Chromosome 1q21 abnormalities refine outcome prediction in patients with multiple myeloma - a meta-analysis of 2,596 trial patients

Weinhold, Niels; Salwender, Hans; Cairns, David A.; Raab, Marc S.; Waldron, George W.; Blau, Igor Wolfgang; Bertsch, Uta; Hielscher, Thomas; Morgan, Gareth J.; Jauch, Anna; Davies, Faith E.; Hänel, Mathias; Cook, Gordon; Scheid, Christoph; Houlston, Richard S.; Goldschmidt, Hartmut; Jackson, Graham; Kaiser, Martin

doi:10.3324/haematol.2021.278888

Cited by 62 publications

(76 citation statements)

References 14 publications

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“…The cut off for +1q positivity is variable, and there is no universal definition for high or low clone sizes. 7 , 8 , 10 , 17 Among studies using the same definition of high (⩾50%) and low clone size (20–49%) including ours herin 7 , 17 that addressed the effect of clone size, there was no significant impact of clone size on survival.…”

Section: Discussionmentioning

confidence: 97%

The impact of bortezomib-based induction in newly diagnosed multiple myeloma with chromosome 1q21 gain

Tang

Fung

Morgan

et al. 2022

Therapeutic Advances in Hematology

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Introduction: Bortezomib has been reported to favourably impact the outcomes of t(4;14) and del(17p) in multiple myeloma (MM), but its impact on gain 1q (+1q) is unknown. Methods: To address this, 250 patients treated with bortezomib-based induction were analysed. All myeloma samples had fluorescence in situ hybridization (FISH) performed on CD138-sorted bone marrow aspirate, and plasma cells were analysed using DNA probes specific for the following chromosomal aberrations: del(13q14), del(17p), t(14;16), t(4;14), and +1q. Presence of +1q was defined as the presence of at least three copies of 1q21 at the cut off level of 20% of bone marrow plasma cells. Results: +1q identified in 167 (66.8%) and associated with t(4;14) and high lactate dehydrogenase (LDH). +1q was not associated with response rate but shorter event-free survival (EFS) (median EFS 35 vs 55 months, p = 0.05) and overall survival (OS) (median OS 74 vs 168 months, p = 0.00025). Copy number and clone size did not impact survival. Multivariate analysis showed +1q was an independent adverse factor for OS together with International Staging System (ISS)3, high LDH, del(17p) and t(4;14). When a risk score of 1 was assigned to each independent adverse factor, OS was shortened incrementally by a risk score from 0 to 4. Post-relapse/progression survival was inferior in those with +1q (median 60 vs 118 months, p = 0.000316). Autologous stem cell transplantation (ASCT) improved OS for those with +1q (median OS 96 vs 49 months, p = 0.000069). Conclusion: +1q is an adverse factor for OS in MM uniformly treated with bortezomib-based induction but was partially mitigated by ASCT. A risk scoring system comprising +1q, LDH, high-risk FISH, and ISS is a potential tool for risk stratification in MM.

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Section: Discussionmentioning

confidence: 97%

The impact of bortezomib-based induction in newly diagnosed multiple myeloma with chromosome 1q21 gain

Tang

Fung

Morgan

et al. 2022

Therapeutic Advances in Hematology

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“…In addition to that, the choice of cytogenetic abnormalities included in R-ISS may be suboptimal. Indeed, some authors have associated other cytogenetics abnormalities with long-term outcomes (e.g., 1p deletion and 1q amplification) [ 19 – 21 ]. Moreover, it has been reported that the weight of each cytogenetic alteration may be different (additive score) [ 22 ], and that some cytogenetic abnormalities can “modulate” the effect of others.…”

Section: Discussionmentioning

confidence: 99%

Unsupervised machine learning improves risk stratification in newly diagnosed multiple myeloma: an analysis of the Spanish Myeloma Group

et al. 2022

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The International Staging System (ISS) and the Revised International Staging System (R-ISS) are commonly used prognostic scores in multiple myeloma (MM). These methods have significant gaps, particularly among intermediate-risk groups. The aim of this study was to improve risk stratification in newly diagnosed MM patients using data from three different trials developed by the Spanish Myeloma Group. For this, we applied an unsupervised machine learning clusterization technique on a set of clinical, biochemical and cytogenetic variables, and we identified two novel clusters of patients with significantly different survival. The prognostic precision of this clusterization was superior to those of ISS and R-ISS scores, and appeared to be particularly useful to improve risk stratification among R-ISS 2 patients. Additionally, patients assigned to the low-risk cluster in the GEM05 over 65 years trial had a significant survival benefit when treated with VMP as compared with VTD. In conclusion, we describe a simple prognostic model for newly diagnosed MM whose predictions are independent of the ISS and R-ISS scores. Notably, the model is particularly useful in order to re-classify R-ISS score 2 patients in 2 different prognostic subgroups. The combination of ISS, R-ISS and unsupervised machine learning clusterization brings a promising approximation to improve MM risk stratification.

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“…For example, recent work has shown that silencing of FLVCR1 led to inhibition of proliferation of synovial sarcoma cells in vitro and in vivo via regulation of cytotoxic autophagy 22 . Although speculative, since FLVCR1 is located on 1q32, it raises the possibility that its expression may be responsible for the poor prognosis associated with 1q32 gain in MM 23 – 27 .…”

Section: Discussionmentioning

confidence: 99%

Exploiting gene dependency to inform drug development for multiple myeloma

Went

Hoang

Law

et al. 2022

Sci Rep

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Despite recent advances in therapy, multiple myeloma essentially remains an incurable malignancy. Targeting tumour-specific essential genes, which constitute a druggable dependency, potentially offers a strategy for developing new therapeutic agents to treat MM and overcome drug resistance. To explore this possibility, we analysed DepMap project data identifying 23 MM essential genes and examined the relationship between their expression and patient outcome in three independent series totalling 1503 cases. The expression of TCF3 and FLVCR1 were both significantly associated with progression-free survival. IKBKB is already a drug target in other diseases, offering the prospect of repurposing to treat MM, while PIM2 is currently being investigated as a treatment for the disease. Our analysis supports the rationale of using large-scale genetic perturbation screens to guide the development of new therapeutic agents for MM.

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Chromosome 1q21 abnormalities refine outcome prediction in patients with multiple myeloma - a meta-analysis of 2,596 trial patients

Cited by 62 publications

References 14 publications

The impact of bortezomib-based induction in newly diagnosed multiple myeloma with chromosome 1q21 gain

The impact of bortezomib-based induction in newly diagnosed multiple myeloma with chromosome 1q21 gain

Unsupervised machine learning improves risk stratification in newly diagnosed multiple myeloma: an analysis of the Spanish Myeloma Group

Exploiting gene dependency to inform drug development for multiple myeloma

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