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Haematologica Jan 2024Treatment of patients with Mayo stage IIIb light chain (AL) amyloidosis is still challenging, and the prognosis remains very poor. Mayo stage IIIb patients were excluded...
Treatment of patients with Mayo stage IIIb light chain (AL) amyloidosis is still challenging, and the prognosis remains very poor. Mayo stage IIIb patients were excluded from the pivotal trial leading to the approval of daratumumab in combination with bortezomib-cyclophosphamide-dexamethasone. This retrospective, multicenter study evaluates the addition of daratumumab to first-line therapy in patients with newly diagnosed stage IIIb AL amyloidosis. In total, data from 119 consecutive patients were analyzed, 27 patients received an upfront treatment including daratumumab, 63 a bortezomibbased regimen without daratumumab, eight received therapies other than daratumumab or bortezomib and 21 pretreated patients or deceased prior to treatment were excluded. In the daratumumab group, median overall survival was not reached after a median follow-up time of 14.5 months, while it was significantly worse in the bortezomib- and the otherwise treated group (6.6 and 2.2 months, respectively) (P=0.002). Overall hematologic response rate at 2 and 6 months was better in the daratumumab group compared to the bortezomib group (59% vs. 37%, P=0.12, 67% vs. 41%, P=0.04, respectively). Landmark survival analyses revealed a significantly improved overall survival in patients with partial hematologic response or better, compared to non-responders. Cardiac response at 6 months was 46%, 21%, 0% in the daratumumab-, bortezomib- and otherwise treated groups, respectively (P=0.04). A landmark survival analysis revealed markedly improved overall survival in patients with cardiac very good partial response vs. cardiac non-responders (P=0.002). This study demonstrates for the first time the superiority of an upfront treatment with daratumumab over standard-of-care in stage IIIb AL amyloidosis.
Topics: Humans; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Immunoglobulin Light-chain Amyloidosis; Retrospective Studies; Treatment Outcome
PubMed: 37439344
DOI: 10.3324/haematol.2023.283325 -
International Journal of Medical... 2022Patients with amyloid light-chain (AL) amyloidosis with a bone marrow plasma cell ratio > 10% (AL-PCMM) have a poorer prognosis than patients with AL amyloidosis with a...
Patients with amyloid light-chain (AL) amyloidosis with a bone marrow plasma cell ratio > 10% (AL-PCMM) have a poorer prognosis than patients with AL amyloidosis with a bone marrow plasma cell ratio of <10% (AL-only), similar to that of patients with AL amyloidosis and multiple myeloma (AL-MM). However, the prognostic factors for AL-PCMM and AL-MM have not been studied. A total of 49 patients with AL-PCMM or AL-MM in the Peking University First Hospital registry in 2010-2018 were enrolled. Clinical and follow-up data were collected. The relationship between clinical parameters and survival time was also assessed. Compared with patients with AL-PCMM, patients with AL-MM only had a higher incidence of bone marrow plasma cell ratio ≥ 20%. In AL-PCMM and AL-MM, the survival time was significantly shorter in patients with alkaline phosphatase (ALP) ≥ 187.5 IU/L, γ-glutamyl transpeptidase (GGT) ≥ 85 IU/L, total bilirubin (TBIL) ≥ 20 µmol/L, cardiac troponin I (CTNI) ≥ 0.1 ng/mL, ejection fraction (EF) < 50%, initial therapeutic effect (ITE) < very good partial response (VGPR), and Boston University (BU) staging system stage ≥ III. ALP at diagnosis was correlated with brain natriuretic peptide (BNP) level, CTNI level, and EF rather than TBIL level. Cox regression analyses revealed that BU staging system stage ≥ III (=0.001, hazard ratio [HR]=5.579), ALP ≥ 187.5 IU/L (=0.011, HR=3.563), and ITE < VGPR (=0.002, HR=7.462) were independent significant risk factors for a poor prognosis of AL-PCMM and AL-MM. ALP level, which is related to cardiac amyloidosis rather than liver involvement, can be a prognostic factor for this group of patients. A BU staging system stage ≥ III, ALP ≥ 187.5 IU/L, and ITE < VGPR were independent significant risk factors for a poor prognosis of AL-PCMM and AL-MM.
