Factor In Multiple Myeloma Research Articles

CT-defined muscle density as a prognostic factor in multiple myeloma undergoing autologous stem cell therapy: a retrospective single center study.

Skeletal muscle quality assessment can be performed by cross-sectional imaging. Skeletal muscle density (SMD) identified to be of prognostic relevance of several clinically outcomes in patients with hematological diseases. The purpose of the present study was to establish the effect of SMD on overall survival (OS) and progression-free survival (PFS) in patients with multiple myeloma (MM). All patients with MM were retrospectively analyzed between 2009 and 2019. 127 patients were included into the analysis. Whole-body computed tomography (CT) was used to calculate skeletal muscle index (SMI), SMD, albumin-gauge score and intramuscular adipose tissue content (IMAC). Overall, 28 patients (22.0%) of the patient sample died. In the discrimination analysis muscle density was higher in non-survivors compared to survivors (mean 30.8 ± 12.5 versus 24.1 ± 15.8, p = 0.03) and IMAC was lower in non-survivors (-0.66 ± 1.8 versus -0.25 ± 0.21, p = 0.01). These differences, however, were not demonstrated in the logistic regression analysis, which could not show prognostic relevance for the investigated muscle density parameters on PFS or OS. CT-defined muscle density parameters have no prognostic relevance on survival in patients with MM undergoing autologous stem cell therapy, which was demonstrated in a comprehensive analysis. These results corroborate previous smaller studies that body composition might have a limited role in this tumor entity.

Impact of bortezomib on 1q21+ in multiple myeloma: A meta-analysis of treatment outcomes and prognostic implications.

The gain of chromosomal region 1q21 is a significant risk factor in multiple myeloma (MM) and is associated with poor prognosis. The introduction of bortezomib has notably improved outcomes for patients with MM. However, recent studies have reported conflicting results regarding the efficacy of bortezomib in mitigating the adverse effects of 1q21 aberration in these patients. To address this, in the present study, a meta-analysis was conducted based on 6 studies encompassing 1,575 patients with MM. The prognosis of patients with 1q21+ who underwent treatment with a bortezomib-based regimen was evaluated in terms of complete response (CR), overall survival (OS) and progression-free survival (PFS) rates. The results demonstrated that patients with 1q21 aberration were more likely to achieve CR than those without 1q21+ under bortezomib-based treatment [odds ratio, 0.64; 95% confidence interval (CI), 0.49-0.83; P=0.0008]. However, 1q21+ remained a high-risk factor in patients with MM even after bortezomib treatment [PFS: hazard ratio (HR), 1.72; 95% CI, 1.53-1.93; P<0.00001; and OS: HR, 1.95; 95% CI, 1.58-2.42; P<0.00001]. In conclusion, although bortezomib improved the likelihood of achieving CR in patients with 1q21+, this genetic aberration continues to be considered a high-risk factor in patients with MM treated with a bortezomib-based regimen.

The Prognostic Impact of Plasma Cell Chromosome 17 Abnormality Percentage Cut-offs on Patient Outcomes in Multiple Myeloma

Abstract Abnormalities in chromosome 17 encompassing the TP53 locus [deletion of the small arm {del (17p)} and monosomy 17] as identified by fluorescent in-situ hybridization (FISH), are a well-established adverse prognostic factor in multiple myeloma (MM). Previous research suggested that higher percentages of these chromosome 17 abnormalities correlate with worse prognoses, proposing various cutoff points to assess this relationship, ranging between 50-60%. Of note, these studies employed extensive plasma cell enrichment protocols and often included only cases with high plasma cell percentages (70-90%). Our study aims to investigate the relationship between the percentage of plasma cells with chromosome 17 abnormalities and patient outcomes at the time of acquisition of the abnormality, scrutinizing various cut-off points for prognostic significance. We retrospectively reviewed 339 MM patients at our institution, including newly diagnosed and relapsed cases, examining chromosome 17 abnormality levels identified by FISH on bone marrow specimens. After CD138 magnetic bead enrichment, 50 nuclei were scored for these abnormalities and the percentage calculated. It is important to note that the precise percentage of plasma cells in the sample was not quantified. We analyzed survival outcomes across different percentage cut-off points (20%, 40%, 50%, 55%, 60%, and 80%) using Kaplan Meier analysis and log-rank tests. Significant differences in median survival were noted at the 40% and 50% cut-offs. Patients with &amp;gt;40% chromosome 17 abnormalities showed a median survival of 17.5 months compared to 25.8 months for those with ≤40% (p&amp;lt;0.05), an absolute difference of 8.3 months. Similarly, the &amp;gt;50% group had a median survival of 19.4 months versus 24.3 months in the ≤50% group (p&amp;lt;0.05), with an absolute difference of 4.9 months. However, these differences, while statistically significant, may not be clinically substantial. Furthermore, a 55% cut-off did not yield a significant survival difference (23.5 months vs. 19.8 months for ≤55% and &amp;gt;55% groups, p&amp;gt;0.05) in our cohort. Our findings confirm some prognostic value of chromosome 17 abnormality levels in MM but suggest that the absolute differences in median survival at certain cut-offs, based on the test as performed in our laboratory, might not be clinically impactful. This may be due to differences in the proportion of non-plasma cells within the samples being scored, resulting in ambiguity when interpreting FISH results. Future research should aim to improve the consistency of plasma cell enrichment, develop approaches to score only plasma cells, establish risk-specific cut-offs, and explore the relationship between chromosome 17 abnormality levels, treatment response, and overall significance. The study raises important questions about the necessity of stratifying patients based on chromosome 17 abnormality levels versus simply detecting their presence for prognostic assessment.

