Muchtar, Eli

Abstract Background Noncoding RNAs such as microRNAs (miRNAs) have attracted attention as biological pathway regulators, which differ from chromosomal translocations and gene point mutations. Their involvement in the molecular mechanisms underlying light chain (AL) amyloidosis pathogenesis is yet to be elucidated. Aims To decipher specific miRNA expression profile in AL‐amyloidosis and to examine how miRNAs are involved in AL pathogenesis. Methods The expression profile of miRNAs and mRNA from bone marrow (BM)‐derived CD138+ cells were determined using the NanoString nCounter assay and RNA‐Seq, respectively. The effect of aberrantly expressed miRNAs on potential molecular targets was analyzed by qRT‐PCR, Western blot, Mito‐potential assay, and Annexin‐PI staining. Results Genes which were significantly differentially expressed between AL‐amyloidosis and MM, were found to be involved in cell growth and apoptotic mechanisms. Specifically, BCL2L1, MCL1, and BCL2 were upregulated in AL‐amyloidosis compared with MM and controls. The levels of miR‐181a‐5p and miR‐9‐5p, which regulate the above‐mentioned genes, were lower in BM samples from AL‐amyloidosis compared with controls, providing a mechanism for BCL2 family gene upregulation. When miR‐9‐5p and miR‐181a‐5p were overexpressed in ALMC1 cells, BCL2L1, MCL1, and BCL2 were downregulated and induced apoptosis. Treatment of ALMC‐1 cells with venetoclax, (BCL‐2 inhibitor), resulted in the upregulation of those miRNAs, the downregulation of BCL2, MCL1, and BCL2L1 mRNA and protein levels, and subsequent apoptosis. Conclusion Our findings suggest that miR‐9‐5p and miR‐181a‐5p act as tumor‐suppressors whose downregulation induces anti‐apoptotic mechanisms underlying the pathogenesis of AL‐amyloidosis. The study highlights the post‐transcriptional regulation in AL‐amyloidosis and provides pathogenetic evidence for the potential use of BCL‐2 inhibitors in this disease.

Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder with multiple clinical presentations. The diagnosis of AL amyloidosis requires a high index of suspicion, making a delay in diagnosis common, which contributes to the high early mortality seen in this disease. Establishing the diagnosis of AL amyloidosis requires the demonstration of tissue deposition of amyloid fibrils. A bone marrow biopsy and fat pad aspirate performed concurrently have a high sensitivity for the diagnosis of AL amyloidosis and negate the need for organ biopsies in most patients. An accurate diagnosis requires amyloid typing via additional testing, including tissue mass spectrometry. Prognostication for AL amyloidosis is largely driven by the organs impacted. Cardiac involvement represents the single most important prognostic marker, and the existing staging systems are driven by cardiac biomarkers. Apart from organ involvement, plasma cell percentage on the bone marrow biopsy, specific fluorescence in situ hybridization findings, age at diagnosis, and performance status are important prognostic markers. This review elaborates on the diagnostic testing and prognostication for patients with newly diagnosed AL amyloidosis.

Abstract POEMS syndrome is a rare paraneoplastic syndrome and therapies are directed against plasma cells that produce the proteins that cause this syndrome. Novel therapies are widely used in multiple myeloma aiming for plasma cell eradication. However, data on their use in POEMS syndrome are lacking. In this case series, we provide the Mayo Clinic experience in treating 16 patients with relapsed POEMS syndrome with novel agents (daratumumab, carfilzomib, pomalidomide, and elotuzumab). The patients were treated with a doublet including dexamethasone (N = 5) (31%) or in various combinations with other agents: DRd (N = 6), DC(V)d (N = 3), KRd (N = 3), KPd (N = 1), DP(V)d (N = 5), and EloRd (N = 1). The outcomes with novel agent therapies were favorable. Overall, twelve patients treated with daratumumab-based therapies (86%) and five patients treated with carfilzomib-based therapies (83%) responded to therapy. Among patients treated with daratumumab based therapies (N = 14), 9 patients achieved CR/VGPRH, 7 patients achieved CRV, and 5 patients achieved CRP. Among patients treated with carfilzomib-based therapies (N = 6), 3 patients achieved CR/VGPRH, and one achieved PRH. At a median follow-up of 38 months since starting of the novel agent (IQR 24–57), 15 of the patients (93%) are still alive, and the median TTNT was not reached. None of the patients discontinued therapy due to adverse events and no deaths occurred on therapy. Novel therapies were safe with 7 events of hospitalization due to pneumonia (4 in daratumumab-based therapies and 3 on carfilzomib-based therapies), and 4 patients were hospitalized due to volume overload. Three patients experienced infusion-related reactions (IRR) to the first dose of IV daratumumab. The response rate to novel agents was high, and the responses were deep. Novel agent therapies were safe, and no death case occurred on therapy. Future studies are needed to clarify the optimal sequence of novel agents and the best combination.