Topics: Humans; Immunoglobulin Light-chain Amyloidosis; Multiple Myeloma; Prognosis; Retrospective Studies; Troponin I
PubMed: 35370457
DOI: 10.7150/ijms.61712 -
Blood Cancer Journal Aug 2021The recent decades have ushered in considerable advancements in the diagnosis and treatment of systemic light chain (AL) amyloidosis. As disease outcomes improve, AL... (Clinical Trial)
Clinical Trial
The recent decades have ushered in considerable advancements in the diagnosis and treatment of systemic light chain (AL) amyloidosis. As disease outcomes improve, AL amyloidosis-unrelated factors may impact mortality. In this study, we evaluated survival trends and primary causes of death among 2337 individuals with AL amyloidosis referred to the Boston University Amyloidosis Center. Outcomes were analyzed according to date of diagnosis: 1980-1989 (era 1), 1990-1999 (era 2), 2000-2009 (era 3), and 2010-2019 (era 4). Overall survival increased steadily with median values of 1.4, 2.6, 3.3, and 4.6 years for eras 1-4, respectively (P < 0.001). Six-month mortality decreased over time from 23% to 13%. Wide gaps in survival persisted amid patient subgroups; those with age at diagnosis ≥70 years had marginal improvements over time. Most deaths were attributable to disease-related factors, with cardiac failure (32%) and sudden unexpected death (23%) being the leading causes. AL amyloidosis-unrelated mortality increased across eras (from 3% to 16% of deaths) and with longer-term survival (29% of deaths occurring >10 years after diagnosis). Under changing standards of care, survival improved and early mortality declined over the last 40 years. These findings support a more optimistic outlook for patients with AL amyloidosis.
Topics: Age Factors; Aged; Antineoplastic Agents, Alkylating; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Longitudinal Studies; Male; Melphalan; Middle Aged; Stem Cell Transplantation; Survival Analysis
PubMed: 34349108
DOI: 10.1038/s41408-021-00529-w -
Blood Cancer Journal Nov 2023
Topics: Humans; Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Immunoglobulin Light Chains; Antibodies, Bispecific; Antineoplastic Agents
PubMed: 38012151
DOI: 10.1038/s41408-023-00950-3 -
Blood Cancer Journal May 2018Immunoglobulin light chain amyloidosis (AL) should be considered in any patient that presents to a cancer care provider with nephrotic range proteinuria, heart failure... (Review)
Review
Immunoglobulin light chain amyloidosis (AL) should be considered in any patient that presents to a cancer care provider with nephrotic range proteinuria, heart failure with preserved ejection fraction, non-diabetic peripheral neuropathy, unexplained hepatomegaly or diarrhea. More importantly, patients being monitored for smoldering multiple myeloma and a monoclonal gammopathy of undetermined significance (MGUS) are at risk for developing AL amyloidosis. MGUS and myeloma patients that have atypical features, including unexplained weight loss; lower extremity edema, early satiety, and dyspnea on exertion should be considered at risk for light chain amyloidosis. Overlooking the diagnosis of light chain amyloidosis leading to therapy delay is common, and it represents an error of diagnostic consideration. Algorithms will be provided on how to evaluate patients with suspected AL amyloid as well as how to manage patients referred from other medical specialties with biopsy-proven amyloid. An organized stepwise approach to the treatment of patients with light chain amyloidosis, including established and investigational therapies, will be reviewed.
Topics: Aged; Algorithms; Antineoplastic Agents, Immunological; Biopsy; Bridged Bicyclo Compounds, Heterocyclic; Combined Modality Therapy; Disease Management; Female; Humans; Immunoglobulin A; Immunoglobulin Light-chain Amyloidosis; Monoclonal Gammopathy of Undetermined Significance; Organ Transplantation; Prealbumin; Proteasome Inhibitors; Sulfonamides
PubMed: 29795248
DOI: 10.1038/s41408-018-0080-9 -
Hematology/oncology and Stem Cell... Jun 2019Cutaneous immunoglobulin (Ig) amyloid light-chain (AL) amyloidosis associated with overt multiple myeloma (MM) is rare and optimal treatment is not well defined. The...
