Concomitant deletion of the short arm (del(1p13.3)) and amplification or gain (1q21) of chromosome 1 by fluorescence in situ hybridization are associated with a poor clinical outcome in multiple myeloma

Mohan, Meera; Gong, Zimu; Ashby, Cody; Hadidi, Samer Al; Thanendrarajan, Sharmilan; Schinke, Carolina; Alapat, Daisy; Shaughnessy, John D.; Zhan, Fenghuang; Rhee, Frits van; Sawyer, J. Scott; Tian, Erming; Zangari, Maurizio

doi:10.1002/cncr.34895

Cited by 6 publications

(10 citation statements)

References 44 publications

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“…Although our analysis focused on the prognostic implications of +1q and not deletion 1p, abnormalities of deletion 1p may coexist with +1q, and may compound the inferior prognostic implications of +1q [48]. Furthermore, biallelic deletion of 1p has been shown to be a particularly poor prognostic factor, based on a retrospective study of 2551 patients [49].…”

Section: Discussionmentioning

confidence: 99%

Alterations in chromosome 1q in multiple myeloma randomized clinical trials: a systematic review

Neupane,

Fortuna,

Dahal

et al. 2024

Blood Cancer J.

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Extra copies of chromosome 1q21 (+1q: gain = 3 copies, amp >= 4 copies) are associated with worse outcomes in multiple myeloma (MM). This systematic review assesses the current reporting trends of +1q, the efficacy of existing regimens on +1q, and its prognostic implications in MM randomized controlled trials (RCTs). Pubmed, Embase and Cochrane Registry of RCTs were searched from January 2012 to December 2022. Only MM RCTs were included. A total of 124 RCTs were included, of which 29 (23%) studies reported on +1q. Among them, 10% defined thresholds for +1q, 14% reported survival data separately for gain and amp, and 79% considered +1q a high-risk cytogenetic abnormality. Amongst RCTs that met the primary endpoint showing improvement in progression free survival (PFS), lenalidomide maintenance (Myeloma XI), selinexor (BOSTON), and isatuximab (IKEMA and ICARIA) were shown to improve PFS for patients with evidence of +1q. Some additional RCT’s such as Myeloma XI+ (carfilzomib), ELOQUENT-3 (elotuzumab), and HOVON-65/GMMG-HD4 (bortezomib) met their endpoint showing improvement in PFS and also showed improvement in PFS in the +1q cohort, although the confidence interval crossed 1. All six studies that reported HR for +1q patients vs. without (across both arms) showed worse OS and PFS for +1q. There is considerable heterogeneity in the reporting of +1q. All interventions that have shown to be successful in RCTs and have clearly reported on the +1q subgroup have shown concordant direction of results and benefit of the applied intervention. A more standardized approach to reporting this abnormality is needed.

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Section: Discussionmentioning

confidence: 99%

Alterations in chromosome 1q in multiple myeloma randomized clinical trials: a systematic review

Neupane,

Fortuna,

Dahal

et al. 2024

Blood Cancer J.

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“…Moreover, evidence suggests that MM subclones with gain/amp(1q) frequently expand during different treatments [ 9 ], implying that a minor clone of gain/amp(1q) may be associated with CIN in MM. Nevertheless, most centers have now established a cutoff value of 20% [ 4 , 8 , 12 , 17 – 19 ] or 30% [ 20 ] for gain/amp(1q), with only a few using slightly smaller cutoff values of 3.5% [ 10 ], 5% [ 21 ] or 5.5% [ 22 ] for gain/amp(1q). These relatively large cutoff values have made it unclear whether a minor clone of gain/amp(1q) should be considered a high-risk CA in MM and whether it is associated with CIN in MM.…”

Section: Introductionmentioning

confidence: 99%

Fluorescence in situ hybridization reveals the evolutionary biology of minor clone of gain/amp(1q) in multiple myeloma

