Therapeutic advances have greatly extended survival times in patients with multiple myeloma, necessitating increasingly lengthy trials when using survival outcomes as primary endpoints. A surrogate ...endpoint that can more rapidly predict survival could accelerate drug development. We conducted a meta-analysis to evaluate minimal residual disease (MRD) status as a valid progression-free survival (PFS) surrogate in patients with newly diagnosed multiple myeloma (NDMM).
We searched abstracts in PubMed, The American Society of Hematology, and the European Hematology Association for "myeloma," "minimal residual disease," and "clinical trial." Because of the need to evaluate the treatment effect on MRD response, only randomized studies for subjects with NDMM were included. Details on the MRD-tested populations were required. The meta-analysis was performed by principles outlined at the 2013 United States Food and Drug Administration workshop on MRD in acute myeloid leukemia.
For samples that were not measured for MRD and within the subset specified for MRD assessment, their MRD status was imputed from the samples that had known MRD status. Patients that were excluded from planned MRD assessment were considered MRD-positive.
Six randomized studies, representing 3283 patients and 2208 MRD samples, met analysis inclusion criteria. MRD negativity rates ranged from 0.06 to 0.70. The treatment effect on the odds ratio for MRD-negative response strongly correlated with the hazard ratio for PFS with a coefficient of determination for the weighted regression line of 0.97. Our meta-analysis suggested that MRD status met both the Prentice criteria for PFS surrogacy.
These results support the claim that MRD status can be used as a surrogate for PFS in NDMM.
•High-risk t(4;14) MM patients can be identified by using the coordinates of the translocation breakpoints in NSD2 gene on chromosome 4.•Large-scale genomic analysis of NDMM patient data identifies ...mutations and copy number aberrations enriched in t(4;14) patients.
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Although translocation events between chromosome 4 (NSD2 gene) and chromosome 14 (immunoglobulin heavy chain IgH locus) (t(4;14)) is considered high risk in newly diagnosed multiple myeloma (NDMM), only ∼30% to 40% of t(4;14) patients are clinically high risk. We generated and compared a large whole genome sequencing (WGS) and transcriptome (RNA sequencing) from 258 t(4;14) (n = 153 discovery, n = 105 replication) and 183 non-t(4;14) NDMM patients with associated clinical data. A landmark survival analysis indicated only ∼25% of t(4;14) patients had an overall survival (OS) <24 months, and a comparative analysis of the patient subgroups identified biomarkers associated with this poor outcome, including translocation breakpoints located in the NSD2 gene and expression of IgH-NSD2 fusion transcripts. Three breakpoints were identified and are designated as: “no-disruption” (upstream of NSD2), “early-disruption” (in the 5' UTR), and “late-disruption” (within the NSD2 gene). Our results show a significant difference in OS based on the location of DNA breakpoints (median OS 28.6 “late-disruption” vs 59.2 “early disruption” vs 75.1 months “no disruption”). These findings have been replicated in an independent replication dataset. Also, univariate and multivariate analysis suggest high-risk markers such as del17p, 1p independently contribute to poor outcome in t(4;14) MM patients.
Translocation t(4;14) between the NSD2 gene and the immunoglobulin heavy-chain locus defines a high-risk subset of patients with newly diagnosed multiple myeloma (NDMM). Stong et al present a whole genome and transcriptome analysis of 258 t(4;14) patients compared to 183 non-t(4;14) patients with NDMM. The authors demonstrate that 3 different breakpoints within the NSD2 gene subdivide these patients prognostically, with only 1 subgroup demonstrating high risk, establishing a role for targeted sequencing in further defining prognosis.
A panel of members of the 2009 International Myeloma Workshop developed guidelines for standard investigative workup of patients with suspected multiple myeloma. Both serum and urine should be ...assessed for monoclonal protein. Measurement of monoclonal protein both by densitometer tracing and/by nephelometric quantitation is recommended, and immunofixation is required for confirmation. The serum-free light chain assay is recommended in all newly diagnosed patients with plasma cell dyscrasias. Bone marrow aspiration and/or biopsy along with demonstration of clonality of plasma cells are necessary. Serum β2-microglobulin, albumin, and lactate dehydrogenase are necessary for prognostic purposes. Standard metaphase cytogenetics and fluorescent in situ hybridization for 17p, t(4;14), and t(14;16) are recommended. The skeletal survey remains the standard method for imaging screening, but magnetic resonance imaging frequently provides valuable diagnostic and prognostic information. Most of these tests are repeated during follow-up or at relapse.