Real-World Evidence on Prognostic Value of MRD in Multiple Myeloma Using Flow Cytometry.

Minimal residual disease (MRD) is one of the most important prognostic factors in multiple myeloma (MM) and a valid surrogate for progression-free survival (PFS) and overall survival (OS). Recently, MRD negativity was approved as an early clinical endpoint for accelerated drug approval in MM. Nevertheless, there is limited evidence of MRD utility in real-world setting. In this retrospective multicenter study, we report outcomes of 331 newly diagnosed MM patients with MRD evaluation at Day+100 after autologous stem cell transplantation using flow cytometry with a median limit of detection of 0.001%. MRD negativity was reached in 47% of patients and was associated with significantly prolonged median PFS (49.2 months vs. 18.4 months; hazard ratios (HR) = 0.37; p < 0.001) and OS (not reached vs. 74.9 months; HR = 0.50; p = 0.007). Achieving MRD negativity was associated with PFS improvements regardless of age, International Staging System (ISS) stage, lactate dedydrogenase (LDH) level, or cytogenetic risk. Importantly, MRD positive patients benefited from lenalidomide maintenance versus no maintenance (18-months PFS: 81% vs. 46%; HR = 0.24; p = 0.002) while in MRD negative patients such benefit was not observed (p = 0.747). The outcomes of our real-world study recapitulate results from clinical trials including meta-analyses and support the idea that MRD positive patients profit more from lenalidomide maintenance than MRD negative ones.

Prognostic Implications of Circulating Plasma Cell Percentage in Multiple Myeloma and Primary Plasma Cell Leukemia Defined by New Criteria

Introduction: The definition of primary plasma cell leukemia (pPCL) has been revised from ≥20% to ≥5% circulating plasma cells (CPC). However, the precise prognosis associated with CPC remains controversial. This study aimed to investigate prognostic biomarkers for myeloma patients based on CPC presence. Methods: A comprehensive analysis was conducted on 309 consecutive patients diagnosed with either multiple myeloma or pPCL, utilizing peripheral blood smears stained with Wright-Giemsa. Results: Patients were grouped by CPC percentage: 0% (221, 71.5%), 1–4% (49, 15.9%), 5–19% (16, 5.2%), ≥20% (23, 7.4%). CPC >5% correlated with unfavorable characteristics, including anemia, renal dysfunction, and advanced International Staging System. Common cytogenetic abnormalities such as 1q21 amplification, 17p deletion, and Myc rearrangement were prevalent among CPC-positive patients. Median progression-free survival (PFS) and overall survival (OS) were shorter in patients with CPC ≥5% (29.47 vs. 10.03 months; 64.10 vs. 12.30 months). Additionally, PFS and OS were shorter in CPC-positive patients without autologous hematopoietic stem cell transplantation (ASCT) and those with response < partial remission to the first-line regimen. Furthermore, an association emerged between soft tissue-related extramedullary disease and inferior PFS, while Myc rearrangement correlated with abbreviated OS. Conclusion: Biological characteristics displayed greater aggressiveness in patients with positive CPC, leading to significantly shorter PFS and OS. The presence of CPC, ASCT, and overall response rate were independent prognostic factors. While no new threshold for pPCL with CPCs is proposed, Myc rearrangements and CPC positivity could serve as ultra-high-risk factors for multiple myeloma.

NSD2 drives t(4;14) myeloma cell dependence on adenylate kinase 2 by diverting one-carbon metabolism to the epigenome

AbstractChromosomal translocation (4;14), an adverse prognostic factor in multiple myeloma (MM), drives overexpression of the histone methyltransferase nuclear receptor binding SET domain protein 2 (NSD2). A genome-wide CRISPR screen in MM cells identified adenylate kinase 2 (AK2), an enzyme critical for high-energy phosphate transfer from the mitochondria, as an NSD2-driven vulnerability. AK2 suppression in t(4;14) MM cells decreased nicotinamide adenine dinucleotide phosphate (NADP[H]) critical for conversion of ribonucleotides to deoxyribonucleosides, leading to replication stress, DNA damage, and apoptosis. Driving a large genome-wide increase in chromatin methylation, NSD2 overexpression depletes S-adenosylmethionine, compromising the synthesis of creatine from its precursor, guanidinoacetate. Creatine supplementation restored NADP(H) levels, reduced DNA damage, and rescued AK2-deficient t(4;14) MM cells. As the creatine phosphate shuttle constitutes an alternative means for mitochondrial high-energy phosphate transport, these results indicate that NSD2-driven creatine depletion underlies the hypersensitivity of t(4;14) MM cells to AK2 loss. Furthermore, AK2 depletion in t(4;14) cells impaired protein folding in the endoplasmic reticulum, consistent with impaired use of mitochondrial adenosine triphosphate (ATP). Accordingly, AK2 suppression increased the sensitivity of MM cells to proteasome inhibition. These findings delineate a novel mechanism in which aberrant transfer of carbon to the epigenome creates a metabolic vulnerability, with direct therapeutic implications for t(4;14) MM.

