Real-world data on regimens for relapsed/refractory multiple myeloma (RRMM) represent an important component of therapeutic decision-making. This multi-centric, retrospective, observational study ...conducted by the treating physicians evaluated the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in 155 patients who received ixazomib via early access programs in Greece, the UK, and the Czech Republic. Median age was 68 years; 17% had an Eastern Cooperative Oncology Group performance status ≥ 2; median number of prior therapies was 1 (range 1–7); 91%, 47%, and 17% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Median duration of exposure to ixazomib was 9.6 months. Overall response rate was 74%, including 35% very good partial response or better (16% complete response). Median progression-free survival (PFS) was 27.6 months (27.6 and 19.9 months in patients with 1 or > 1 prior lines, respectively). IRd treatment for ≥ 6 months was associated with longer PFS (hazard ratio 0.06). Fourteen patients (9%) discontinued IRd due to adverse events/toxicity in the absence of disease progression. Peripheral neuropathy was reported in 35% of patients (3% grades 3–4). These findings support the results of the phase III TOURMALINE-MM1 trial in a broader real-world RRMM population.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We have performed a head to head comparison of all-oral triplet combination of ixazomib, lenalidomide and dexamethasone (IRD) versus lenalidomide and dexamethasone (RD) in patients with relapsed and ...refractory multiple myeloma (RRMM) in the routine clinical practice.
A total of 344 patients treated with IRD (N = 127) or RD (N = 217) were selected for analysis from the Czech Registry of Monoclonal Gammopathies (RMG). Descriptive statistics were used to assess patient's characteristics associated with the respective therapy. The primary endpoint was progression free survival (PFS), secondary end points included response rates and overall survival (OS). Survival endpoints were plotted using Kaplan-Meier methodology at 95% Greenwood confidence interval. Univariable and multivariable Cox proportional hazards models were used to evaluate the effect of treatment regimens and the significance of uneven variables. Statistical tests were performed at significance level 0.05.
In the whole cohort, median PFS for IRD was 17.5 and for RD was 11.5 months favoring the all-oral triplet, p = 0.005; in patients within relapse 1-3, the median PFS was 23.1 vs 11.6 months, p = 0.001. The hazard ratio for PFS was 0.67 (95% confidence interval CI 0.51-0.89, p = 0.006). The PFS advantage translated into improved OS for patients treated with IRD, median 36.6 months vs 26.0 months (p = 0.008). The overall response rate (ORR) was 73.0% in the IRD group vs 66.2% in the RD group with a complete response rate (CR) of 11.1% vs 8.8%, and very good partial response (VGPR) 22.2% vs 13.9%, IRD vs RD respectively. The IRD regimen was most beneficial in patients ≤75 years with ISS I, II, and in the first and second relapse. Patients with the presence of extramedullary disease did not benefit from IRD treatment (median PFS 6.5 months). Both regimens were well tolerated, and the incidence of total as well as grade 3/4 toxicities was comparable.
Our analysis confirms the results of the TOURMALINE-MM1 study and shows benefit of all-oral triplet IRD treatment versus RD doublet. It demonstrates that the addition of ixazomib to RD improves key survival endpoints in patients with RRMM in a routine clinical setting.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
Progress in multiple myeloma treatment allows patients to achieve deeper responses, for which the assessment of minimal residual disease (MRD) is critical. Typically, bone marrow samples ...are used for this purpose; however, this approach is site‐limited. Liquid biopsy represents a minimally invasive and more comprehensive technique that is not site‐limited, but equally challenging.
Methods
While majority of current data comes from short‐term studies, we present a long‐term study on blood‐based MRD monitoring using tumor‐specific cell‐free DNA detection by ASO‐qPCR. One hundred and twelve patients were enrolled into the study, but long‐term sampling and analysis were feasible only in 45 patients.
Results
We found a significant correlation of quantity of tumor‐specific cell‐free DNA levels with clinically meaningful events induction therapy (P = .004); ASCT (P = .012). Moreover, length of cfDNA fragments is associated with better treatment response of patients.
