Early relapse within 18 months is a powerful dynamic predictor for prognosis and could revise static risk distribution in multiple myeloma.

BACKGROUND: The duration of response to treatment is a major prognostic factor, and early relapse (ER) strongly predicts inferior survival in multiple myeloma (MM). However, the definitions of ER in MM vary from study to study and how to dynamically integrate risk distribution is still unsolved. METHODS: This study evaluated these ER definitions and further investigated the underlying relationship with static risk distribution in 629 newly diagnosed MM (NDMM) patients from the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199). RESULTS: These data indicated that early relapse within 18 months (ER18) after initial treatment was the best time point for identifying early progression and dynamic high-risk in MM. The ER18 population (114 of 587, 19.4%) presented with more aggressive biologic features and the inferior response to treatment compared to a reference cohort (p < .001), with a significantly short median overall survival (OS) of 28.9 months. Multivariate analyses confirmed the most significant prognostic value of ER18 on OS in the context of International Staging System stage, elevated lactate dehydrogenase, thrombocytopenia, cytogenetic abnormalities, and treatment (hazard ratio, 4.467; p < .001). The authors also described the specific transitions from static risk profile to dynamic risk distribution and then constructed a mixed-risk-pattern to identify four novel populations with distinct survival (p < .001). Additionally, the authors proposed a second-state model that predicts dynamic risk changes, enabling a complementary role to the Revised International Staging System model in facilitating individualized systematic treatment. CONCLUSIONS: Collectively, this study concludes that ER18 is a simple and dynamic prognostic predictor in MM. In addition to static risk assessment, dynamic risk plays an important role in survival prediction.

Minor clone of del(17p) provides a reservoir for relapse in multiple myeloma.

The deletion of chromosome 17p (del(17p)) is considered a crucial prognostic factor at the time of diagnosis in patients with multiple myeloma (MM). However, the impact of del(17p) on survival at different clonal sizes at relapse, as well as the patterns of clonal evolution between diagnosis and relapse and their prognostic value, has not been well described. To address these issues, we analyzed the interphase fluorescence in situ hybridization (iFISH) results of 995 newly diagnosed MM (NDMM) patients and 293 patients with MM at their first relapse. Among these patients, 197 had paired iFISH data at diagnosis and first relapse. Our analysis of paired iFISH revealed that a minor clone of del(17p) at relapse but not at diagnosis was associated with poor prognosis in MM (hazard ratio for median overall survival 1.64 vs. 1.44). Fifty-six and 12 patients developed one or more new cytogenetic abnormalities at relapse, mainly del(17p) and gain/amp(1q), respectively. We classified the patients into six groups based on the change patterns in the clonal size of del(17p) between the two time points. Patients who did not have del(17p) during follow-up showed the best outcomes, whereas those who acquired del(17p) during their disease course, experienced compromised survival (median overall survival: 61.3 vs. 49.4 months; hazard ratio =1.64; 95% confidence interval: 1.06-2.56; P<0.05). In conclusion, our data confirmed the adverse impact of a minor clone of del(17p) at relapse and highlighted the importance of designing optimal therapeutic strategies to eliminate high-risk cytogenetic abnormalities (clinicaltrials gov. identifier: NCT04645199).

Immunophenotypic profile defines cytogenetic stability and unveils distinct prognoses in patients with newly-diagnosed multiple myeloma (NDMM).

Prognostic significance of multiple immune antigens in multiple myeloma has been well established. However, a level of uncertainty remains regarding the intrinsic relationship between immunophenotypes and cytogenetic stability and precise risk stratification. To address these unresolved issues, we conducted a study involving 1389 patients enrolled in the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199). Our results revealed that the correlation between antigen expression and cytogenetics is more prominent than cytopenia or organ dysfunction. Most immune antigens, apart from CD38, CD138, and CD81, exhibit significant associations with the incidence of at least one cytogenetic abnormality. In turn, we identified CD138-low/CD27-neg as specific adverse immunophenotypic profile, which remaining independent impact on progression-free survival (HR, 1.49; P = 0.007) and overall survival (HR, 1.77; P < 0.001) even in the context of cytogenetics. Importantly, CD138-low/CD27-neg profile was also associated with inferior survival after first relapse (P < 0.001). Moreover, the antigen expression profiles were not strictly similar when comparing diagnosis and relapse; in particular, the CD138-low/CD27-neg pattern was notably increased after disease progression (19.1 to 29.1%; P = 0.005). Overall, our study demonstrates that diverse immune profiles are strongly associated with cytogenetic stability, and a specific immunophenotype (CD138-low/CD27-neg) could effectively predict prognoses across different disease stages.

