CoChat
Sign Up
Cited by 16Multiple Myeloma Research and TreatmentsChronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and Treatment

Genomic profiling to contextualize the results of intervention for smoldering multiple myeloma

Open access
Kazandjian, Dickran, Diamond, Benjamin, Papadimitriou, Marios, Hill, Elizabeth, Sklavenitis-Pistofidis, Romanos, Ziccheddu, Bachisio, Blaney, Patrick, Chojnacka, Monika +11 more·2024·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-24-0210PMC PMC11444893

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

Purpose: Early intervention for high-risk smoldering multiple myeloma (HR-SMM) achieves deep and prolonged responses. It is unclear if beneficial outcomes are due to the treatment of less complex, susceptible disease or inaccuracy in clinical definition of cases entered. Experimental Design: In this study, we interrogated whole-genome and whole-exome sequencing for 54 patients across two HR-SMM interventional studies (NCT01572480 and NCT02279394). Results: We reveal that the genomic landscape of treated HR-SMM is generally simple as compared with newly diagnosed multiple myeloma counterparts with less inactivation of tumor suppressor genes, RAS pathway mutations, MYC disruption, and APOBEC contribution. The absence of these events parallels that of indolent precursor conditions, possibly explaining overall excellent outcomes. However, some patients harboring genomic complexity fail to sustain response and experience resistant, progressive disease. Overall, clinical risk scores do not effectively discriminate between genomically indolent and aggressive disease. Conclusions: Genomic profiling can contextualize the advantage of early intervention in SMM and guide personalization of therapy. See related commentary by Weinhold and Rasche, p. 4263

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1158/1078-0432.ccr-24-0210

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Several trials have reported the advantages and risks of early intervention in high-risk SMM.

    “Several trials have reported the advantages and risks of early intervention in high risk SMM.105-112”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [112]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 44