Abstract 7058: NSD2 overexpression drives multiple myeloma dependence on adenylate kinase 2 by diverting one-carbon metabolism to the epigenome

Abstract Chromosomal translocation (4;14), an adverse prognostic factor in multiple myeloma (MM), drives overexpression of the oncogenic histone methyltransferase NSD2. Genome-wide CRISPR screens in isogenic MM cells with high and low NSD2 expression identified adenylate kinase 2 (AK2), an enzyme critical for transport of ATP from the mitochondria, as an NSD2-driven vulnerability. AK2 suppression in t(4;14) MM cells decreased NADP(H) critical for conversion of ribonucleotides to deoxyribonucleosides by the enzyme ribonucleotide reductase (RNR). Consequently, metabolomic studies revealed depletion of deoxynucleotide triphosphates (dNTPs) in AK2-deficient t(4;14) MM cells, which resulted in replication stress, DNA damage and apoptosis. Exogenous supplementation with deoxynucleosides rescued AK2 depleted MM cells confirming the role of AK2 in dNTP homeostasis. In addition, NSD2 overexpression drives a large genome-wide increase in chromatin methylation, which depletes the methyl donor S-adenosylmethionine (SAM). Accordingly, we found that high NSD2 expression in MM cells disrupts creatine biosynthesis, a process dependent on SAM. The creatine/phosphocreatine system represents an alternative means of transporting high energy phosphate from the mitochondria. Hence, creatine supplementation restored NADP(H) levels and rescued AK2-deficient t(4;14) MM cells indicating that the hypersensitivity of these cells to AK2 depletion is driven by creatine deficiency due to NSD2 overexpression. Furthermore, AK2 inhibition impaired ATP-dependent protein folding increasing sensitivity of t(4;14) MM cells to proteasome inhibition. These findings delineate a novel mechanism in which aberrant transfer of carbon to the epigenome creates a metabolic vulnerability, with direct therapeutic implications for t(4;14) MM. Citation Format: Amin Sobh, Elena Encinas, Alisha Patel, Greeshma Surapaneni, Charlotte Kaestner, Janai Poullard, Monica Clerio, Karthik Vasan, Tzipporah Freeman, Dongwen Lv, Daphne Dupere-Richer, Alberto Riva, Benjamin Barwick, Daohong Zhou, Lawrence Boise, Constantine Mitsiades, Baek Kim, Richard Bennett, Navdeep Chandel, Jonathan Licht. NSD2 overexpression drives multiple myeloma dependence on adenylate kinase 2 by diverting one-carbon metabolism to the epigenome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7058.

MiR-125b targeted regulation of MKNK2 inhibits multiple myeloma proliferation and invasion.

An increasing number of studies demonstrate that abnormal miRNA expression contributes to the advancement of many tumors. Nonetheless, the potential role of miR-125b in multiple myeloma (MM) remains unknown. To explore the potential effects and mechanism of miR-125b in MM. Real-time quantitative PCR was used to measure the expression levels of miR-125b and MKNK2 in a variety of MM samples. Colony formation and cell counting Kit-8 (CCK-8) assays were used to assess cell proliferation, the transwell assay was used to evaluate the cell invasion capability, and dual luciferase reporter gene assay and Western blot were used to examine the interaction between miR-125b and MKNK2. The levels of miR-125b were higher in MM tissue samples, alongside increased expression of MKNK2. There was a negative correlation between MKNK2 and miR-125b expression in MM tissues. MKNK2 was identified as a direct target gene of miR-125b in MM cells. Overexpression of miR-125b suppressed MM cell growth, colony formation, and invasion. In addition, MKNK2 was found to mediate the effects of miR-125b on cell proliferation, colony formation, and invasion in MM. miR-125b acts as a suppressive factor in multiple myeloma and can affect the malignant behavior of MM by regulating the expression of MKNK2.

Distinct Genetic Features in Peripheral Blood Represent the Characteristics of Circulating Plasma Cells in Primary Plasma Cell Leukemia