Conclusions
These results support the concept of tumor‐specific cell‐free DNA as a prognostic marker.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Background: We confirmed the benefit of addition of ixazomib to lenalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma (RRMM) in unselected real-world population. We ...report the final analysis for overall survival (OS), second progression free survival (PFS-2), and the subanalysis of the outcomes in lenalidomide (LEN) pretreated and LEN refractory patients. Methods: We assessed 344 patients with RRMM, treated with IRD (N = 127) or RD (N = 217). The data were acquired from the Czech Registry of Monoclonal Gammopathies (RMG). With prolonged follow-up (median 28.5 months), we determined the new primary endpoints OS, PFS and PFS-2. Secondary endpoints included the next therapeutic approach and the survival measures in LEN pretreated and LEN refractory patients. Results: The final overall response rate (ORR) was 73.0% in the IRD cohort and 66.8% in the RD cohort. The difference in patients reaching ≥VGPR remained significant (38.1% vs. 26.3%, p = 0.028). Median PFS maintained significant improvement in the IRD cohort (17.5 vs. 12.5 months, p = 0.013) with better outcomes in patients with 1–3 prior relapses (22.3 vs. 12.7 months p = 0.003). In the whole cohort, median OS was for IRD vs. RD patients 40.9 vs. 27.1 months (p = 0.001), with further improvement within relapse 1-3 (51.7 vs. 27.8 months, p ˂ 0.001). The median PFS of LEN pretreated (N = 22) vs. LEN naive (N = 105) patients treated by IRD was 8.7 vs. 23.1 months (p = 0.001), and median OS was 13.2 vs. 51.7 months (p = 0.030). Most patients in both arms progressed and received further myeloma-specific therapy (63.0% in the IRD group and 53.9% in the RD group). Majority of patients received pomalidomide-based therapy or bortezomib based therapy. Significantly more patients with previous IRD vs. RD received subsequent monoclonal antibodies (daratumumab—16.3% vs. 4.3%, p = 0.0054; isatuximab 5.0% vs. 0.0%, p = 0.026) and carfilzomib (12.5 vs. 1.7%, p = 0.004). The median PFS-2 (progression free survival from the start of IRD/RD therapy until the second disease progression or death) was significantly longer in the IRD cohort (29.8 vs. 21.6 months, p = 0.016). There were no additional safety concerns in the extended follow-up. Conclusions: The IRD regimen is well tolerated, easy to administer, and with very good therapeutic outcomes. The survival measures in unsorted real-world population are comparable to the outcomes of the clinical trial. As expected, patients with LEN reatment have poorer outcomes than those who are LEN-naive. The PFS benefit of IRD vs. RD translated into significantly better PFS-2 and OS, but the outcomes must be accounted for imbalances in pretreatment group characteristics (especially younger age and stem cell transplant pretreatment), and in subsequent therapies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background: Evaluation of minimal residual disease (MRD) in multiple myeloma (MM) has become a standard procedure and has been incorporated to International Myeloma Working Group updated response ...criteria in 2016. Its value as an important prognostic factor with impact on survival as well as a relevant end-point in clinical trials has been established by many studies. Assessment of MRD inside the bone marrow is performed basically by two standardized techniques: i) next generation flow cytometry (NGF) and ii) next generation sequencing (NGS). Positron emission tomography and computed tomography (PET/CT) is currently considered as a best tool to evaluate MRD outside of the bone marrow. The standard timepoint to assess the MRD by PET/CT in transplant eligible newly diagnosed multiple myeloma (TE NDMM) patients is considered Day +100 post-autologous stem cell transplantation (ASCT) according to largest CASSIOPET study (Moreau et al., Blood, 2019). Nevertheless, this kind of data from real-world outside the clinical trials setting remains limited.
Aim: To evaluate the prognostic impact of PET/CT performed on Day +100 post-ASCT in consecutive cohort of real-world TE NDMM patients from a single center in the Czech Republic.
Methods: 18 TE NDMM patients with median age of 59 years (range 42 - 71 years), ISS stage III 17% (3/18) diagnosed between September 2017 and June 2019 received proteasome inhibitor plus immunomodulatory drug containing induction. Patients who reached at least very good partial response (VGPR) after ASCT were indicated for MRD evaluation using NGF technique according to standardized EuroFlow protocol with sensitivity to 10e-6 and for PET/CT evaluation - both at Day +100 post-ASCT. For the evaluation of PET/CT scans complex evaluation by nuclear medicine specialist based on Italian Myeloma criteria for PET Use (IMPeTUs) criteria were used (IMPeTUs) criteria were used (Nanni et al., Eur. J. Nucl. Med. Mol. Imaging. 2018).
Results: Of 18 evaluated TE NDMM patients (17 in complete remission (CR), 1 in VGPR), there were 78% (14/18) considered PET/CT negative and 22% (4/18) were considered PET/CT positive at Day +100 post-ASCT. Patients who were PET/CT positive had significantly shorter median PFS (mPFS 29 days) versus those who were PET/CT negative (mPFS not reached); p value < 0.001. Calculated median follow-up for the whole cohort was 245 days. Interestingly, one patient who was NGF MRD negative within the bone marrow was considered PET/CT positive and has early relapse after ASCT.