Impact of residual tumor cells in the stem cell collection on multiple myeloma patients receiving autologous stem cell transplantation.

Autologous stem cell transplantation (ASCT) is the standard therapy for patients with transplant-eligible multiple myeloma (TEMM). However, the ideal depth of response required before ASCT and the impact of residual tumor cells in the stem cell collection (SCC) on survival remains unclear. Here we collected data of 89 patients with TEMM undergoing ASCT and analyzed the minimal residual disease of SCC (cMRD) and bone marrow (BM) (mMRD) before transplantation. Before ASCT, 31.5% and 76.4% of patients achieved MRD negativity in BM and SCC, respectively. Tumor cells were less in SCC samples than that in BM samples. Neoplastic cells in SCC could be observed in patients with different responses after induction therapy, and there were no significant differences in the percentage and level of cMRD among these subgroups (P > 0.05). No correlation was found between the cMRD status and the response patients achieved after ASCT (P > 0.05). The median follow-up was 26.8 months. mMRD negativity before ASCT was associated with longer PFS (55.9 vs. 27.1 months; P = 0.009) but not OS (not reached vs. 58.9 months; P = 0.115). Patients with different cMRD statuses before ASCT experienced similar PFS (40.5 vs. 76.4 months for negativity vs. positivity; P = 0.685) and OS (not reached vs. 58.8 months for negativity vs. positivity; P = 0.889). These results suggested that detectable cMRD does not significantly predict the inferior post-ASCT response or shorter survival, and patients are eligible to undergo ASCT upon achieving partial response.

Effects of Polyunsaturated Fatty Acids on Colorectal Cancer Patients: A Meta-Analysis of Randomized Controlled Trials.

This study aimed to investigate the effects of polyunsaturated fatty acids (PUFAs) on patients with colorectal cancer (CRC). Electronic databases such as PubMed and Web of Science were searched. Studies on the application of PUFAs in patients with CRC, published up to January 2022, were conducted. Twelve studies involving 702 CRC patients were included. For patients undergoing surgery, subgroup analyses indicated that preoperative supplementation with PUFAs improved total postoperative infectious complications (RR: 0.37, p = 0.02). Furthermore, the supplementation of PUFAs in preoperative (WMD: -2.27, p < 0.001) and postoperative (WMD: -2.66, p = 0.01) groups was effective in shortening the postoperative hospital stay for patients with CRC. Tumor necrosis factor-α (TNF-α) (SMD: -0.56, p = 0.007) and interleukin-6 (IL-6) (SMD: -0.54, p = 0.004) levels were lower in all CRC patients receiving PUFAs intervention than in the control group. Moreover, supplementation with PUFAs in chemotherapy patients significantly increased albumin (WMD: 0.48, p = 0.03) and decreased C-reactive protein (CRP) (WMD: -6.12, p = 0.02) compared to the control group. This study demonstrated that PUFAs intervention could diminish the total postoperative infection complications of CRC patients, shorten the postoperative hospital stay, and reduce inflammation.

Systematic Review and Meta-Analysis: Association between Preoperative Ustekinumab and Surgical Complications in Crohn's Disease Patients.