Clonal plasma cells in peripheral blood (PB) are crucial for diagnosing plasma cell neoplasm. The diagnostic criteria for plasma cell leukemia (PCL) have recently been revised to 5% or more circulating plasma cells (CPCs) in PB. Considering that CPCs are an independent worse prognostic factor in multiple myeloma (MM), elucidating how many CPCs are sufficient for distinguishing patients between PCL and other plasma cell neoplasm is important yet uncertain. These CPCs have been recently discussed in MM, characterized by more immature phenotype, clonogenic potential, and high expression of cancer stem cell (CTC) markers. Though the exact mechanism of peripheral circulation still needs further studies, MM CTCs are considered subclones of bone marrow (BM) plasma cells. On the other hand, previous studies regarding PB plasma cells in primary PCL (pPCL) have been mainly focused on similar characteristics to BM plasma cells. Considering significant prognostic differences based on CPCs, PB from PCL patients should have distinct features. Previous studies on PCL revealed that high genetic heterogeneity and accumulation of diverse high-risk genetic abnormalities eventually led to the disease. Therefore, we aimed to investigate the genetic profile of CPCs in PCL to exhibit proper evidence for diagnostic criteria and improve the current practices. We retrospectively identified patients diagnosed with PCL from 2015 to 2017 at Seoul National University Hospital. Our study population included 4 pPCL and 2 secondary PCL (sPCL) patients. We retrospectively collected patients' clinical information and laboratory test results and performed targeted sequencing using the NGS panel of 647 genes related to hematologic malignancies. In all analyzed samples, 51 in PB and 40 variants in BM were detected in pPCL. The median number of variants in pPCL patients was 11 per patient (range 5-25) in PB and 10 per patient (range 3-17) in BM. When comparing variant allele frequency (VAF) between the paired samples, there was a moderate correlation (R=0.44, P&amp;lt;0.05). Similarly, a moderate correlation was observed in both pPCL (R=0.41, P&amp;lt;0.05) and sPCL (R=0.47, P&amp;lt;0.05) groups. When comparing paired variants between PB and BM, 38 were commonly detected in both samples in pPCL patients. Fifteen variants were identified in only one of the two samples, 12 in PB and 3 in BM. Most variants showed a heterogeneous distribution of genes. We checked the paired samples using an Integrative genomics viewer. As a result, twelve pPCL and thirteen sPCL variants were identified in the paired samples. These variants were initially excluded in the filtering process because of low VAF. Consequently, three unique variants were identified in each pPCL and sPCL group, which were considered truly unique. In pPCL patients, MED12, VPS13B variant from PB, and ZMYM3 variant from BM were identified in one of the paired samples. In sPCL patients, unique variants were identified in ARID1A, FANCE, and TP53. In addition, we determined that PB VAF is higher than BM VAF in shared variants of pPCL patients. Conversely, BM VAF tended to be higher than PB VAF in sPCL. However, plasma cell% was generally higher in BM than PB, regardless of pPCL or sPCL. Therefore, the differences in the percentage of plasma cells between PB and BM samples cannot explain the unique variants detected in only one of the paired samples. pPCL is an aggressive disease characterized by a markedly high diversity of heterogeneous mutation distribution and high mutational burden. The clinical outcomes of pPCL are still poor in the novel agent era. There is an urgent need to improve the current diagnosis and treatment strategy. As shown in this study, CPCs in pPCL are not simply part of the malignant plasma cells shed from the BM but have characteristics distinct from them. In this study, we exhibited that PB variants had higher VAF than BM variants, and some unique variants were identified only in the PB samples. Conversely, in sPCL, more diverse variants were detected mainly in BM samples, and VAF was also higher in BM than PB. Considering unique variants detected in PB and the high genetic heterogeneity of the disease, PB should be included in the diagnosis of PCL to determine the exact genetic profile.

Outcomes after CAR T Cells in Multiple Myeloma Patients with Extramedullary and Paramedullary Disease

Background: Extramedullary disease (EMD) is a poor prognostic factor for multiple myeloma patients even in the era of novel therapies, while patients with paramedullary disease (PMD) have historically fared better. We sought to characterize EMD and PMD in the peri-CAR T period, assess their effects on outcomes after CAR T, and evaluate the ability of CAR T-cell therapy to clear EMD. Methods: We retrospectively analyzed patients with relapsed/refractory multiple myeloma (RRMM) treated with CAR T-cell therapy in a clinical trial or with a commercially approved product at The Mount Sinai Hospital who had at least 3 months of follow-up. EMD was defined as the presence of soft tissue lesions not contiguous with bone and was quantified by measuring the sum of the product of the two longest perpendicular diameters (SPD) of each lesion. PMD was defined as the presence of soft tissue lesions contiguous with bone. Results: A total of 134 patients received CAR T-cell therapy for RRMM between April 2017 and February 2023 and were followed for a median of 18.6 months, with 59 patients treated with ciltacabtagene autoleucel, 52 with idecabtagene vicleucel, and 23 with other products on clinical trials. Thirty-four patients (25.4%) had EMD at baseline (EMD+), while patients without EMD were further subdivided into those with PMD (PMD-only, 25 patients, 18.7%) and those with neither EMD nor PMD (75 patients, 56.0%). Among patients with measurable EMD, median SPD was 11.15 cm 2 (range 0.25-200.10 cm 2). Patients were heavily pretreated with triple-class refractory status present in 94.1% of EMD+ patients, 96.0% of PMD-only patients, and 74.7% of patients with neither. Compared to patients with neither EMD nor PMD, PMD-only patients had similar PFS (HR 0.98, 95% CI 0.51-1.87) and OS (HR 1.34, 95% CI 0.48-3.76), while EMD+ patients exhibited significantly worse PFS (HR 1.87, 95% CI 1.13-3.09) and OS (HR 3.78, 95% CI 1.81-7.92). Overall response rates (ORR) were 76.5% in EMD+, 92.0% in PMD-only, and 88.0% in patients with neither. Among EMD+ patients, those with the highest tumor burdens (SPD ≥50 cm 2, n = 7) had ORR of 57.1% with no complete responses (3 PD, 3 PR, 1 VGPR). Conversely, EMD+ patients with SPD &amp;lt;50 cm 2 (n = 27) had 81.5% ORR and deeper responses (66.7% complete response). Of the 134 patients, 69 patients relapsed including 34 with EMD at relapse. Among the 34 patients with baseline EMD, 23 (67.6%) relapsed including 21 (61.8%) who relapsed with EMD. EMD was present in its prior location for 13 patients, while EMD cleared in prior locations and was present in new locations for 8 patients. Of 100 patients who had no EMD at baseline, only 13 (13.0%) relapsed with EMD. All patients with bulky EMD (SPD ≥50 cm 2) relapsed with EMD. Among the 34 patients with EMD at relapse, 28 were assessed for MRD status in the bone marrow at the time of relapse, of which 12 (42.9%) remained MRD negative by next generation flow (sensitivity 10 -5). EMD post-BCMA CAR T was biopsied and stained for BCMA in 7 relapsing patients, of which 6 were BCMA positive and 1 was BCMA negative. Conclusion: EMD is a well-recognized poor prognostic factor in multiple myeloma. In our single-center retrospective analysis, the presence of EMD but not PMD was associated with significantly worse PFS and OS following CAR T-cell therapy. EMD+ patients with SPD &amp;lt;50 cm 2 experienced high response rates and deep responses following CAR T-cell therapy (with two-thirds of patients clearing EMD), while patients with the highest extramedullary tumor burdens (SPD ≥50 cm 2) did not. This shows the ability of CAR T-cell therapy to benefit patients in this high-risk group when extramedullary tumor burden is lower. We contend that controlling extramedullary sites of disease prior to CAR T-cell therapy with optimal bridging chemotherapy and/or radiation therapy may be an effective strategy for improving outcomes. Half of patients relapsing after CAR T-cell therapy had EMD, and the majority of patients with baseline EMD ultimately relapsed with EMD despite having been radiographically EMD negative following CAR T treatment. Finally, 42.9% of patients relapsing with EMD after CAR T-cell therapy remained MRD negative in the marrow, showing bone marrow MRD does not adequately represent overall disease control post-CAR T.

