Stability and uniqueness of clonal immunoglobulin CDR3 sequences for MRD tracking in multiple myeloma

Rustad, Even H.; Misund, Kristine; Bernard, Elsa; Coward, Eivind; Yellapantula, Venkata; Hultcrantz, Malin; Ho, Caleb; Kazandjian, Dickran; Korde, Neha; Mailankody, Sham; Keats, Jonathan J.; Akhlaghi, Theresia; Viny, Aaron D.; Mayman, David J.; Carroll, Kaitlin M.; Patel, Minal; Famulare, Christopher; Bruinink, Davine Hofste op; Hutt, Kasey R.; Jacobsen, Austin; Huang, Ying; Miller, Jeffrey E.; Maura, Francesco; Papaemmanuil, Elli; Waage, Anders; Arcila, Maria E.; Landgren, Ola

doi:10.1002/ajh.25641

Cited by 27 publications

(45 citation statements)

References 37 publications

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“…There are very few studies addressing the serial assessment of MRD in MM, although this strategy has been successfully used in other diseases, such as lymphoma or leukemia, [18][19][20] even knowing the stability of VDJ along the natural history of MM. 21 Here, we have demonstrated that MRD monitoring by NGS is feasible and provides reproducible data, as shown in Figure 2B.…”

Section: Discussionsupporting

confidence: 52%

Clinical value of measurable residual disease testing for assessing depth, duration, and direction of response in multiple myeloma

et al. 2020

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Few clinical studies have reported results of measurable residual disease (MRD) assessments performed as part of routine practice. Herein we present our single-institution experience assessing MRD in 234 multiple myeloma (MM) patients (newly diagnosed [NDMM = 159] and relapsed [RRMM = 75]). We describe the impact of depth, duration, and direction of response on prognosis. MRD assessments were performed by next-generation sequencing of immunoglobulin genes with a sensitivity of 10−6. Those achieving MRD negativity at 10−6, as well as 10−5, had superior median progression-free survival (PFS). In the NDMM cohort, 40% of the patients achieved MRD negativity at 10−6 and 59% at 10−5. Median PFS in the NDMM cohort was superior in those achieving MRD at 10−5 vs <10−5 (PFS: 87 months vs 32 months; P < .001). In the RRMM cohort, 36% achieved MRD negativity at 10−6 and 47% at 10−5. Median PFS was superior for the RRMM achieving MRD at 10−5 vs <10−5 (PFS: 42 months vs 17 months; P < .01). Serial MRD monitoring identified 3 categories of NDMM patients: (A) patients with ≥3 MRD 10−6 negative samples, (B) patients with detectable but continuously declining clonal numbers, and (C) patients with stable or increasing clonal number (≥1 log). PFS was superior in groups A and B vs C (median PFS not reached [NR], NR, 55 respectively; P < .001). This retrospective evaluation of MRD used as part of clinical care validates MRD as an important prognostic marker in NDMM and RRMM and supports its use as an endpoint in future clinical trials as well as for clinical decision making.

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Section: Discussionsupporting

confidence: 52%

Clinical value of measurable residual disease testing for assessing depth, duration, and direction of response in multiple myeloma

et al. 2020

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“…Interestingly, the CDR3 sequences were identical across sample pairs in all patients. Highly conserved CDR3 sequences over time in MM is consistent with previous studies 33 , including CDR3 reconstruction from RNA sequencing of sequential samples in the CoMMpass cohort 34 .…”

Section: Resultssupporting

confidence: 89%

Timing the initiation of multiple myeloma

et al. 2020

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The evolution and progression of multiple myeloma and its precursors over time is poorly understood. Here, we investigate the landscape and timing of mutational processes shaping multiple myeloma evolution in a large cohort of 89 whole genomes and 973 exomes. We identify eight processes, including a mutational signature caused by exposure to melphalan. Reconstructing the chronological activity of each mutational signature, we estimate that the initial transformation of a germinal center B-cell usually occurred during the first 2 nd -3 rd decades of life. We define four main patterns of activation-induced deaminase (AID) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutagenesis over time, including a subset of patients with evidence of prolonged AID activity during the premalignant phase, indicating antigen-responsiveness and germinal center reentry. Our findings provide a framework to study the etiology of multiple myeloma and explore strategies for prevention and early detection.

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“…1,000,000 0 10,000,000 20,000,000 30,000,000 40,000,000 50,000,000 60,000,000 70,000,000 80,000,000 90,000,000 100,000,000 110,000,000 120,000,000 130,000,000 140,000,000 150,000,000 160,000,000 170,000,000 180,000,000 190,000,000 Highly conserved CDR3 sequences over time in MM is consistent with previous studies 33 , including CDR3 reconstruction from RNA sequencing of sequential samples in the CoMMpass cohort 34 .…”

Section: Resultssupporting

confidence: 88%

Timing the initiation of multiple myeloma

Maura

Rustad

Yellapantula

et al. 2019

Clinical Lymphoma Myeloma and Leukemia

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The evolution and progression of multiple myeloma and its precursors over time is poorly understood. Here, we investigate the landscape and timing of mutational processes shaping multiple myeloma evolution in a large cohort of 89 whole genomes and 973 exomes. We identify eight processes, including a mutational signature caused by exposure to melphalan. Reconstructing the chronological activity of each mutational signature, we estimate that the initial transformation of a germinal center B-cell usually occurred during the first 2 nd-3 rd decades of life. We define four main patterns of activation-induced deaminase (AID) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutagenesis over time, including a subset of patients with evidence of prolonged AID activity during the premalignant phase, indicating antigen-responsiveness and germinal center reentry. Our findings provide a framework to study the etiology of multiple myeloma and explore strategies for prevention and early detection.

show abstract

Stability and uniqueness of clonal immunoglobulin CDR3 sequences for MRD tracking in multiple myeloma

Cited by 27 publications

References 37 publications

Clinical value of measurable residual disease testing for assessing depth, duration, and direction of response in multiple myeloma

Clinical value of measurable residual disease testing for assessing depth, duration, and direction of response in multiple myeloma

Timing the initiation of multiple myeloma

Timing the initiation of multiple myeloma

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