INTRODUCTION: The impact of ustekinumab (UST) therapy on surgical complications in patients with Crohn's disease (CD) remains controversial. The aim of this meta-analysis is to explore the link between these two. METHODS: Databases (PubMed, Web of Science, Cochrane, and Springer Link) were searched until April 2022. Studies of CD patients who received UST and no UST prior to surgery (including no biological therapy, anti-tumor necrosis factor-α [anti-TNF-α] agent, and vedolizumab [VDZ]) were included. Primary outcomes included overall complications, infectious complications, and noninfectious complications. RESULTS: Nine studies totaling 3,225 CD patients were enrolled; 332 patients received UST treatment. There was no evidence of difference in the overall complications (odds ratio [OR] = 0.84, p = 0.37, 95% confidence interval [CI] = [0.57-1.23], I2 = 40%) between CD patients who had UST treatment preoperatively and those who had no UST treatment. There was no evidence of a difference in infectious complications (OR = 1.15, p = 0.35, 95% CI = [0.86-1.53], I2 = 2%). Additionally, there was no significant evidence of difference between these groups in terms of noninfectious complications and death. Specifically, there was no evidence of difference in overall complications, infection complications (including wound complications, sepsis, abscess, and anastomotic leakage), and noninfection complications (ileus, readmission, and return to operation), compared with no biological therapy and anti-TNF-α agents. At the same time, no significant evidence of difference was discovered in the comparison of preoperative UST and VDZ therapy in terms of overall complications, infectious complications (sepsis and abscess), and noninfectious complications (intestinal obstruction, readmission, and recovery surgery). CONCLUSION: In general, compared with other biological agents, preoperative use of UST in the treatment of CD patients is usually safe and does not increase surgical complications.

Schisandrin B Protects against Acute Ethanol-Induced Cardiac Injury by Downregulating Autophagy via the NOX4/ROS Pathway.

INTRODUCTION: Although oxidative stress has been demonstrated to mediate acute ethanol-induced changes in autophagy in the heart, the precise mechanism behind redox regulation in acute ethanol heart disease remains largely unknown. METHODS: Wild-type C57BL/6 mice were intraperitoneally injected with ethanol (3 g/kg/day) for 3 consecutive days. The effects of ethanol on cultured primary cardiomyocytes and H9c2 myoblasts were also studied in vitro. Levels of autophagic flux, cardiac apoptosis and function, reactive oxygen species (ROS) accumulation, NOX4, and NOX2 were examined. The NOX4 gene was knocked down with NOX4 siRNA. RESULTS: In this study, we demonstrated that schisandrin B inhibited acute ethanol-induced autophagy and sequent apoptosis. In addition, schisandrin B treatment improved cardiac function in ethanol-treated mice. Furthermore, NOX4 protein expression was increased during acute ethanol exposure, and the upregulation of NOX4 was significantly inhibited by schisandrin B treatment. The knockdown of NOX4 prevented ROS accumulation, cell autophagy, and apoptosis. CONCLUSION: These results highlight that NOX4 is a critical mediator of ROS and elaborate the role of the NOX4/ROS axis in the effect of schisandrin B on autophagy and autophagy-mediated apoptosis in acute ethanol exposure, which suggests a therapeutic strategy for acute alcoholic cardiomyopathy.

Fructus mori: An Updated Review on Botany, Phytonutrient, Detection, Bioactivity, Quality Marker, and Application.

BACKGROUND: Fructus mori (mulberry) is not only a delicious fruit with rich phytonutrients and health functions but also a medicinal plant with many clinical therapeutic values for tonifying kidneys and consolidating essence, making hair black and eyes bright. METHODS: The related references about F. mori in this review from 1996 to 2022 had been collected from both online and offline databases, including PubMed, Elsevier, SciFinder, Willy, SciHub, Scopus, Web of Science, ScienceDirect, SpringerLink, Google Scholar, Baidu Scholar, ACS publications, and CNKI. The other information was acquired from ancient books and classical works about F. mori. RESULTS: An updated summary of phytonutrients from F. mori was listed as fellows: flavonoids (1-20) (23.5%), phenolic acids (21-34) 16.5%), alkaloids (35-75) (48.2%), polysaccharides (76- 78) (3.5%), other compounds (79-85) (8.3%). The above chemical components were detected by TLC, UV-Vis, HPLC, GC-MS, and AAS methods for their quality standards. The various bioactivities (hepatoprotective, immunomodulatory, anti-oxidant, hypoglycemic, anti-cancer, and other activities) of mulberry are summarized and discussed in this review, which laid an important basis for analyzing their mechanisms and quality markers. This review summarized its applications for vinegar, wine, yogurt, drink, jelly, and sweetmeat in food fields, and the existing problems and future development directions are also discussed in this review. CONCLUSIONS: This review made a comprehensive description of F. mori, including botany, phytonutrient, detection, bioactivity, quality marker, and application. It will not only provide some important clues for further studying F. mori, but also provide some valuable suggestions for indepth research and development of F. mori.