Blood-Based Mass Spectrometry MRD Tracking (M-InSight) in Multiple Myeloma Patients from Clinical Trial NCT02513186

Multiple Myeloma (MM) is a type of cancer of the bone marrow characterized by an anormal growth of the number of plasma cells, which produce a monoclonal antibody (M-protein). Measurable residual disease (MRD) is an important prognostic factor in multiple myeloma to evaluate the depth of treatment response which is widely used in clinical trials. MRD is therefore monitored using techniques that measure the number of tumor cells in the bone marrow (BM). On top of being invasive for the patient, BM-MRD might not represent accurately the disease burden because of the heterogeneous nature of a single area measure in the BM. With new drugs and treatment regimen guided by MRD soon, collecting samples at more frequent timepoints is critical to evaluate the depth of response, thus the need of less invasive sampling becomes evident. To overcome all these difficulties, M-InSight (Sebia), a cutting-edge mass spectrometry (MS) technique that allows quantitation of the M-protein in blood has been developed. MS is used to sequence the M-protein then select and quantifies clonotypic peptides from the variable (CDR) region which are used to track the M-protein level of MM patients. The high sensitivity of M-InSight enables the quantification of M-protein at much lower concentrations than current blood techniques used for diagnostic, which makes it possible to track low level M-protein and potentially detect a relapse before the apparition of new symptoms. The main objective of this study was to show that M-insight can monitor MRD in blood samples of MM patients treated by isatuximab during the maintenance phase. Samples from 15 newly diagnosed non eligible for transplantation MM patients from a Sanofi clinical trial (NCT02513186) were chosen to monitor MRD by M-InSight. All patients were selected from the VRDI Part B (bortezomib, lenalidomide, dexamethasone) consisting of evaluating the preliminary efficacy (complete response [CR] rate) of isatuximab administered at the selected dose in combination with bortezomib based regimen. The treatment period included 4 induction cycles (24-week duration), followed by a maintenance period consisting of 4 weeks cycles until progression, unacceptable AE, or patient willingness to discontinue. M-InSight was used to sequence the M-protein (collected predose at Day 1 of Cycle 1) and to measure M-protein concentration in the serum samples collected during the maintenance phase. Results were compared to SPEP, IFE and MRD at 10-6 sensitivity by clonoSEQ®️ (Adaptive Biotechnologies). After 4 cycles of induction, all patients had Very Good Partial Response. Rate of 9/15 CR, 5/15 VGPR and 1 sCR was observed as the best overall response. NGS MRD data were obtained for 14 patients of which 8 reached MRD negativity at 10 -6 sensitivity. 4 of the remaining 6 patients relapsed during maintenance. Clonotypic peptides were identified in all 15 patients from the baseline sample. A total of 302 serum samples collected during maintenance were analyzed. M-protein quantification was highly concordant with the one obtained by SPEP when available (Pearson R=0.78, p&amp;lt;0.01). 100% of patients that were MRD positive by NGS 10 -6 were MS-MRD positive and could be quantified by M-InSight. 60% of patients that were MRD negative by NGS 10 -6 were still positive and quantifiable by M-InSight, suggesting higher sensitivity. The remaining 40% was negative by both NGS and MS. M-insight was able to monitor the disease on 5 patients that had sustained MRD (consecutive MRD negativity) and stable M-protein levels (no increase or decrease of M-protein by 2-fold for 2 consecutive time points). All 4 patients that developed PD had an increase of M-protein of at least 2-fold in 2 consecutive time points showing that M-InSight was able to provide an earlier detection of relapse, when SPEP was still negative for 3 of these. Only one patient had unmeasurable M-protein concentration, staying unmeasurable for 1 year and negative by NGS MRD. The lowest M-protein concentration measured by M-InSight was 0.01 mg/dL (10 mg/dL). This study shows that MRD monitoring on blood is feasible using an ultra-sensitive technique, avoiding invasive bone-marrow aspiration. M-InSight shows accurate monitoring of the depth and kinetics of response to treatment thanks to frequent timepoints. M-InSight can track low level of M-protein in CR patients and detect early relapse.

