Free Light-Chain Levels in Patients with Transthyretin Amyloid Cardiomyopathy in Attr-ACT

Introduction: In cardiac amyloidosis (CA), immunoglobulin-derived light chains (AL) and transthyretin (TTR) are the most common amyloidogenic proteins infiltrating the heart. 1 Identification of the specific precursor protein leading to amyloid deposition is needed to establish the correct therapeutic approach. 2 In both AL- and TTR-related CA, an early and accurate diagnosis is critical to achieving the best treatment outcomes. TTR amyloid cardiomyopathy (ATTR-CM) is often misdiagnosed as other causes of heart failure (HF), including AL CA. 3 While almost all patients with AL amyloidosis have elevated serum free light-chain (sFLC) levels and abnormal free kappa:lambda (κ:λ) ratios, 4 patients with ATTR-CM can also have abnormal sFLC levels due to either an unrelated monoclonal gammopathy or relative κ-predominance in renal dysfunction. 2,5 Because ATTR-CM most often occurs in elderly adults and is commonly accompanied by renal comorbidity, we theorized that patients with ATTR-CM may have κ:λ ratios that approach, or exceed, the upper limit of the normal reference range (0.26-1.65 6). High light-chain ratios in these patients have the potential to increase the likelihood of misdiagnosis of a monoclonal plasma cell disorder and may lead to unnecessary referrals to hematologists and/or inappropriate treatments. To explore this theory, we evaluated κ:λ ratios in patients with biopsy-proven ATTR-CM who were enrolled in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). 7 Methods: In ATTR-ACT, a double-blind, placebo-controlled, randomized study, patients with biopsy-proven ATTR-CM, and without light-chain amyloidosis, received tafamidis or placebo for 30 months. In the current analysis, sFLC levels and κ:λ ratios were assessed in the intent-to-treat population (N=441), excluding patients with a prior diagnosis of monoclonal gammopathies (n=13; defined by MedDRA preferred terms: 'monoclonal gammopathy', 'plasma cell myeloma', 'plasma cell disorder', and 'hypergammaglobulinemia benign monoclonal'). Subgroup analyses were performed by estimated glomerular filtration rate (eGFR) category (≥60 vs ≥40 to <60 vs <40 mL/min/1.73 m 2). Findings were summarized using descriptive statistics (min/max, mean, median, and interquartile range [IQR]). Results: In 422 patients with ATTR-CM and available sFLC data, and without a prior diagnosis of monoclonal gammopathies, the mean κ:λ ratio was 1.45 (median, 1.20 [IQR, 0.98, 1.47]) (Figure). The ratio increased with declining renal function: eGFR ≥60 mL/min/1.73 m 2, mean, 1.25 (median [IQR], 1.11 [0.94, 1.38]); ≥40 to <60 mL/min/1.73 m 2, 1.52 (1.22 [0.99, 1.49]); and <40 mL/min/1.73 m 2, 1.62 (1.30 [1.05, 1.68)]. Conclusions: In patients with biopsy-proven ATTR-CM without known monoclonal gammopathies who were enrolled in ATTR-ACT, the mean κ:λ ratio showed a κ-predominance, often exceeding the upper range of normal in patients with more advanced kidney dysfunction. The findings suggest that individuals with ATTR-CM can have higher sFLC levels than those normally seen in the general population, and such elevations do not necessarily indicate the presence of monoclonal gammopathy of undetermined significance or AL CA. In an era when most patients with ATTR-CM and without monoclonal gammopathies are diagnosed noninvasively using bone scintigraphy, age- and renal-function-based sFLC norms are critical to ensure appropriate use of diagnostic testing modalities. References: 1. Maleszewski JJ. Cardiovasc Pathol. 2015;24:343-50. 2. Donnelly JP, et al. Cleve Clin J Med. 2017;84:12-26. 3. Witteles RM, et al. JACC Heart Fail. 2019;7:709-716. 4. Falk RH, et al. J Am Coll Cardiol. 2016;68:1323-41. 5. Geller HI, et al. Mayo Clin Proc. 2017;92:1800-5. 6. Katzmann JA, et al. Clin Chem. 2002;48:1437-44. 7. Maurer MS, et al. N Engl J Med. 2018;379:1007-16. Figure 1 Figure 1. Disclosures Hoffman: BMS, Celgene: Honoraria. Sultan: Pfizer: Current Employment, Current equity holder in publicly-traded company. Gundapaneni: Pfizer: Current Employment, Current equity holder in publicly-traded company. Witteles: Pfizer: Honoraria, Research Funding; Alnylam: Honoraria, Research Funding; Eidos: Research Funding.

Hypocholesterolemia and Statins in Multiple Myeloma

Statins are lipid-lowering agents. They also have immunomodulatory, anti-inflammatory, anti-angiogenic, and anti-proliferative functions. In this context, they are demonstrated to have beneficial effects on mortality in several malignancies including esophageal, breast, lung, liver, pancreatic, endometrial, and colorectal cancers. Multiple myeloma is considered as an incurable plasma cell disorder with current therapy; however due to the current knowledge about the correlation between cholesterol-lowering agents and myeloma; it’s suggested to have lower mortality rates for patients using statins. Patients with multiple myeloma usually have a low cholesterol level which is often underestimated by clinicians. Hereby we aimed to summarize the myeloma-hypocholesterolemia relationship and emphasize the importance of statins as an inexpensive and beneficial approach for these patients.

