 patients (13.67%). Thirty patients (25.64%) showed deletion 13q14.3. Three patients (2.56%) were detected to have t(4:14).Two patients (1.7%) had t(11:14) and t(14:16), respectively. Total of 19 patients (16.23%) in our study exhibited high risk cytogenetics and two among them had more than one high risk cytogenetic abnormalities. There was a 66.4% moderate correlation between ISS-III and high-risk cytogenetics which was statistically insignificant. Of the total 117 patients, 37 (31.62%) were staged R-ISS III. CONCLUSION: High risk cytogenetics was found in 16.23 % of our study population and del 17p13 was the most common high-risk cytogenetic abnormality. Of the studied subjects, 31.62% had R-ISS III, which is significantly higher compared to western population.

The role of CT in PET/CT for assessing diffuse infiltration of bone marrow in multiple myeloma using the Durie-Salmon PLUS staging system.

PET/CT has been identified as one of the routine methods for the assessment of multiple myeloma (MM) bone marrow infiltration. In the routine method of performing PET/CT, the 18F-Fludeoxyglucose (18F-FDG) uptake in this disease is often used in the assessment of this condition, however CT diagnosis is not currently commonly used. The aim of the present study was to investigate the importance of CT in PET/CT for assessing diffuse infiltration (DI) of bone marrow in MM. MRI was used as a control in the present study, which is the gold standard for assessing DI of bone marrow and is divided into 3 levels: Mild, moderate and severe DI. Subsequently, a total of four combinations of PET and CT results were listed using the enumeration method for the evaluation of DI in the bone marrow. These combinations were respectively compared with the three levels of MR imaging to screen the most consistent method. The concordances of the new method and routine 18F-FDG PET/CT for the assessment of DI with MR imaging were compared using the McNemar test, respectively. The results of the DI assessment from the two methods were verified by performing Durie-Salmon (D-S) PLUS staging. Compared with MR imaging, the results were as follows: PET and CT exhibited negative results, suggesting mild DI; one of them was positive, suggesting moderate DI; and two were positive, suggesting severe DI. The results of concordance between two methods (new and routine) and MR imaging are indicated as follows: For the new method, McNemar test, P=0.513 and Kappa=0.745; for the routine 18F-FDG PET/CT method, McNemar test, P=0.03 and Kappa=0.547. Re-performance of D-S PLUS staging presented the following results: New method, McNemar test, P=0.317 and Kappa=0.93; for the routine method, McNemar test, P=0.223 and Kappa=0.811. These findings indicated that the CT component of PET/CT could improve the concordance with MRI results in the assessment of DI, and the same results were obtained when D-S PLUS staging was performed. The CT in PET/CT can enhance diagnostic accuracy in the assessment of DI by reducing the false negatives when compared with the routine 18F-FDG method.

Improved survival outcomes and relative youthfulness of multiple myeloma patients with t(4;14) receiving novel agents are associated with poorer performance of the revised international staging system in a real aging society.

The Revised International Staging System (R-ISS) was developed for a more accurate risk stratification of patients with symptomatic multiple myeloma (MM). However, original and subsequent validation studies of the R-ISS included relatively younger patients, many of whom were treated without bortezomib. Hence, we investigated the real-world prognostic performance of the R-ISS in 400 patients with MM treated with novel agents in Japan, an aging society. The patients had a median age of 72 years, and 96.0% were treated with bortezomib. Patients in R-ISS stage II were significantly older and failed to show significantly longer overall survival (OS) compared to patients in R-ISS stages III (median age; 74 and 70 years, respectively; P = 0.001, and median OS; 63.4 vs. 54.7 months, respectively; P = 0.32). However, OS differed significantly among patients with all conventional ISS stages. ISS stage III patients recategorized to R-ISS stage III were significantly younger than those recategorized to R-ISS stage II and had a relatively longer OS. As a reason for these findings, patients with the high-risk cytogenetic abnormality t(4;14) were significantly younger and had an improved OS compared to others, which can be attributed to a young age and bortezomib therapy, as previously suggested. In conclusion, the R-ISS was less successful than the ISS in discriminating between stages II and III among bortezomib-treated patients with MM in an aging society, which might be attributable to the inclusion of t(4;14) in the R-ISS categorization strategy.

The Revised International Staging System Compared to the Classical International Staging System Better Discriminates Risk Groups among Transplant-Ineligible Multiple Myeloma Patients.

BACKGROUND: The Revised International Staging System (R-ISS) has recently been introduced as a comprehensive prognostic score for multiple myeloma (MM). Validation of the R-ISS in patients treated outside of clinical trials is the focus of current investigations. The aim of this study was to test the prognostic role of the R-ISS in MM patients ineligible for autologous stem cell transplantation. PATIENTS AND METHODS: A total of 102 newly diagnosed MM patients were analyzed. All patients were initially treated with thalidomide-based combinations. RESULTS: An overall response rate was achieved in 77.4% patients. Both the International Staging System (ISS) and the R-ISS influenced the event-free survival and the overall survival (OS). However, the ISS was unable to discriminate patients in stages ISS1 and ISS2 regarding OS. On the contrary, the R-ISS clearly differentiated risk categories regarding OS and provided an improved discriminative power of 6.3% compared to the ISS. Furthermore, among the parameters that were significant in univariate analysis (presence of renal impairment, anemia, platelet count < 130 × 109/l, and R-ISS), the multivariate model pointed to the R-ISS (p = 0.001) as the most important parameter influencing OS. CONCLUSION: The R-ISS represents a useful tool for risk stratification of transplant-ineligible MM patients and should be considered as a prognostic index in daily clinical practice.