  1. [2]Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin PJ, Hodnefield JM, Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. New England Journal of Medicine. 2007; 356(25): 2582– 2590. 17582068
  2. [4]Landgren O, Weiss B. Patterns of monoclonal gammopathy of undetermined significance and multiple myeloma in various ethnic/racial groups: support for genetic factors in pathogenesis. Leukemia. 2009; 23(10): 1691– 1697. 19587704
  3. [5]Maura F, Bolli N, Rustad EH, Hultcrantz M, Munshi N, Landgren O. Moving from cancer burden to cancer genomics for smoldering myeloma: a review. JAMA oncology. 2020; 6(3): 425– 432. 31830214 PMC7430066
  4. [6]Rajkumar SV, Landgren O, Mateos M-V. Smoldering multiple myeloma. Blood, The Journal of the American Society of Hematology. 2015; 125(20): 3069– 3075. PMC4432003 25838344
  5. [7]Lakshman A, Rajkumar SV, Buadi FK, Binder M, Gertz MA, Lacy MQ, Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood cancer journal. 2018; 8(6): 59. 29895887 PMC5997745
  6. [8]Dispenzieri A, Kyle RA, Katzmann JA, Therneau TM, Larson D, Benson J, Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood, The Journal of the American Society of Hematology. 2008; 111(2): 785– 789. PMC2200851 17942755
  7. [9]Pérez-Persona E, Vidriales M-B, Mateo G, García-Sanz R, Mateos M-V, de Coca AG, New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood, The Journal of the American Society of Hematology. 2007; 110(7): 2586– 2592. 17576818
  8. [10]Kazandjian D, Hill E, Dew A, Morrison C, Roswarski J, Korde N, Carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide maintenance for prevention of symptomatic multiple myeloma in patients with high-risk smoldering myeloma: a phase 2 nonrandomized controlled trial. JAMA oncology. 2021; 7(11): 1678– 1685. 34529025 PMC8446896
  9. [11]Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. Journal of Clinical Oncology. 2020; 38(11): 1126. 31652094 PMC7145586
  10. [13]Sklavenitis-Pistofidis R, Aranha MP, Redd RA, Baginska J, Haradhvala NJ, Hallisey M, Immune biomarkers of response to immunotherapy in patients with high-risk smoldering myeloma. Cancer Cell. 2022; 40(11): 1358– 1373. e1358. 36379208 PMC10019228
  11. [14]Hill E, Dew A, Morrison C, Yuan C, Stetler-Stevenson M, Landgren O, Assessment of discordance among smoldering multiple myeloma risk models. JAMA oncology. 2021; 7(1): 132– 134. 33211080 PMC7677870
  12. [15]Manier S, Salem KZ, Park J, Landau DA, Getz G, Ghobrial IM. Genomic complexity of multiple myeloma and its clinical implications. Nature reviews Clinical oncology. 2017; 14(2): 100– 113. 27531699
  13. [16]Walker BA, Mavrommatis K, Wardell CP, Ashby TC, Bauer M, Davies FE, Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma. Blood, The Journal of the American Society of Hematology. 2018; 132(6): 587– 597. PMC6097138 29884741
  14. [17]Oben B, Froyen G, Maclachlan KH, Leongamornlert D, Abascal F, Zheng-Lin B, Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities. Nature communications. 2021; 12(1): 1861. PMC7994386 33767199
  15. [18]Bolli N, Maura F, Minvielle S, Gloznik D, Szalat R, Fullam A, Genomic patterns of progression in smoldering multiple myeloma. Nature communications. 2018; 9(1): 3363. PMC6105687 30135448
  16. [19]Maura F, Bolli N, Angelopoulos N, Dawson KJ, Leongamornlert D, Martincorena I, Genomic landscape and chronological reconstruction of driver events in multiple myeloma. Nature communications. 2019; 10(1): 3835. PMC6707220 31444325
  17. [20]Rustad EH, Yellapantula VD, Glodzik D, Maclachlan KH, Diamond B, Boyle EM, Revealing the impact of structural variants in multiple myeloma. Blood cancer discovery. 2020; 1(3): 258– 273. 33392515 PMC7774871
  18. [21]Rustad EH, Yellapantula V, Leongamornlert D, Bolli N, Ledergor G, Nadeu F, Timing the initiation of multiple myeloma. Nature communications. 2020; 11(1): 1917. PMC7174344 32317634
  19. [22]Diamond B, Yellapantula V, Rustad EH, Maclachlan KH, Mayerhoefer M, Kaiser M, Positive selection as the unifying force for clonal evolution in multiple myeloma. Leukemia. 2021; 35(5): 1511– 1515. 33483619 PMC12336412
  20. [23]Jones D, Raine KM, Davies H, Tarpey PS, Butler AP, Teague JW, cgpCaVEManWrapper: simple execution of CaVEMan in order to detect somatic single nucleotide variants in NGS data. Current protocols in bioinformatics. 2016; 56(1): 15.10.11– 15.10.18. PMC6097605 27930805
  21. [24]Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C, Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nature biotechnology. 2013; 31(3): 213– 219. PMC3833702 23396013
  22. [25]Koboldt DC, Zhang Q, Larson DE, Shen D, McLellan MD, Lin L, VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome research. 2012; 22(3): 568– 576. 22300766 PMC3290792
  23. [26]Saunders CT, Wong WS, Swamy S, Becq J, Murray LJ, Cheetham RK. Strelka: accurate somatic small-variant calling from sequenced tumor–normal sample pairs. Bioinformatics. 2012; 28(14): 1811– 1817. 22581179
  24. [27]Wala JA, Bandopadhayay P, Greenwald NF, O’Rourke R, Sharpe T, Stewart C, SvABA: genome-wide detection of structural variants and indels by local assembly. Genome research. 2018; 28(4): 581– 591. 29535149 PMC5880247
  25. [28]Van Loo P, Nordgard SH, Lingjærde OC, Russnes HG, Rye IH, Sun W, Allele-specific copy number analysis of tumors. Proceedings of the National Academy of Sciences. 2010; 107(39): 16910– 16915. PMC2947907 20837533
  26. [29]Nadeu F, Mas-de-Les-Valls R, Navarro A, Royo R, Martín S, Villamor N, IgCaller for reconstructing immunoglobulin gene rearrangements and oncogenic translocations from whole-genome sequencing in lymphoid neoplasms. Nature communications. 2020; 11(1): 3390. PMC7341758 32636395
  27. [30]Chen X, Schulz-Trieglaff O, Shaw R, Barnes B, Schlesinger F, Källberg M, Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics. 2016; 32(8): 1220– 1222. 26647377
  28. [31]Rausch T, Zichner T, Schlattl A, Stütz AM, Benes V, Korbel JO. DELLY: structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics. 2012; 28(18): i333– i339. 22962449 PMC3436805
  29. [32]Rustad EH, Yellapantula VD, Glodzik D, Maclachlan KH, Diamond B, Boyle EM, Revealing the impact of structural variants in multiple myeloma. Blood cancer discovery. 2020; 1(3): 258. 33392515 PMC7774871
  30. [33]Maclachlan KH, Rustad EH, Derkach A, Zheng-Lin B, Yellapantula V, Diamond B, Copy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma. Nature communications. 2021; 12(1): 5172. PMC8397708 34453055
  31. [34]Maura F, Degasperi A, Nadeu F, Leongamornlert D, Davies H, Moore L, A practical guide for mutational signature analysis in hematological malignancies. Nature communications. 2019; 10(1): 1– 12. PMC6611883 31278357
  32. [35]Alexandrov LB, Kim J, Haradhvala NJ, Huang MN, Ng AWT, Wu Y, The repertoire of mutational signatures in human cancer. Nature. 2020; 578(7793): 94– 101. 32025018 PMC7054213
  33. [36]Rustad EH, Nadeu F, Angelopoulos N, Ziccheddu B, Bolli N, Puente XS, mmsig: a fitting approach to accurately identify somatic mutational signatures in hematological malignancies. Communications biology. 2021; 4(1): 1– 12. 33782531 PMC8007623
  34. [37]Landgren O, Hultcrantz M, Diamond B, Lesokhin AM, Mailankody S, Hassoun H, Safety and effectiveness of weekly carfilzomib, lenalidomide, dexamethasone, and daratumumab combination therapy for patients with newly diagnosed multiple myeloma: the MANHATTAN nonrandomized clinical trial. JAMA oncology. 2021; 7(6): 862– 868. 33856405 PMC8050789
  35. [38]Martincorena I, Raine KM, Gerstung M, Dawson KJ, Haase K, Van Loo P, Universal patterns of selection in cancer and somatic tissues. Cell. 2017; 171(5): 1029– 1041. e1021. 29056346 PMC5720395
  36. [40]Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos M-V, International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. The lancet oncology. 2014; 15(12): e538– e548. 25439696
  37. [42]Cowan A, Ferrari F, Freeman SS, Redd R, El-Khoury H, Perry J, Personalised progression prediction in patients with monoclonal gammopathy of undetermined significance or smouldering multiple myeloma (PANGEA): a retrospective, multicohort study. The Lancet Haematology. 2023; 10(3): e203– e212. 36858677 PMC9991855
  38. [43]Maura F, Petljak M, Lionetti M, Cifola I, Liang W, Pinatel E, Biological and prognostic impact of APOBEC-induced mutations in the spectrum of plasma cell dyscrasias and multiple myeloma cell lines. Leukemia. 2018; 32(4): 1043– 1047. PMC5886048 29209044
  39. [44]Maura F, Rustad EH, Yellapantula V, Łuksza M, Hoyos D, Maclachlan KH, Role of AID in the temporal pattern of acquisition of driver mutations in multiple myeloma. Leukemia. 2020; 34(5): 1476– 1480. 31836853
  40. [45]Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng W-J, Promiscuous mutations activate the noncanonical NF-κB pathway in multiple myeloma. Cancer cell. 2007; 12(2): 131– 144. 17692805 PMC2083698
  41. [49]Gay F, Musto P, Rota-Scalabrini D, Bertamini L, Belotti A, Galli M, Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): a randomised, open-label, phase 2 trial. The Lancet Oncology. 2021; 22(12): 1705– 1720. 34774221
  42. [50]Kumar SK, Jacobus SJ, Cohen AD, Weiss M, Callander N, Singh AK, Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. The Lancet Oncology. 2020; 21(10): 1317– 1330. 32866432 PMC7591827
  43. [51]Samur MK, Samur AA, Fulciniti M, Szalat R, Han T, Shammas M, Genome-wide somatic alterations in multiple myeloma reveal a superior outcome group. Journal of Clinical Oncology. 2020; 38(27): 3107. 32687451 PMC7499613
  44. [52]Rasche L, Chavan S, Stephens O, Patel P, Tytarenko R, Ashby C, Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing. Nature communications. 2017; 8(1): 268. PMC5559527 28814763

