Author response for "Daratumumab for Relapsed or Refractory AL Amyloidosis with high Plasma Cell Burden"

The vast majority of patients with light-chain (AL) amyloidosis are not eligible for stem cell transplant and are treated with conventional chemotherapy. Conventional regimens are based on various combinations of dexamethasone, alkylating agents, proteasome inhibitors, and immunomodulatory drugs. The choice of these regimens requires a careful risk stratification, based on the extent of amyloid organ involvement, comorbidities, and the characteristics of the amyloidogenic plasma cell clone. Most patients are treated upfront with bortezomib and dexamethasone combined with cyclophosphamide or melphalan. Cyclophosphamide does not compromise stem cell mobilization and harvest and is more manageable in renal failure. Melphalan can overcome the effect of t(11;14), which is associated with lower response rates and shorter survival in subjects treated with bortezomib and dexamethasone, or in combination with cyclophosphamide. Lenalidomide and pomalidomide are the mainstay of rescue treatment. They are effective in patients exposed to bortezomib, dexamethasone, and alkylators, but deep hematologic responses are rare. Ixazomib, alone or in combination with lenalidomide, increases the rate of complete responses in relapsed/refractory patients. Conventional chemotherapy regimens will represent the backbone for future combinations, particularly with anti-plasma-cell immunotherapy, that will further improve response rates and outcomes.

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Sjögren syndrome-related plasma cell disorder and multifocal nodular AL amyloidosis: clinical picture and pathological findings

Amyloid ◽

10.1080/13506129.2019.1660636 ◽

2019 ◽

Vol 26 (4) ◽

pp. 225-233 ◽

Cited By ~ 1

Author(s):

Shu-ichi Ikeda ◽

Akiyo Hineno ◽

Tsuneaki Yoshinaga ◽

Kiyoshi Matsuo ◽

Tomoaki Suga ◽

...

Keyword(s):

Plasma Cell ◽

Clinical Picture ◽

Sjögren Syndrome ◽

Al Amyloidosis ◽

Sjogren Syndrome ◽

Pathological Findings ◽

Plasma Cell Disorder ◽

Cell Disorder

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Cytogenetic intraclonal heterogeneity of plasma cell dyscrasia in AL amyloidosis as compared with multiple myeloma

Blood Advances ◽

10.1182/bloodadvances.2018023200 ◽

2018 ◽

Vol 2 (20) ◽

pp. 2607-2618 ◽

Cited By ~ 11

Author(s):

Tilmann Bochtler ◽

Maximilian Merz ◽

Thomas Hielscher ◽

Martin Granzow ◽

Korbinian Hoffmann ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Clonal Evolution ◽

Statistical Significance ◽

Hematologic Malignancies ◽

Absolute Difference ◽

Plasma Cell Dyscrasia ◽

Al Amyloidosis ◽

Clone Size

Abstract Analysis of intraclonal heterogeneity has yielded insights into the clonal evolution of hematologic malignancies. We compared the clonal and subclonal compositions of the underlying plasma cell dyscrasia in 544 systemic light chain amyloidosis (PC-AL) patients with 519 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or symptomatic MM; ie, PC–non-AL patients). Using interphase fluorescence in situ hybridization, subclones were stringently defined as clone size below two thirds of the largest clone and an absolute difference of ≥30%. Subclones were found less frequently in the PC-AL group, at 199 (36.6%) of 544 as compared with 267 (51.4%) of 519 in the PC–non-AL group (P < .001), and were not associated with the stage of plasma cell dyscrasia in either entity. In both groups, translocation t(11;14), other immunoglobulin heavy chain translocations, and hyperdiploidy were typically found as main clones, whereas gain of 1q21 and deletions of 8p21, 13q14, and 17p13 were frequently found as subclones. There were no shifts in the subclone/main clone ratio depending on the MGUS, SMM, or MM stage of plasma cell dyscrasia. In multivariate analysis, t(11;14) was associated with lower rates of subclone formation and hyperdiploidy with higher rates. PC-AL itself lost statistical significance, demonstrating that the lower subclone frequency in AL is a reflection of its exceptionally high t(11;14) frequency. In summary, the subclone patterns in PC-AL and PC–non-AL are closely related, implying that subclone formation depends on the main cytogenetic categories and is independent of disease entity and stage.

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Recent Advances in the Diagnosis, Risk Stratification, and Management of Systemic Light-Chain Amyloidosis

Acta Haematologica ◽

10.1159/000495455 ◽

2019 ◽

Vol 141 (2) ◽

pp. 93-106 ◽

Cited By ~ 28

Author(s):

Iuliana Vaxman ◽

Morie Gertz

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Cell Clone ◽

Proteasome Inhibitors ◽

Clinical Manifestations ◽

Al Amyloidosis ◽

Amyloid Deposits ◽

Protein Fibrils ◽

Risk Patients ◽

Intensive Search

The term amyloidosis refers to a group of disorders in which protein fibrils accumulate in certain organs, disrupt their tissue architecture, and impair the function of the effected organ. The clinical manifestations and prognosis vary widely depending on the specific type of the affected protein. Immunoglobulin light-chain (AL) amyloidosis is the most common form of systemic amyloidosis, characterized by deposition of a misfolded monoclonal light-chain that is secreted from a plasma cell clone. Demonstrating amyloid deposits in a tissue biopsy stained with Congo red is mandatory for the diagnosis. Novel agents (proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, venetoclax) and autologous stem cell transplantation, used for eliminating the underlying plasma cell clone, have improved the outcome for low- and intermediate-risk patients, but the prognosis for high-risk patients is still grave. Randomized studies evaluating antibodies that target the amyloid deposits (PRONTO, VITAL) were recently stopped due to futility and currently there is an intensive search for novel treatment approaches to AL amyloidosis. Early diagnosis is of paramount importance for effective treatment and prognosis, due to the progressive nature of this disease.

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Differential diagnosis of monoclonal gammopathy of undetermined significance

Hematology ◽

10.1182/asheducation.v2012.1.595.3798563 ◽

2012 ◽

Vol 2012 (1) ◽

pp. 595-603 ◽

Cited By ~ 57

Author(s):

Giampaolo Merlini ◽

Giovanni Palladini

Keyword(s):

Differential Diagnosis ◽

Plasma Cell ◽

Monoclonal Gammopathy ◽

Cell Clone ◽

Organ Damage ◽

Organ Injury ◽

Al Amyloidosis ◽

Monoclonal Protein ◽

Undetermined Significance

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic plasma cell disorder occurring in 4.2% of adults > 50 years of age, which can progress into symptomatic diseases either through proliferation of the plasma cell clone, giving rise to multiple myeloma and other lymphoplasmacellular neoplasms, or through organ damage caused by the monoclonal protein, as seen in light-chain amyloidosis and related conditions. Differential diagnosis of asymptomatic and symptomatic monoclonal gammopathies is the determinant for starting therapy. The criteria for determining end-organ damage should include markers of organ injury caused by the monoclonal protein. Patient assessment and optimal follow-up are now performed using risk stratification models that should also take into account the risk of developing AL amyloidosis. Patients with low-risk MGUS (approximately 40% of all MGUS patients) need limited assessment and very infrequent follow-up. The ongoing development of novel molecular biomarkers and advanced imaging techniques will improve the identification of high-risk patients who may benefit from early therapeutic intervention through innovative clinical trials.

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