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Non-secretory multiple myeloma with unusual TFG-ALK fusion showed dramatic response to ALK inhibition.

ABSTRACT: Non-secretory multiple myeloma (NSMM) constitutes a distinct entity of multiple myeloma characterized by the absence of detectable monoclonal protein and rarely an absence of free light chains in the serum and urine. Given its rarity, the genomic landscape, clinical course, and prognosis of NSSM are not well characterized. Here, we report a case of a patient with relapsed and refractory NSMM with brain metastasis harboring a TFG-ALK fusion showing a dramatic and durable (over two years) response to commercially available anaplastic lymphoma kinase (ALK) inhibitors. The case emphasizes the beneficial role of molecular profiling in this target-poor disease.

SUBMITTER: Masood A

PROVIDER: S-EPMC7969947 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Non-secretory multiple myeloma with unusual TFG-ALK fusion showed dramatic response to ALK inhibition.

Masood Ashiq A Christ Trevor T Asif Samia S Rajakumar Priya P Gustafson Beth A BA Shune Leyla O LO Salahudeen Ameen A Nedvad Drew D Nanua Suparna S Paner Agne A Kuzel Timothy M TM Levy Mia M Subramanian Janakiraman J Raza Shahzad S

NPJ genomic medicine 20210317 1

Non-secretory multiple myeloma (NSMM) constitutes a distinct entity of multiple myeloma characterized by the absence of detectable monoclonal protein and rarely an absence of free light chains in the serum and urine. Given its rarity, the genomic landscape, clinical course, and prognosis of NSSM are not well characterized. Here, we report a case of a patient with relapsed and refractory NSMM with brain metastasis harboring a TFG-ALK fusion showing a dramatic and durable (over two years) response ...[more]

PMID: 33731690

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Project description:BackgroundNonsecretory multiple myeloma (NSMM) is a rare type of multiple myeloma (MM). Few studies have described the clinical features and outcomes of NSMM in novel agents. Additionally, the prognostic characteristics have remained controversial in recent years.PurposeTo investigate the clinical and prognostic features of NSMM and explore the prognostic value of involved free light chain (FLC) levels in NSMM patients in the Chinese population.MethodsWe retrospectively enrolled 176 newly diagnosed NSMM cases between January 2005 and December 2021 from 19 clinical centers in China. The control group was selected using a 1:4 propensity score matching technique of newly diagnosed secretory MM, with age, sex and diagnosis time as the matching variables.ResultsThe median age of NSMM patients was 60 years, and 22.6% of patients were classified as ISS stage 3. The ORR of the NSMM patients was 87.4%, and the CR was 65.8%. Compared to the matched secretory MM patients, more NSMM patients achieved CR after first-line treatment (65.8% vs. 36%, p = 0.000). The ORR of first-line treatment was not significantly different between NSMM and secretory MM (89.45% vs. 84.7%, p = 0.196). The first-line PFS was 27.5 m and 23 m (p = 0.063), and the median OS was 81 m and 70 months (p = 0.401). However, for CR-achieved NSMM and CR-not-achieved NSMM patients, the median PFS was 37 m vs. 16 m (p = 0.021), while the median OS showed no difference (107 m vs. 87 m, p = 0.290). In multivariate analysis, the significant factors for PFS were age ≥ 65 and ISS-3. ISS-3 was the only independent prognostic factor of OS. The iFLC ≥ 50 mg/L group had a high ORR of 97.3%, and the median PFS and OS were 48 m and NR, respectively. Compared to the matched secretory MM, the iFLC ≥ 50 mg/L group also showed more CR and longer OS (NR vs. 70 m, p = 0.006) and PFS (48 m vs. 23 m, p = 0.003).ConclusionsOur results revealed that Chinese NSMM patients are younger and have a higher CR but not superior survival. The subgroup of NSMM patients with iFLC ≥ 50 mg/L had better outcomes than secretory MM.

Project description:Crizotinib was a first generation of ALK tyrosine kinase inhibitor approved for the treatment of ALK-positive non-small-cell lung carcinoma (NSCLC) patients. COMPARE and cluster analyses of transcriptomic data of the NCI cell line panel indicated that genes with different cellular functions regulated the sensitivity or resistance of cancer cells to crizotinib. Transcription factor binding motif analyses in gene promoters divulged two transcription factors possibly regulating the expression of these genes, i.e., RXRA and GATA1, which are important for leukemia and erythroid development, respectively. COMPARE analyses also implied that cell lines of various cancer types displayed varying degrees of sensitivity to crizotinib. Unexpectedly, leukemia but not lung cancer cells were the most sensitive cells among the different types of NCI cancer cell lines. Re-examining this result in another panel of cell lines indeed revealed that crizotinib exhibited potent cytotoxicity towards acute myeloid leukemia and multiple myeloma cells. P-glycoprotein-overexpressing CEM/ADR5000 leukemia cells were cross-resistant to crizotinib. NCI-H929 multiple myeloma cells were the most sensitive cells. Hence, we evaluated the mode of action of crizotinib on these cells. Although crizotinib is a TKI, it showed highest correlation rates with DNA topoisomerase II inhibitors and tubulin inhibitors. The altered gene expression profiles after crizotinib treatment predicted several networks, where TOP2A and genes related to cell cycle were downregulated. Cell cycle analyses showed that cells incubated with crizotinib for 24 h accumulated in the G2M phase. Crizotinib also increased the number of p-H3(Ser10)-positive NCI-H929 cells illustrating crizotinib's ability to prevent mitotic exit. However, cells accumulated in the sub-G0G1 fraction with longer incubation periods, indicating apoptosis induction. Additionally, crizotinib disassembled the tubulin network of U2OS cells expressing an α-tubulin-GFP fusion protein, preventing migration of cancer cells. This result was verified by in vitro tubulin polymerization assays. In silico molecular docking also revealed a strong binding affinity of crizotinib to the colchicine and Vinca alkaloid binding sites. Taken together, these results demonstrate that crizotinib destabilized microtubules. Additionally, the decatenation assay showed that crizotinib partwise inhibited the catalytic activity of DNA topoisomerase II. In conclusion, crizotinib exerted kinase-independent cytotoxic effects through the dual inhibition of tubulin polymerization and topoisomerase II and might be used to treat not only NSCLC but also multiple myeloma.

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Non-secretory multiple myeloma with unusual TFG-ALK fusion showed dramatic response to ALK inhibition.

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Non-secretory multiple myeloma with unusual TFG-ALK fusion showed dramatic response to ALK inhibition.

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