The most recent update to the International Myeloma Working Group consensus criteria places a strong emphasis on the need for more sensitive haematological markers of response driven by the success ...of novel therapies. One such marker is serum free light chain (sFLC) analysis, which was first incorporated into the definition of stringent complete response in 2006. However, over the past decade there has been some reluctance to extend the role of the sFLC assays to replace 24 h urine electrophoresis for monitoring multiple myeloma (MM). In this review, we lay out the evidence in favour of serum over urine for monoclonal FLC measurements and propose modified criteria for response assignment in myeloma.
Tumor-promoting inflammation and avoiding immune destruction are hallmarks of cancer. Here, we demonstrate that the pro-inflammatory cytokine interleukin (IL)-18 is critically involved in these ...hallmarks in multiple myeloma (MM). Mice deficient for IL-18 were remarkably protected from Vk∗MYC MM progression in a CD8+ T cell-dependent manner. The MM-niche-derived IL-18 drove generation of myeloid-derived suppressor cells (MDSCs), leading to accelerated disease progression. A global transcriptome analysis of the immune microenvironment in 73 MM patients strongly supported the negative impact of IL-18-driven MDSCs on T cell responses. Strikingly, high levels of bone marrow plasma IL-18 were associated with poor overall survival in MM patients. Furthermore, our preclinical studies suggested that IL-18 could be a potential therapeutic target in MM.
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•IL-18 critically promotes MM progression through the generation of MDSCs•IL-18-driven MDSCs are key players in MM-associated immunosuppression•High BM IL-18 levels are associated with poor prognosis in MM patients•Dysregulated IL-18 might be a potential therapeutic target in MM
Nakamura et al. show that IL-18 produced by the multiple myeloma (MM) niche promotes MM progression in a CD8+ T cell-dependent manner in a mouse model and that IL-18 could be a potential therapeutic target in MM. High levels of bone marrow plasma IL-18 are associated with poor overall survival in MM patients.
Genomics in multiple myeloma Munshi, Nikhil C; Avet-Loiseau, Hervé
Clinical cancer research,
2011-Mar-15, Letnik:
17, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Multiple myeloma (MM) is a complex disease that is driven by numerous genetic and epigenetic alterations. Comprehensive oncogenomic analysis indicates the presence of many highly recurrent and highly ...focal amplifications and/or deletions in the MM genome. Integrated oncogenomic analyses of human MM have identified candidates resident within regions of amplification and/or deletions that are predicted to be involved in MM pathogenesis and progression. The biological behavior and clinical outcome in MM are dependent on these molecular determinants, which are also attractive therapeutic targets. The data obtained from extensive analysis of patient samples, with annotated clinical outcomes, are providing insights into molecular mechanisms of disease behavior, helping to develop sensitive prognostic models, identifying novel therapeutic targets, providing the framework for the development of molecularly based therapies, and, eventually, will help in developing individualized therapy to improve outcomes, with reduced toxicity.
Therapeutic strategies for patients with newly diagnosed multiple myeloma (NDMM) have considerably improved during the last 10 years. The IFM2014-03 trial proposed an all-oral triplet ...induction/consolidation regimen in transplant-eligible NDMM patients, followed by lenalidomide maintenance. Induction consisted of three 21-day cycles of ixazomib, lenalidomide and dexamethasone (IRd), before high-dose Melphalan with transplant followed by eight 28-day cycles of IRd consolidation before 13 cycles of lenalidomide maintenance. Forty-six patients were enrolled and received at least one dose of therapy, and 39 entered the maintenance phase. The primary end-point was stringent complete response after consolidation, and was achieved in nine patients (20.9%, 90% CI 11.4-33.7; p = 0.998). Ten patients (24.4%) had an undetectable minimal residual disease. The overall response rate was 95.7%. The 3-year progression-free survival was 66.3%. No unexpected toxicities were recorded, and only eight patients suspended from any study drug. Of note, 21 (45.7%) patients reported peripheral neuropathy (PN) (grades 1-2 with no serious adverse events). IRd induction and consolidation with transplant before lenalidomide maintenance shows lower response rates compared to other triplet therapies. It could be an alternative for patients who require an all-oral regimen and/or with pre-existent PN, especially if quadruplet regimens including anti-CD38 antibody are not available.