Nephrolithiasis and Multicystic Kidneys in a Young Patient: A Quiz

Nephrolithiasis and Multicystic Kidneys in a Young Patient: A Quiz

CT-defined body composition as a prognostic factor in multiple myeloma

ABSTRACTObjectivesBody composition assessment is comprised by skeletal muscle mass (SMM) and subcutaneous and visceral adipose tissue (SAT and VAT) and can be quantified by imaging. It can be predictive of several clinically outcomes in patients with hematological diseases. Our aim was to establish the effect of body composition parameters on overall survival (OS) and progression-free survival (PFS) in patients with multiple myeloma (MM).Materials and methodsAll patients with MM were retrospectively analyzed between 2009 and 2019. One hundred twenty-three patients were included into the analysis. Whole-body computed tomography (CT) was used to calculate SMM, VAT, and SAT.ResultsOverall, 22 patients (17.9%) of the patient sample died. Forty patients were sarcopenic (32.5%), 79 patients were visceral obese (64.2%), and 18 patients (14.6%) were sarcopenic obese. Parameter of body composition did not influence OS: sarcopenia, hazard ratio (HR) = 1.3 (95% CI 0.50–3.34), p = .59; visceral obesity, HR = 1.6 (95% CI 0.70–3.76), p = .26; sarcopenic obesity, HR = 2.3 (95% CI 0.90–5.63), p = 0.08. Patients with infectious complications showed higher VAT values.ConclusionsCT-defined body composition parameters have no influence on survival in patients with MM undergoing autologous stem-cell therapy. These results corroborate previous smaller studies that body composition might have a limited role in this tumor entity. VAT may predict the occurrence of infectious complications.

BRD9 Degradation Disrupts Ribosome Biogenesis in Multiple Myeloma.

BRD9 is a defining component of the noncanonical SWI/SNF complex, which regulates gene expression by controlling chromatin dynamics. Although recent studies have found an oncogenic role for BRD9 in multiple cancer types including multiple myeloma, its clinical significance and oncogenic mechanism have not yet been elucidated. Here, we sought to identify the clinical and biological impact of BRD9 in multiple myeloma, which may contribute to the development of novel therapeutic strategies. We performed integrated analyses of BRD9 in vitro and in vivo using multiple myeloma cell lines and primary multiple myeloma cells in established preclinical models, which identified the molecular functions of BRD9 contributing to multiple myeloma cell survival. We found that high BRD9 expression was a poor prognostic factor in multiple myeloma. Depleting BRD9 by genetic (shRNA) and pharmacologic (dBRD9-A; proteolysis-targeting chimera; BRD9 degrader) approaches downregulated ribosome biogenesis genes, decreased the expression of the master regulator MYC, and disrupted the protein-synthesis maintenance machinery, thereby inhibiting multiple myeloma cell growth in vitro and in vivo in preclinical models. Importantly, we identified that the expression of ribosome biogenesis genes was associated with the disease progression and prognosis of patients with multiple myeloma. Our results suggest that BRD9 promotes gene expression by predominantly occupying the promoter regions of ribosome biogenesis genes and cooperating with BRD4 to enhance the transcriptional function of MYC. Our study identifies and validates BRD9 as a novel therapeutic target in preclinical models of multiple myeloma, which provides the framework for the clinical evaluation of BRD9 degraders to improve patient outcome.

Treatment attrition rates and relevant risk factors in multiple myeloma: A real-world study in China.

Background: For multiple myeloma (MM), the proportions of patients reaching the subsequent line of therapy (LOT) decline gradually and real-world data describing the attrition rates of LOT in Chinese MM were limited. Herein, we investigated the attrition rates by subsequent LOTs and their relevant risk factors in MM patients in China. Methods: MM patients who had been hospitalized and received at least one LOT from January 2008 to August 2019 in West China Hospital Sichuan University were retrospectively recruited. Demographic and clinical characteristic data were obtained from the "HemaTank" Chinese Multiple Myeloma Database. The Cox proportional hazards regression model was applied to analyze the risk factors of frontline treatment attrition. Results: A total of 1,255 newly diagnosed MM were enrolled, with 573 (45.7%) patients receiving only one LOT and 682 (54.3%) patients receiving more than one LOT. Thalidomide with dexamethasone/prednisone was the most common frontline treatment before 2017, while bortezomib-based regimens constituted the majority of frontline treatment in 2017 and beyond. The attrition rates from the first to the fifth LOT exhibited a gradual upward trend (45.7%, 48.7%, 58.9% and 62.5%, respectively). Meanwhile, 54.3%, 27.9%, 11.5%, and 4.3% of all the enrolled MM patients received a second, third, fourth and fifth LOT. MM who underwent autologous stem cell transplantation (ASCT) showed lower attrition rates across all LOTs (range 12%-56.8%) than MM without ASCT (range 49.1%-64.5%). The multivariate Cox regression model revealed that ISS stage III (HR 2.07, p < .001), elevated LDH (HR 1.47, p = .006), and comorbidities such as amyloidosis (HR 1.63, p = 0 .01), hepatic disease (HR 1.36, p = .022), pulmonary disease (HR 1.38, p = .022), and cardiac disease (HR 1.62, p = .004) were independent risk factors for MM patients attritted from the frontline treatment. Conclusion: In this study, the attrition rates were generally high and increased gradually across all LOTs. Nearly half of MM patients received only one LOT, and higher tumor burden and more comorbidities may be associated with fewer subsequent LOTs. The high attrition rates highlight the importance of applying the most optimal frontline treatment regimen rather than salvaging subsequent LOTs.

