Second malignancies in multiple myeloma; emerging patterns and future directions

Maclachlan, Kylee; Diamond, Benjamin; Maura, Francesco; Hillengaß, Jens; Turesson, Ingemar; Landgren, C. Ola; Kazandjian, Dickran

doi:10.1016/j.beha.2020.101144

Cited by 35 publications

(33 citation statements)

References 127 publications

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“…With each increment of calendar period, used as a surrogate for the evolution of MM therapy, we observed an overall increase of SPMs, particularly squamous-cell carcinomas of the skin, MDS, and AML. This is in accordance with findings from clinical trials [ 1 , 4 ], retrospective (population-based) studies [ 9 – 11 ], as well as with data discussed in a recently published review [ 8 ]. A potential mechanism may lie in the cumulative exposure to mutagenic anti-MM agents (e.g., alkylating drugs), thereby increasing the risk of subsequent MDS/AML development [ 11 , 12 ].…”

supporting

confidence: 91%

“…However, there is also a concurrrent increase in the incidence of subsequent primary malignancies (SPMs) [ 1 – 3 ]. Risk factors associated with SPMs in MM encompass treatment with alkylating agents or immunomodulatory drugs (IMiDs) [ 1 , 4 – 6 ], environmental exposures, genetic susceptibility to cancer, or combinations of these risk factors [ 7 , 8 ]. As MM survivorship is expected to increase, it is vital for clinicians to know how these risk factors influence SPM development in MM patients.…”

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confidence: 99%

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Increased mortality risk in multiple-myeloma patients with subsequent malignancies: a population-based study in the Netherlands

et al. 2022

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confidence: 91%

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confidence: 99%

Increased mortality risk in multiple-myeloma patients with subsequent malignancies: a population-based study in the Netherlands

et al. 2022

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“…This, in turn, has resulted in dramatically improved overall survival 5,42 . Given that recent studies show that high‐dose melphalan exposure causes significant increase in somatic mutations (on average a ~20% increase), 43‐45 it seems reasonable to hypothesize that the long‐term risks are currently under‐estimated.…”

Section: Discussionmentioning

confidence: 99%

Cumulative exposure to melphalan chemotherapy and subsequent risk of developing acute myeloid leukemia and myelodysplastic syndromes in patients with multiple myeloma

Jonsdottir

Björkholm

Turesson

et al. 2021

European J of Haematology

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Objectives The aim of this study was to determine risk factors for development of acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) in patients with multiple myeloma (MM). Methods We identified all patients diagnosed with MM in Sweden from January 1st, 1958 to December 31, 2011. A total of 26 627 patients were diagnosed with MM with during the study period. Of these, 124 patients (0.5%) developed subsequent AML/MDS. For each patient with MM and a subsequent AML/MDS diagnosis, we randomly selected a matched (age, sex, and date of MM diagnosis) MM patient without a subsequent second malignancy diagnosis. Results The cumulative melphalan exposure was significantly higher (OR = 2.8, 95% CI 1.7‐5.2; P < .001) among cases (median 988 mg; IQR 644‐1640) compared with controls (median 578 mg; IQR 360‐967). Median time to AML/MDS development was 3.8 years (IQR 2.8‐5.8). Risk of AML/MDS was not statistically altered by M protein isotype, anemia, renal failure, hypercalcemia, lytic bone lesions, or radiation therapy. Conclusion In this nationwide population‐based study, we show that increased cumulative doses of alkylating therapy with melphalan increases the subsequent risk of developing AML/MDS in patients with MM. Given improved survival in MM patients over the last decade future studies will be important to better define long‐term risks.

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“…It is possible that the change from the main clone to subclones during MM treatment causes a change in the clinical and hematological phenotype of MM and, thus, explains the inefficiency of the previously conducted therapy. Noteworthy, patients with MM or its precursors have an increased risk of developing secondary primary malignancies (SPMs), such as myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and others [ 64 , 65 , 66 , 67 ]. The origin of these tumors is likely related to the genotoxic action of some therapeutic agents [ 65 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ], although an excess risk for hematopoietic neoplasms other than MM in MGUS patients supports an idea that endogenous factors play an essential role in SPMs’ development [ 9 , 75 , 76 , 77 ].…”

Section: Clinical Manifestation Of Multiple Myeloma and Recent Research Approachesmentioning

confidence: 99%

Genome Instability in Multiple Myeloma: Facts and Factors

Aksenova

Zhuk

Lada

et al. 2021

Cancers

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Multiple myeloma (MM) is a malignant neoplasm of terminally differentiated immunoglobulin-producing B lymphocytes called plasma cells. MM is the second most common hematologic malignancy, and it poses a heavy economic and social burden because it remains incurable and confers a profound disability to patients. Despite current progress in MM treatment, the disease invariably recurs, even after the transplantation of autologous hematopoietic stem cells (ASCT). Biological processes leading to a pathological myeloma clone and the mechanisms of further evolution of the disease are far from complete understanding. Genetically, MM is a complex disease that demonstrates a high level of heterogeneity. Myeloma genomes carry numerous genetic changes, including structural genome variations and chromosomal gains and losses, and these changes occur in combinations with point mutations affecting various cellular pathways, including genome maintenance. MM genome instability in its extreme is manifested in mutation kataegis and complex genomic rearrangements: chromothripsis, templated insertions, and chromoplexy. Chemotherapeutic agents used to treat MM add another level of complexity because many of them exacerbate genome instability. Genome abnormalities are driver events and deciphering their mechanisms will help understand the causes of MM and play a pivotal role in developing new therapies.

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Second malignancies in multiple myeloma; emerging patterns and future directions

Cited by 35 publications

References 127 publications

Increased mortality risk in multiple-myeloma patients with subsequent malignancies: a population-based study in the Netherlands

Increased mortality risk in multiple-myeloma patients with subsequent malignancies: a population-based study in the Netherlands

Cumulative exposure to melphalan chemotherapy and subsequent risk of developing acute myeloid leukemia and myelodysplastic syndromes in patients with multiple myeloma

Genome Instability in Multiple Myeloma: Facts and Factors

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