Fluorescence in situ hybridization reveals the evolutionary biology of minor clone of gain/amp(1q) in multiple myeloma.

Growing evidence suggests that gain or amplification [gain/amp(1q)] accumulates during disease progression of multiple myeloma (MM). Previous investigations have indicated that small gain/amp(1q) subclones present at the time of diagnosis may evolve into dominant clones upon MM relapse. However, the influence of a minor clone of gain/amp(1q) on MM survival, as well as the correlation between different clonal sizes of gain/amp(1q) and the chromosomal instability (CIN) of MM, remains poorly understood. In this study, we analyzed fluorescence in situ hybridization (FISH) results of 998 newly diagnosed MM (NDMM) patients. 513 patients were detected with gain/amp(1q) at diagnosis. Among these 513 patients, 55 had a minor clone (≤20%) of gain/amp(1q). Patients with a minor clone of gain/amp(1q) displayed similar survival outcomes compared to those without gain/amp(1q). Further analysis demonstrated patients with a minor clone of gain/amp(1q) exhibited a clonal architecture similar to those without gain/amp(1q). Lastly, our results showed a significant increase in the clonal size of the minor clone of gain/amp(1q), frequently observed in MM. These findings suggested that a minor clone of gain/amp(1q) might represent an earlier stage in the pathogenesis of gain/amp(1q) and propose a "two-step" process in the clonal size changes of gain/amp(1q) in MM.

Monitoring Minimal Residual Disease in Patients with Multiple Myeloma by Targeted Tracking Serum M-Protein Using Mass Spectrometry (EasyM).

PURPOSE: We investigated both the clinical utilities and the prognostic impacts of the clonotypic peptide mass spectrometry (MS)-EasyM, a blood-based minimal residual disease (MRD) monitoring protocol in multiple myeloma. EXPERIMENTAL DESIGN: A total of 447 sequential serum samples from 56 patients with multiple myeloma were analyzed using EasyM. Patient-specific M-protein peptides were sequenced from diagnostic samples; sequential samples were quantified by EasyM to monitor the M-protein. The performance of EasyM was compared with serum immunofixation electrophoresis (IFE), bone marrow multiparameter flow cytometry (MFC), and next-generation flow cytometry (NGF) detection. The optimal balance of EasyM sensitivity/specificity versus NGF (10-5 sensitivity) was determined and the prognostic impact of MS-MRD status was investigated. RESULTS: Of the 447 serum samples detected and measured by EasyM, 397, 126, and 92 had time-matching results for comparison with serum IFE, MFC-MRD, and NGF-MRD, respectively. Using a dotp >0.9 as the MS-MRD positive, sensitivity was 99.6% versus IFE and 100.0% versus MFC and NGF. Using an MS negative cutoff informed by ROC analysis (<1.86% of that at diagnosis), EasyM sensitivity remained high versus IFE (88.3%), MFC (85.1%), and NGF (93.2%), whereas specificity increased to 90.4%, 55.8%, and 93.2%, respectively. In the multivariate analysis, older diagnostic age was an independent predictor for progression-free survival [PFS; high risk (HR), 3.15; 1.26-7.86], the best MS-MRD status (MS-MRD negative) was independent predictor for both PFS (HR, 0.25; 0.12-0.52) and overall survival (HR, 0.16; 0.06-0.40). CONCLUSIONS: EasyM is a highly sensitive and minimal invasive method of MRD monitoring in multiple myeloma; MS-MRD had significant predictive ability for survival outcomes.

Development of a novel long-acting antidiabetic FGF21 mimetic by targeted conjugation to a scaffold antibody.