Conclusion: We demonstrated on limited number of real-world TE NDMM patients that those who are PET/CT positive at Day +100 post-ASCT have significantly shorter mPFS compared to those who are PET/CT negative. The aim of myeloma community should lead to the implementation of simultaneous assessment of MRD inside the bone marrow in combination with imaging technique (PET/CT) outside the bone marrow, as this combined evaluation seems to be the most important prognostic factor. Moreover, great effort should be make to establish standardized evaluation protocols for nuclear medicine specialists as well as the most appropriate time-points to perform PET/CT, such as Day +100 post-ASCT in TE NDMM.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction
Extramedullary disease (EMD) is a less frequent manifestation of multiple myeloma (MM), where MM plasma cells become independent of the bone marrow (BM) microenvironment and infiltrate ...other tissues and organs. The incidence of EMD is increasing and is associated with worse prognosis and drug resistance. The specific and efficient treatment is lacking. Therefore, a better understanding of EMD pathogenesis is desperately needed.
Aims
To identify biological pathways leading to EMD development and to evaluate therapeutic targets in EMD plasma cells with further focus on EMD tumor microenvironment to reveal presence of effector immune cells that are crucial for immunotherapy.
Methods
To identify EMD specific genes, FACS/MACS sorted aberrant plasma cells were collected from: i) fresh 11 EMD relapse tumors for which we had ii) 7 corresponding cryopreserved paired BM samples from the time of MM diagnosis (NDMM), iii) 9 unpaired fresh NDMM without EMD confirmed by PET-CT and iv) 6 unpaired fresh relapsed MM (RRMM). For library preparation, we used total RNA with rRNA depletion protocol and Illumina sequencing. Residual rRNA was filtered out by SortMeRNA. Differential expression analysis was performed using Salmon for read mapping and quantification and Deseq2 package. For single-cell RNAseq we used 10x Genomics technology for sequencing and CellRanger and Seurat for data processing and analysis.
Results
To better understand the aggressive nature of EMD, we have analyzed bulk RNA samples (7 EMD samples plus 7 corresponding cryopreserved paired BM samples from the time of MM diagnosis). Our preliminary analysis revealed a unique EMD profile (Fig 1A) with 423 up-regulated and 421 down-regulated genes in EMD samples (adjusted p-value < 0.1; absolute fold change > 1.5), with G2M checkpoint proteins being the most enriched hallmark pathways pointing to higher proliferation of EMD cells. EMD down-regulated genes mainly belong to genes of the adaptive immune response which together with lower immunoglobulin production suggest loss of mature plasma cell function.
Among the top genes uniquely overexpressed in EMD (versus RRMM or NDMM) were SCD and ELOVL6 that regulate crucial steps in unsaturated fatty acids synthesis. Also their transcription factor SREBF1 was significantly up-regulated. The importance of these genes in EMD pathogenesis can be supported by the involvement of SREBP1 in stem cell differentiation and mediation of bortezomib resistance by ELOVL6 (Yi et al. 2018, Lipchick et al. 2021). Our dataset also revealed several deregulated lncRNA in EMD compared to NDMM. MALAT1 was highly expressed, however, we did not confirm results by Handa et al. 2017 showing lncRNA MALAT1 as upregulated in EMD.
Furthermore, we aimed to evaluate expression of known immunotherapy MM targets being currently in use or under investigation. We compared the information about expression level in EMD vs paired NDMM, with unpaired NDMM without EMD lesion confirmed by PET/CT, and with RRMM. The analysis revealed a decrease in the expression of several antigens commonly used in anti-MM immunotherapy (e.g. CD38, SLAMF7, BCMA or PDL1) on EMD PCs (Fig 1B). Intriguingly, our data show EMD specific elevated expression of EZH2 gene being promising target in preclinical MM investigation which can prove efficient especially for the aggressive MM stage - EMD.
Effective immunotherapy depends on the presence of effector immune cells. Therefore, we have evaluated immune cell types and their proportion in EMD tumors. Using flow cytometry we identified T and NK cells as the only immune cell subsets present in EMD tumors (median 0.9% and 0.5%, respectively). Single-cell RNAseq analysis of two EMD samples supported these findings.