Monoclonal gammopathy of undetermined significance

Monoclonal gammopathy of undetermined significance is a premalignant, plasma cell disorder. Due to the potential risk of progression to multiple myeloma or a plasma cell-related disorder, it is important for GPs to recognise and manage patients in this cohort appropriately. This article aims to improve understanding, recognition and management of these patients in primary care.

2021 European Myeloma Network review and consensus statement on smoldering multiple myeloma: how to distinguish (and manage) Dr. Jekyll and Mr. Hyde

According to the updated International Myeloma Working Group criteria, smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by an M-component >3 g/dL, bone marrow plasma cell infiltration >10% and

Two cases of special POEMS syndrome without monoclonal protein expression: a case report and literature review

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome is rare, with polyneuropathy and monoclonal plasma cell disorder generally considered as essential diagnostic symptoms. We report two cases of POEMS syndrome without monoclonal protein expression. The first case was a 72-year-old man who had experienced recurrent edema of the lower limbs for 2 years and abdominal distention for 2 months. The other case was a 62-year-old man with a 5-year history of recurrent numbness of the extremities and muscle weakness, which had become serious over the preceding 3 months. Both patients had various symptoms that matched those of POEMS syndrome, but neither had monoclonal protein expression. However, a diagnosis of POEMS syndrome was made in each case. Both patients were treated with lenalidomide and dexamethasone, after which their symptoms improved and laboratory test results normalized. The findings in these two cases suggest the possibility that POEMS syndrome may occur without monoclonal protein expression. The diagnostic criteria of POEMS syndrome may thus need further investigation.

Pathway-Directed Therapy in Multiple Myeloma

Multiple Myeloma (MM) is a malignant plasma cell disorder with an unmet medical need, in particular for relapsed and refractory patients. Molecules within deregulated signaling pathways, including the RAS/RAF/MEK/ERK, but also the PI3K/AKT-pathway belong to the most promising evolving therapeutic targets. Rationally derived compounds hold great therapeutic promise to target tumor-specific abnormalities rather than general MM-associated vulnerabilities. This paradigm is probably best depicted by targeting mutated BRAF: while well-tolerated, remarkable responses have been achieved in selected patients by inhibition of BRAFV600E alone or in combination with MEK. Targeting of AKT has also shown promising results in a subset of patients as monotherapy or to resensitize MM-cells to conventional treatment. Approaches to target transcription factors, convergence points of signaling cascades such as p53 or c-MYC, are emerging as yet another exciting strategy for pathway-directed therapy. Informed by our increasing knowledge on the impact of signaling pathways in MM pathophysiology, rationally derived Precision-Medicine trials are ongoing. Their results are likely to once more fundamentally change treatment strategies in MM.

Missed diagnosis of POEMS syndrome with onset of progressive fatigue and numbness: a case report

POEMS syndrome is a rare multisystem disease associated with an underlying plasma cell disorder. Its name is an acronym for peripheral neuropathy (P), endocrinopathy (E), organomegaly (O), monoclonal plasma cell proliferative disorder (M), and skin changes (S). This case report describes a patient with POEMS syndrome who presented with progressive fatigue and numbness in the lower extremities. Initially, the patient was erroneously diagnosed with diabetes and diabetic peripheral neuropathy because of the endocrinopathy associated with POEMS syndrome. After a second hospitalization, the patient was diagnosed with POEMS syndrome and recovered with alkylator therapy and a peripheral blood stem cell transplant. The patient’s overall condition was improved at the 1-year follow-up. POEMS syndrome should be considered if a patient presents with endocrinopathy and unexplained peripheral neuropathy.

From light chain deposition to multiple myeloma – Case report and literature review

Monoclonal gammopathies consist of a broad spectrum of diseases, ranging from asymptomatic monoclonal gammopathy of undetermined significance to multiple myeloma (MM). Multiple myeloma is a malignant plasma cell disorder and accounts for 10% of all hematological malignancies and 1% of all malignancies. Differential diagnosis may be challenging, considering the variety of clinical entities with similar behavior. About 15­‑20% of MM only secretes monoclonal light chains, called light chain MM, which is associated with poorer outcome. Two intermediate concepts were recently introduced, monoclonal gammopathy of renal significance (MGRS) and a wider concept of monoclonal gammopathy of clinical significance (MGCS). The former behaves as a clonal proliferative disorder with associated nephrotoxicity, but does not have the hematological criteria for MM, while MGCS expands this concept to other organs. A subtype of MGCS is monoclonal immunoglobulin deposition disease, a multisystemic disorder characterized by light or heavy chain deposition of monoclonal immunoglobulin in various organs and encompasses three clinical entities: Light­‑Chain, Light­‑ and Heavy­‑Chain, and Heavy­‑Chain Deposition Disease (LCDD, LHCDD and HCDD, respectively). We describe an unusual case of LCDD in which MM was subsequently considered although the proposed criteria are not met. We demonstrate the variability of clinical­‑pathological presentation of LCDD, requiring a rapid decision­‑making, particularly in terms of kidney and survival outcomes.