Biallelic deletion of 1p32 defines ultra-high-risk myeloma, but monoallelic del(1p32) remains a strong prognostic factor

AbstractCytogenetic abnormalities (CAs) are known to be the preponderant prognostic factor in multiple myeloma. Our team has recently developed a prognostic score based on 6 CAs, with which del(1p32) appears to be the second worst abnormality after del(17p). This study aimed to confirm the adverse effect of 1p32 deletion in patients with newly diagnosed multiple myeloma (NDMM). Among 2551 patients with newly diagnosed multiple myeloma, 11% were harboring del(1p32). Their overall survival (OS) was significantly inferior compared with patients without del(1p32) (median OS: 49 months vs 124 months). Likewise, progression-free survival was significantly shorter. More importantly, biallelic del(1p32) conferred a dramatically poorer prognosis than a monoallelic del(1p32) (median OS: 25 months vs 60 months). As expected, the OS of patients with del(1p32) significantly decreased when this abnormality was associated with other high-risk CAs [del(17p), t(4;14), or gain(1q)]. In the multivariate analysis, del(1p32) appeared as a negative prognostic factor; after adjustment for age and treatment, the risk of progression was 1.3 times higher among patients harboring del(1p32), and the risk of death was 1.9 times higher. At the dawn of risk-adapted treatment strategies, we have confirmed the adverse effect of del(1p32) in multiple myeloma and the relevance of its assessment at diagnosis.

CD43 is an adverse prognostic factor in newly diagnosed multiple myeloma

Currently, the expression pattern and prognostic value of CD43 expression in multiple myeloma (MM) remain unknown. 109 newly diagnosed MM patients were recruited and CD43 expression was determined by multiparameter flow cytometry, of which 77 (70.6%) were CD43 positive. Patients with positive CD43 expression were more likely to present with, hemoglobin < 85 g/L (p = 0.008), International Staging System (ISS) stage III (p = 0.044), 13q14 deletion (p = 0.034) and more monoclonal plasma cells (p = 0.003). Patients with CD43 positive had significantly poor treatment response (p = 0.021), progression-free survival (PFS) (p = 0.012), and overall survival (OS) (p = 0.023) than those without CD43. The poorer prognosis of CD43-positive patients was retained in multivariate analysis (p = 0.005 for PFS; p = 0.013 for OS). Our study indicated that CD43 was an independent adverse prognostic factor in multiple myeloma.

Myeloma Patients with Deletion of 17p: Impact of Tandem Transplant and Clone Size