Fibroblast growth factor (FGF)21 improves insulin sensitivity, reduces body weight, and reverses hepatic steatosis in preclinical species. We generated long-acting FGF21 mimetics by site-specific conjugation of the protein to a scaffold antibody. Linking FGF21 through the C terminus decreased bioactivity, whereas bioactivity was maintained by linkage to selected internal positions. In mice, these CovX-Bodies retain efficacy while increasing half-life up to 70-fold compared with wild-type FGF21. A preferred midlinked CovX-Body, CVX-343, demonstrated enhanced in vivo stability in preclinical species, and a single injection improved glucose tolerance for 6 days in ob/ob mice. In diet-induced obese mice, weekly doses of CVX-343 reduced body weight, blood glucose, and lipids levels. In db/db mice, CVX-343 increased glucose tolerance, pancreatic ß-cell mass, and proliferation. CVX-343, created by linkage of the CovX scaffold antibody to the engineered residue A129C of FGF21 protein, demonstrated superior preclinical pharmacodynamics by extending serum half-life of FGF21 while preserving full therapeutic functionality.

Synthesis and biological evaluation of nucleoside analogues than contain silatrane on the basis of the structure of acyclovir (ACV) as novel inhibitors of hepatitis B virus (HBV).

Hepatitis B virus (HBV) infection causes major public health problems worldwide. Acyclovir (ACV) is mainly used to inhibit herpes simplex virus (HSV) rather than HBV. In this study, we used the combination principle to design and synthesize nucleoside analogues that contain silatrane on the basis of the structure of ACV. We found that the compounds were effective inhibitors of HBV, both in vitro and in vivo. All of the compounds showed suppressive activity on the expression of HBV surface antigen (HBsAg) and HBV e antigen (HBeAg) in the HepG2.2.15 cell line with low cytotoxicity. One of compounds was studied in HBV transgenic mice model, and the test results showed its ability to reduce the levels of HBsAg, HBeAg and HBV DNA by ELASE and qPCR. Furthermore, significant improvement of T lymphocyte was observed after treatment, as evaluated by flow cytometry (FCM).

Chemical generation of bispecific antibodies.

Bispecific antibodies (BsAbs) are regarded as promising therapeutic agents due to their ability to simultaneously bind two different antigens. Several bispecific modalities have been developed, but their utility is limited due to problems with stability and manufacturing complexity. Here we report a versatile technology, based on a scaffold antibody and pharmacophore peptide heterodimers, that enables rapid generation and chemical optimization of bispecific antibodies, which are termed bispecific CovX-Bodies. Two different peptides are joined together using a branched azetidinone linker and fused to the scaffold antibody under mild conditions in a site-specific manner. Whereas the pharmacophores are responsible for functional activities, the antibody scaffold imparts long half-life and Ig-like distribution. The pharmacophores can be chemically optimized or replaced with other pharmacophores to generate optimized or unique bispecific antibodies. As a prototype, we developed a bispecific antibody that binds both vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2) simultaneously, inhibits their function, shows efficacy in tumor xenograft studies, and greatly augments the antitumor effects of standard chemotherapy. This unique antiangiogenic bispecific antibody is in phase-1 clinical trials.

Peganum harmala L.: A Review of Botany, Traditional Use, Phytochemistry, Pharmacology, Quality marker, and Toxicity.

BACKGROUND: Peganum harmala L. is a perennial herb of Peganum in Zygophyllaceae family. It has been used as a national medicinal herb with the efficacy of strengthening muscle, warming stomach, dispelling cold, and removing dampness in Chinese folk. Clinically, it is mainly used to treat diseases such as weak muscles and veins, joint pain, cough and phlegm, dizziness, headache, and irregular menstruation. METHODS: The relevant information about P. harmala L. in this review is based on online databases, including Elsevier, Willy, Web of Science, PubMed, ScienceDirect, SciFinder, SpringLink, Google Scholar, Baidu Scholar, ACS publications, SciHub, Scopus, and CNKI. The other information was acquired from ancient books and classical works about P. harmala L. RESULTS: P. harmala L. is an important medicinal plant with a variety of traditional uses according to the theory of Chinese medicine. Phytochemical research revealed that P. harmala L. contained alkaloids, volatile oils, flavonoids, triterpenoids, coumarins, lignins, anthraquinones. Modern studies showed P. harmala L. possessed multiple bioactivities, including anti-cancer, neuroprotective, anti-bacterial, anti-inflammatory, hypoglycemic, anti-hypertensive, anti-asthmatic, and insecticidal activities. Furthermore, the contents of the quality marker and toxicity of P. harmala L. were summarized and analyzed in this review. CONCLUSION: The botany, traditional use, phytochemistry, pharmacology, quality marker, and toxicity of P. harmala L. were reviewed in this paper. It will not only provide an important clue for further studying P. harmala L., but also supply an important theoretical basis and valuable reference for in-depth research and exploitations of this plant in the future.