Multiple myeloma (MM) is accompanied by heterogeneous somatic alterations. The overall goal of this study was to describe the genomic landscape of myeloma using deep whole-genome sequencing (WGS) and ...develop a model that identifies patients with long survival.
We analyzed deep WGS data from 183 newly diagnosed patients with MM treated with lenalidomide, bortezomib, and dexamethasone (RVD) alone or RVD + autologous stem cell transplant (ASCT) in the IFM/DFCI 2009 study (ClinicalTrials.gov identifier: NCT01191060). We integrated genomic markers with clinical data.
We report significant variability in mutational load and processes within MM subgroups. The timeline of observed activation of mutational processes provides the basis for 2 distinct models of acquisition of mutational changes detected at the time of diagnosis of myeloma. Virtually all MM subgroups have activated DNA repair-associated signature as a prominent late mutational process, whereas APOBEC signature targeting C>G is activated in the intermediate phase of disease progression in high-risk MM. Importantly, we identify a genomically defined MM subgroup (17% of newly diagnosed patients) with low DNA damage (low genomic scar score with chromosome 9 gain) and a superior outcome (100% overall survival at 69 months), which was validated in a large independent cohort. This subgroup allowed us to distinguish patients with low- and high-risk hyperdiploid MM and identify patients with prolongation of progression-free survival. Genomic characteristics of this subgroup included lower mutational load with significant contribution from age-related mutations as well as frequent
mutation. Surprisingly, their overall survival was independent of International Staging System and minimal residual disease status.
This is a comprehensive study identifying genomic markers of a good-risk group with prolonged survival. Identification of this patient subgroup will affect future therapeutic algorithms and research planning.
Since the mid 1990s, high-dose therapy followed by autologous stem-cell transplantation (ASCT) has been considered the standard of care for frontline therapy in younger patients with multiple myeloma ...(MM). During the past 10 years, thalidomide, bortezomib, and lenalidomide have been widely incorporated to the therapeutic armamentarium for the treatment of this disease. These agents show promise for improving the rate of complete remission both before and after ASCT without increasing toxicity. However, it is not clear whether such therapies are superior if they are used as an alternative to transplantation or whether they may reduce the need for and use of transplantation in patients in whom treatment is indicated. Therefore, the role of ASCT itself is a matter of debate: Should it be used upfront or as salvage treatment at the time of progression in patients initially treated with novel agents? This review presents current trends in ASCT for MM in the era of novel therapies.
In relapsed and/or refractory multiple myeloma, daratumumab reduced the risk of progression or death by > 60% in POLLUX (daratumumab/lenalidomide/dexamethasone D-Rd) and CASTOR ...(daratumumab/bortezomib/dexamethasone D-Vd). Minimal residual disease (MRD) is a sensitive measure of disease control. Sustained MRD negativity and outcomes were evaluated in these studies.
MRD was assessed via next-generation sequencing (10
) at suspected complete response (CR), 3 and 6 months following confirmed CR (POLLUX), 6 and 12 months following the first dose (CASTOR), and every 12 months post-CR in both studies. Sustained MRD negativity (≥ 6 or ≥ 12 months) was evaluated in the intention-to-treat (ITT) and ≥ CR populations.
The median follow-up was 54.8 months in POLLUX and 50.2 months in CASTOR. In the ITT population, MRD-negativity rates were 32.5% versus 6.7% for D-Rd versus lenalidomide and dexamethasone (Rd) and 15.1% versus 1.6% for D-Vd versus bortezomib and dexamethasone (Vd; both
< .0001). Higher MRD negativity rates were achieved in ≥ CR patients in POLLUX (D-Rd, 57.4%; Rd, 29.2%;
= .0001) and CASTOR (D-Vd, 52.8%; Vd, 17.4%;
= .0035). More patients in the ITT population achieved sustained MRD negativity ≥ 6 months with D-Rd versus Rd (20.3%
2.1%;
< .0001) and D-Vd versus Vd (10.4%
1.2%;
< .0001), and ≥ 12 months with D-Rd versus Rd (16.1%
1.4%;
< .0001) and D-Vd versus Vd (6.8%
0%). Similar results for sustained MRD negativity were observed among ≥ CR patients. More patients in the daratumumab-containing arms achieved MRD negativity and sustained MRD negativity, which were associated with prolonged progression-free survival.
Daratumumab-based combinations induce higher rates of sustained MRD negativity versus standard of care, which are associated with durable remissions and prolonged clinical outcomes.
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