IntroductionThe presence of deletion 17p or monosomy 17 (del(17p)/-17) detected by fluorescence in situ hybridization (FISH) is well-established as a high-risk (HR) factor in multiple myeloma (MM). The del(17p)/-17 clone size and the clinical impact in patients that have ≥60% involved nuclei is controversial. Optimal treatment is also controversial, with tandem autologous stem cell transplantation (ASCT) explored but not uniformly adopted in the real world (ENM02, StaMMina). At our center, we have routinely offer tandem transplantation for del(17p)/-17 and now review our experience over a 10-year period, including the significance of del(17p)/-17 genetic variations on outcomes.MethodsWe performed a retrospective chart review of all patients identified with del(17p)/-17 patients who were offered tandem transplant and underwent at least one ASCT at Princess Margaret Cancer Centre from 2009-2019. Patient and disease characteristics, responses, and survival outcomes were collected from the Myeloma and Transplant databases and electronic patient records under REB approval.ResultsPatient, disease, and treatment characteristics.We identified 100 patients with del(17p)/-17 who underwent ASCT at our center. These patients were separated into three groups: those with a deletion of the TP53 locus (57%), those that had monosomy 14 (17%), and those with a relative loss the TP53 locus (eg. aneusomy or polyploidy,13%). The median % of nuclei with del(17p) was 39% (range 5-93%), with 27 (25%) over 60%. 28% of patients carried at least one other cytogenetic abnormality besides del(17p), most commonly t(4;14). All patients were intended for tandem transplant, but only 69 (69%) completed both transplants. Reasons for not proceeding to a second transplant were: patient declined (29%), toxicity (26%), clinical trial (19%), progression prior to the second transplant (13%), with one early death (3%). Median age at transplant was 61 years (range 40-72); most were male (61%) with advanced R-ISS II and III (97%).The most common induction regimen used was cyclophosphamide, bortezomib and dexamethasone (CYBORD)(87%), with 10% requiring a 2 nd induction regimen for inadequate response/progression. Standard conditioning was melphalan 200mg/m 2 for both first and second transplants. Median time from diagnosis to first ASCT was 5.9 months (range 3-24) and time from first to second transplant was 3.3 months (range 1-7). Most patients (90; 84%) received maintenance therapy post-transplant: 47% lenalidomide, 29% multiple agents (commonly lenalidomide and a proteasome inhibitor)Response and survival outcomesAfter induction, the rate of VGPR (very good partial response) or greater was 53%, increasing to 73% after 1 st ASCT, 85% after 2 nd ASCT. At a median follow-up of 32 months (range 3-130), the median PFS for all patients was 39.2 months 95% CI (24.1-46) and median OS was not yet reached (NYR) (95% CI 57.9-NYR). When analyzed by whether single or tandem transplant was performed, median PFS was 21.8 months (95% CI 10.3-43.3) for single ASCT, and 42.1 months (95% CI 32.8-NYR) for tandem ASCT (P=0.0096). The median OS was 57.6 months for single ASCT (95% CI 22.2-86.5), but NYR for tandem ASCT (95% CI 105.6-NYR) (p=0.0022).On subgroup analysis, patients with ≥60% del(17p) achieved a median PFS 45 months (95% CI 14.4-NYR) and median OS 68.5 months (95% CI 20.9-68.5), median was only PFS 24.9 months (95% CI0.4-NYR) and median OS 29.3 months (95% CI 0.4-68.5) for those who received single ASCT. (table1)TP53 signal pattern analysis (table 2) showed the median OS for patients with monosomy 17 was NYR, while it was 105.7 months for patients with deletion, and 86.5 months for those with relative loss. Median PFS was 43.3 months for the monosomy group, 32.8 months for deletion group, and NYR for relative loss.ConclusionsOur experience shows that MM patients with del(17p)/-17 appear to have deeper responses and improved outcomes with more aggressive tandem transplantation. However, approximately 1/3 of our patients intended for tandem transplant did not undergo a second transplant, identifying a focus of future investigation and optimization. Our analysis also suggests that clone size of del(17p) >60% does impact OS negatively, but improved with tandem transplantation. The type of deletion also appears to affect outcomes with deletion having worse PFS but not worse OS. [Display omitted] DisclosuresPrica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria. Reece: Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Millennium: Research Funding; Sanofi: Honoraria; BMS: Honoraria, Research Funding; Karyopharm: Consultancy, Research Funding; GSK: Honoraria. Trudel: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Roche: Consultancy; Sanofi: Honoraria; Pfizer: Honoraria, Research Funding. Chen: Beigene: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy.

Study of prognostic factors in multiple myeloma

Background: Multiple myeloma (MM) is cancer of the plasma cell characterized by interpatient heterogeneity, in most of the cases it is incurable. It is the second most common hematological malignancy. Overall survival of patients has significantly increased recently. Lot of research is going on for prognostic factors, which can predict disease and response to therapy. During the past decades, biomarkers: M protein and β2 microglobulin have shaped the knowledge about MM. This study was undertaken to evaluate the role of prognostic factors in newly diagnosed and few follow up patients of MM before, during and after the treatment in Indian population.Methods: We analyzed 177 samples (90 MM patients and 87 healthy control) for creatinine, calcium, phosphorus, LDH, total protein, albumin, globulin, β2M, Immunoglobulines (Igs), IgG, IgA, IgM, Kappa light chain and Lambda light chains, serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE).Results: The result of our study are significant at p&lt;0.0001 for creatinine, β2M, LDH, albumin, globulin and immunoglobulins whereas for calcium and phosphorus results are not significant at p&lt;0.005. We observed that the levels of β2m, creatinine, LDH and M band concentration declined during the treatment (chemotherapy).Conclusions: We conclude that these results will help the clinicians to tailor-made the chemotherapy doses for betterment of patients and improve survival rate in MM patients.

Harmonization of Flow Cytometric Minimal Residual Disease Assessment in Multiple Myeloma in Centers of Polish Myeloma Consortium.

Minimal residual disease (MRD) status is now considered as one of the most relevant prognostic factors in multiple myeloma (MM) while MRD negativity became an important endpoint in clinical trials. Here, we report the results of the first study evaluating the reproducibility of high-sensitivity flow cytometry MM MRD assessment in four laboratories in Poland. EuroFlow protocols for instrument setting standardization and sample preparation in MM MRD assessment were implemented in each laboratory. In the inter-laboratory reproducibility study, 12 bone marrow samples from MM patients were distributed and processed in participant laboratories. In the inter-operator concordance study, 13 raw data files from MM MRD measurements were analyzed by five independent operators. The inter-laboratory study showed high 95% overall concordance of results among laboratories. In the inter-operator study, 89% of MRD results reported were concordant, and the highest immunophenotype interpretation differences with regard to expression of CD27, CD45, CD81 were noticed. We confirmed the applicability and feasibility of the EuroFlow protocol as a highly sensitive method of MRD evaluation in MM. Results of our inter-center comparison study demonstrate that the standardization of MM MRD assessment protocols is highly desirable to improve quality and comparability of results within and between different clinical trials.