Effect of Metformin on the Prognosis of Gastric Cancer Patients with Type 2 Diabetes Mellitus: A Meta-Analysis Based on Retrospective Cohort Studies.

Background: Metformin is one of the most common drugs for type 2 diabetes mellitus (T2DM) treatment. In addition, metformin intends to have a positive effect on the prognosis of several cancers. However, the therapeutic effect of metformin on gastric cancer (GC) remains controversial. This study explores and updates the therapeutic effect of metformin in GC patients with T2DM. Methods: We searched through PubMed, Embase, Web of Science, and the Cochrane Library for relevant articles by July 2022. The relationship between metformin therapy and the prognosis of GC patients with T2DM was evaluated based on the hazard ratio (HR) at a 95% confidence interval (95% CI). Overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) were the primary outcomes analyzed. Results: Seven retrospective cohort studies with a combined 2,858 patients met the inclusion criteria. OS and CSS were reported in six studies, and PFS was reported in four studies. Pooled results showed that, compared to the nonmetformin group, the prolonged OS (HR = 0.72, p = 0.001), CSS (HR = 0.81, p = 0.001), and PFS (HR = 0.70, p = 0.008) of the experimental group may be associated with the exposure to metformin. Conclusion: Metformin may have a beneficial effect on the prognosis of GC patients with T2DM.

The age-dependent changes in risk weights of the prognostic factors for multiple myeloma.

OBJECTIVE: Multiple myeloma is a highly heterogenous plasma cell malignancy, commonly seen in older patients. Age is one of the important prognostic factors. However, nearly all the prognostic staging systems are based on clinical trials, where patients were relatively fit and young. It is unknown how the presence of biochemical or cytogenetic prognostic factors and their risk weights changes with older age. To further investigate this question, we retrospectively analyzed the data from a consecutive cohort of patients treated with either bortezomib or thalidomide-based therapy. METHODS: This retrospective study was carried out on a cohort of 1125 newly diagnosed multiple myeloma patients, from January 2008 to December 2019. Patients received bortezomib or thalidomide-based induction and maintenance therapy. Patients accepted hematopoietic stem cell transplantation if eligible. Statistical analysis was conducted by Stata/MP 16.0 and SPSS 26.0. RESULTS: With age increasing, the proportion of patients with ISS 3, performance status score ≥2, and the incidence rate of gain(1q) significantly increased. We also found that ISS became less important in older patients. However, cytogenetic abnormalities exerted a consistently adverse impact on survival, both in young and old patients. Older patients had an inferior outcome than their young counterparts. All patients in our cohort benefitted more from bortezomib than thalidomide-based induction therapy, except for patients ≥71 years old. CONCLUSIONS: ISS may lose prognostic value in patients ≥71 years old. Older patients had an inferior outcome and needed more effective and less toxic treatment.Plain Language SummaryMultiple myeloma is a type of blood cancer commonly seen in older people. To treat this disease, genetic abnormality, the poor physical status of patients and the abundance of tumor cells are the main difficulties. We often draw these conclusions from clinical trials. However, clinical trials always enrolled relatively younger patients, so the presence and significance of these factors may vary from clinical trials to the real world. We conducted the study to find out the real risk in both young and old patients. We found that older patients were more likely to have anemia, poor nutritional status and renal function. We also found older patients had more risk of relapse, progression or death than young patients. Frail physical status is the key obstacle to treating older patients, and tumor burden no longer impacts the outcome of these people. Bortezomib is a powerful drug to treat this disease, but patients ≥71 years old had less benefit than younger ones. More studies should focus on older or frail patients as these patients need more effective and less toxic treatment.