Cited by

Sorted by citations

Authors
Kazandjian, D., Diamond, B., Papadimitriou, M., Hill, E., Sklavenitis-Pistofidis, R., Ziccheddu, B., Blaney, P., Chojnacka, M., Durante, M., Maclachlan, K., Young, R., Usmani, S., Davies, F., Getz, G., Ghobrial, I., Korde, N., Morgan, G., Maura, F., & Landgren, O.
Affiliations
  • National Institutes of Health (US)
  • University of Miami (US)
  • Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. 3
  • NYU Langone Health (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • Broad Institute (US)
  • Harvard University (US)
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2024-04-23
Volume
30
Issue
19
Pages
4482-4490
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-24-0210
PMC
PMC11444893
OpenAlex
W4395029563
Cited by
16
References
4
Citations by year
2026: 4 · 2025: 8 · 2024: 4
FWCI
4.96
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
National Cancer Institute (P30 CA 240139)
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
Keywords
smoldering multiple myeloma, early intervention, genomic profiling, tumor suppressor inactivation, RAS pathway mutations, APOBEC mutagenesis, genome complexity, treatment response, disease progression, clinical risk score, personalized treatment
MeSH terms
Whole Genome Sequencing, Exome Sequencing, Smoldering Multiple Myeloma, Aged, Female, Humans, Male, Middle Aged, Multiple Myeloma, Mutation, Biomarkers, Tumor, Gene Expression Profiling, Genomics

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review