Cui,

Liu,

et al. 2024

Leukemia

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Growing evidence suggests that gain or amplification [gain/amp(1q)] accumulates during disease progression of multiple myeloma (MM). Previous investigations have indicated that small gain/amp(1q) subclones present at the time of diagnosis may evolve into dominant clones upon MM relapse. However, the influence of a minor clone of gain/amp(1q) on MM survival, as well as the correlation between different clonal sizes of gain/amp(1q) and the chromosomal instability (CIN) of MM, remains poorly understood. In this study, we analyzed fluorescence in situ hybridization (FISH) results of 998 newly diagnosed MM (NDMM) patients. 513 patients were detected with gain/amp(1q) at diagnosis. Among these 513 patients, 55 had a minor clone (≤20%) of gain/amp(1q). Patients with a minor clone of gain/amp(1q) displayed similar survival outcomes compared to those without gain/amp(1q). Further analysis demonstrated patients with a minor clone of gain/amp(1q) exhibited a clonal architecture similar to those without gain/amp(1q). Lastly, our results showed a significant increase in the clonal size of the minor clone of gain/amp(1q), frequently observed in MM. These findings suggested that a minor clone of gain/amp(1q) might represent an earlier stage in the pathogenesis of gain/amp(1q) and propose a “two-step” process in the clonal size changes of gain/amp(1q) in MM.

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“…In this issue of Cancer, Mohan et al 5 describe the impact of C1A on the outcomes of 1133 patients who were treated on the total therapy (TT) 2-6 trials at the University of Arkansas Medical Center (UAMS). Although +1q21 was evaluated in this study, a particular emphasis was placed on the prognostic impact of del(1p).…”

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“…In this issue of Cancer , Mohan et al 5 . describe the impact of C1A on the outcomes of 1133 patients who were treated on the total therapy (TT) 2–6 trials at the University of Arkansas Medical Center (UAMS).…”

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confidence: 99%

“…High‐risk disease remains a critical unmet need in multiple myeloma, and the first step to improving outcomes for such patients is for clinicians to recognize patients who are, indeed, high‐risk. Mohan et al 5 . have strengthened the case that chromosome 1 abnormalities, including del(1p), should be considered an important part of risk assessment for patients with multiple myeloma.…”

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Making a case for del(1p) as a high‐risk abnormality in multiple myeloma

Schmidt

2023

Cancer

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Making a case for del(1p) as a high-risk abnormality in multiple myelomaOver the past 2 decades, remarkable scientific and therapeutic discoveries have transformed multiple myeloma (MM) from a disease with few effective therapies and unacceptably high mortality to a condition that can often be successfully managed for years with a plethora of active treatments. However, despite this progress and nearly universal responses to initial therapy, MM is still largely considered an incurable disease. Although it is now commonplace for patients with MM to survive well beyond a decade, outcomes remain variable and some patients experience a more aggressive disease course. It is essential for clinicians to recognize biomarkers that might herald "high-risk" disease in order to set reasonable expectations with patients and to provide context for management decisions.One of the most powerful biomarkers in MM is the presence of recurrent chromosomal abnormalities within myeloma cells as detected by fluorescence in situ hybridization (FISH). Three chromosomal abnormalities-t(4;14), t(14;16), and del(17p)-were included in the Revised International Staging System (R-ISS), 1 reflecting that these abnormalities are often associated with high-risk disease. However, a variety of other factors known to affect prognosis are not included in the R-ISS. Chromosome 1 abnormalities (C1A), particularly copy gain and/or amplification (amp) of its long arm (+1q), are identified frequently in MM. Whereas amp(1q), defined as four or greater copies of the 1q locus, has been universally associated with worse outcomes, the prognostic impact of gain(1q), defined as three copies of the 1q locus, is debated. Nonetheless, due to its independent association with worse outcomes in several large data sets, +1q has been included as a high-risk abnormality in new proposed staging systems. [2][3][4] Deletions involving chromosome 1p are also commonly identified in MM, but the prognostic impact of del(1p)

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Concomitant deletion of the short arm (del(1p13.3)) and amplification or gain (1q21) of chromosome 1 by fluorescence in situ hybridization are associated with a poor clinical outcome in multiple myeloma

Cited by 6 publications

References 44 publications

Alterations in chromosome 1q in multiple myeloma randomized clinical trials: a systematic review

Alterations in chromosome 1q in multiple myeloma randomized clinical trials: a systematic review

Fluorescence in situ hybridization reveals the evolutionary biology of minor clone of gain/amp(1q) in multiple myeloma

Making a case for del(1p) as a high‐risk abnormality in multiple myeloma

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