Clinical Benefit of Autologous Stem Cell Transplantation for Patients with Multiple Myeloma Achieving Undetectable Minimal Residual Disease after Induction Treatment.

Attaining undetectable minimal residual disease (MRD) is the current therapeutic goal for multiple myeloma. But there is a current lack of data regarding the clinical benefit of autologous stem cell transplantation (ASCT) for patients with myeloma achieving early MRD-negative status after induction treatment, in addition to the interaction of longitudinal MRD status with ASCT. The current study included 407 patients with transplant-eligible multiple myeloma with available MRD status from the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199), of whom 147 (34.4%) achieved early undetectable MRD and 182 (44.7%) received ASCT. Early MRD-negative status was associated with a lower risk of disease progression [HR = 0.447; 95% confidence interval (CI), 0.333-0.600; P < 0.001] and death (HR = 0.473; 95% CI, 0.320-0.700; P < 0.001). Of note, patients who achieved undetectable MRD early still benefitted from ASCT, with a remarkable improvement in the median MRD-negative duration (33.5-58.0 months, P < 0.001), progression-free survival (PFS; 46.0-88.3 months, P < 0.001), and overall survival (OS; 76.4 months to not reached, P = 0.003). These clinical benefits were more pronounced in patients with aggressive features (high-risk cytogenetic abnormalities or high tumor burden) compared with standard-risk patients. Similar results were observed in patients with detectable MRD after induction treatment. In addition, we identified four MRD-status transformation patterns following ASCT, which were strongly correlated with diverse survival outcomes (P < 0.001). Our study revealed the enhanced clinical significance of ASCT in patients with transplant-eligible myeloma, regardless of early MRD status, particularly for high-risk patients. Subsequent prospective trials are essential to validate these observations. Significance: Achieving and maintaining undetectable MRD is the current treatment goal for multiple myeloma. Our results emphasized the remarkable clinical benefit of ASCT on MRD-negative duration, PFS, and OS in patients with multiple myeloma regardless of early MRD status. These favorable impacts were more evident in patients with aggressive features. Importantly, dynamic MRD monitoring among ASCT could facilitate personalized stratification of therapeutic approaches.

The prognostic utility of dynamic risk stratification at disease progression in patients with multiple myeloma.

OBJECTIVES: There may be a shift in risk stratification at progression compared to that at diagnosis in patients with multiple myeloma (MM). We aimed to evaluate whether re-staging and stage migration is of prognostic impact. METHODS: Real-world data from the National Longitudinal Cohort of Hematologic Diseases-multiple myeloma were collected; 263 consecutive patients demonstrating disease progression were finally included. Staging at diagnosis and re-staging at progression were performed using the International Staging System (ISS) and Revised International Staging System (RISS). RESULTS: Based on ISS re-staging, the median post-progression survival (mPPS) of patients with stage I, II, and III was 44.2, 21.7, and 11.6 months, respectively (P < 0.0001). Based on RISS re-staging, the mPPS of patients with stage I, II, and III was 50.3, 22.2, and 11.4 months, respectively (P < 0.0001). The mPPS in patients with improved, maintained, and deteriorated ISS stage migration from diagnosis was 33.6, 20.9, and 16 months, respectively (P = 0.0051) and that with improved, maintained, and deteriorated RISS stage migration was 48.4, 23.1, and 13.9 months, respectively (P < 0.001). Compared to patients with maintained or improved disease stage, those with deteriorated ISS/RISS migration showed significantly higher incidence of Del(17P) at progression and worse PPS. Multivariate analyses indicated both re-staging and stage migration by ISS/RISS at progression were independent predictors for PPS. CONCLUSIONS: We demonstrated that ISS/RISS re-staging showed superior prognostic utility over ISS/RISS staging in predicting PPS. Patients with deteriorated stage migration or maintained advanced stage at progression may need more individualized treatment.