Conclusions
Here, we present up to our knowledge the worldwide largest cohort of 11 EMD samples (including 7 longitudinal pre-EMD/EMD samples) analysed using RNAseq with focus on biological pathways and dysregulation of particular genes leading to EMD development. Drop of expression of several known drug targets may suggest limited efficacy of the modern treatment in EMD as already presented by Jelinek et al., 2021. Importantly, we are also providing the initial insight into the microenvironment (including single-cell RNA analysis) of EMD tumors, where we detected presence of T cell and NK cells in very limited numbers.
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Hajek: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Pharma MAR: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction: Multiple myeloma (MM) is the second most common blood cancer, and despite recent treatment advances, the majority of patients will ultimately die due to progression. Extramedullary ...disease (EMD) is a less frequent manifestation of MM often occurring during the course of disease where tumor plasma cells become independent of bone marrow microenvironment and infiltrate other tissues and organs. The development of EMD is always considered a high-risk feature with poor prognosis.
Aim: To identify molecular mechanisms responsible for the development of EMD using DNA and RNA sequencing and thus reveal potentially novel druggable targets. Currently, available anti-myeloma agents are not effective in patients with EMD. Thus it is critical to perform this kind of translational research that will ultimately lead to discovering new treatment strategies in this prognostically poor subset of MM patients.
Methods: We collected a unique set of FACS/MACS sorted aberrant plasma cells from 4 freshly obtained EMD samples from relapse and their respective cryopreserved bone marrow samples from diagnosis (available in 3 cases). In the 3 longitudinal ND and EMD samples we analyzed somatic mutations in the whole-exome sequencing data (Illumina, Sure select V6) using a combination of Mutect2 and Strelka2. To analyze differential gene expression, we used Deseq2 R package and Salmon for read mapping and quantification and Cytospace for the pathway enrichment analysis. Besides, to investigate the effect of cryopreservation on the gene expression in longitudinal samples from diagnosis, we compared all 4 EMD samples with 5 fresh unrelated BM samples from ND patients with PET/CT confirmed lack of EMD.
Results: Analysis of somatic mutations revealed an only partial overlap of mutated genes between ND and respective EMD sample (23% on average) and 1.49x increased number of variants in EMD. In our samples (ND and EMD), we identified 11 mutated myeloma drivers (Walker 2018) that mostly affected epigenetic processes and MAPK pathway, with the latter being mutated in all three patients in both stages. Interestingly, we identified two genes, both exclusively mutated only in 2/3 EMD samples and not mutated in any ND sample, DNAJC16 and HERC1. DNAJC16 is a member of heat shock proteins (Hsp40; Kampinga 2009). HERC1 is an E3 ubiquitin ligase that regulates p38 signaling and cell migration (Padrazza 2020), and thus, it represents a potentially interesting target for further analysis of EMD development.
Differential expression analysis of 3 paired ND-EMD samples revealed 131 deregulated transcripts with the TNFSF9 (CD137L) ligand, HECW1 ubiquitin ligase, and UNC13C gene being top upregulated genes. Among the top downregulated were immunoglobulin genes and S1PR4 signaling receptor, MPO myeloperoxidase, and SLAMF1 (CD150) signaling lymphocytic activation molecule. Analysis of a larger cohort of fresh unpaired 5 ND and 4 EMD samples resulted in more distinct clusters of ND/EMD samples and the total number of 673 deregulated genes (Fig. 1). EMD downregulated genes mostly belong to cell adhesion, chemokine signaling pathway, and neutrophil activation process. Upregulated genes belong to proliferation, cell cycle, and DNA damage signaling pathways. Evaluation of currently available druggable targets revealed that only LAG3 (lymphocyte activation 3 protein) is significantly downregulated in EMD. For three upregulated genes (FGFR3, NTRK3, EZH2), we found interaction with potential cancer inhibitors (Erdafitinib, Entrectinib, Tazemetostat). Notably, the latter agent targeting EZH2 methyltransferase gene has been recently approved by the FDA for follicular lymphoma treatment, and clinical trials for MM are ongoing.
Conclusion: Here, we report the preliminary analysis of the genomic and transcriptomic profile of EMD samples with their respective paired samples from the new diagnosis. The genomic alterations proved to be heterogeneous; though, we were able to identify 2 genes exclusively mutated in EMD samples. Moreover, deregulated transcriptome clearly separated ND and EMD stage in unrelated cohorts and pointed to rapid proliferation and increased DNA damage response pathways and pinpointed several potential drug targets. However, our findings warrant a more in-depth analysis on the bigger patient cohort.
Acknowledgement: Work was supported by project ENOCH (No. CZ.02.1.01/0.0/0.0/16_019/0000868)
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No relevant conflicts of interest to declare.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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