OBJECTIVE/BACKGROUND
Cutaneous immunoglobulin (Ig) amyloid light-chain (AL) amyloidosis associated with overt multiple myeloma (MM) is rare and optimal treatment is not well defined. The recently developed highly efficacious MM therapy has brought on a new set of challenges to this field for consideration. The goal of this paper is to describe the characteristics of cutaneous manifestations of systemic AL amyloidosis associated with MM according to age, sex, race, Ig type, plasma cell percentage, and cytogenetic and fluorescent in situ hybridization studies along with their outcomes.
METHODS
An electronic search of the PubMed database was performed to obtain key literature in AL amyloidosis and MM, using the following search terms: multiple myeloma, immunoglobulin light chain amyloidosis, and cutaneous amyloidosis. The search results were narrowed by selecting studies in English. Results were confined to the following articles types: case reports, case series, and systematic reviews.
RESULTS
We identified 32 cases from the PubMed database search and examined their potential relevance. We found the following: (a) higher prevalence in women (two-thirds) and white population; (b) IgG and IgA were equally distributed with lambda (λ) light chain occurring in 53-66% of cases; (c) majority of cases (56%) presented as hemorrhagic bullous lesions, followed by purpura/ecchymosis in 25% of cases; and (d) majority (64%) died within 6 months since diagnosis.
CONCLUSIONS
We reviewed the constellation of the cutaneous manifestations of AL amyloidosis with concurrent MM. We found a female predominance, and more than half presented as hemorrhagic bullous lesions. There is a preponderance of λ light chains over kappa (κ) light chains, both as a free light chain (15% vs. 4%) and as an intact Ig (38% vs. 24%; absolute number of 14 vs. 7 patients, respectively). In the subgroup of patients with bullous skin lesions, λ light chain was present in eight cases and κ light chain in seven cases. All κ light chain subtypes presented with bullous lesions and no other cutaneous types of lesions. They carried very poor prognosis with majority of cases surviving only 6 months, much worse than overall patients with AL amyloidosis without myeloma or myeloma without amyloidosis.
Topics: Adult; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Middle Aged; Multiple Myeloma; Neoplasm Proteins; Sex Factors; Skin Neoplasms
PubMed: 30261180
DOI: 10.1016/j.hemonc.2018.09.003 -
Acta Dermatovenerologica Alpina,... Mar 2018Primary systemic amyloidosis is characterized by the deposition of insoluble monoclonal immunoglobulin light chains in various tissues and is usually associated with an...
Primary systemic amyloidosis is characterized by the deposition of insoluble monoclonal immunoglobulin light chains in various tissues and is usually associated with an underlying plasma cell dyscrasia. In the early stage of the disease, dermatological findings can be the only manifestation, as opposed to organ involvement in the later stages. A dermatologist can diagnose amyloidosis early with a skin biopsy stained with Congo red dye and other appropriate investigations. This case report describes a female patient with primary systemic amyloidosis confirmed histologically from a skin biopsy. When the diagnosis was established, cardiac involvement and monoclonal gammopathy were already present. Treatment with bortezomib and dexamethasone was initiated; due to side effects, the treatment was later switched to lenalidomide, which was better tolerated.
Topics: Aged; Antineoplastic Agents; Biopsy, Needle; Bortezomib; Dexamethasone; Diagnosis, Differential; Drug Therapy, Combination; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Immunohistochemistry; Paraproteinemias; Prognosis; Risk Assessment; Severity of Illness Index; Treatment Outcome
PubMed: 29589647
DOI: No ID Found -
Acta Haematologica 2019The 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... (Review)
Review
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.
Topics: Chromosome Aberrations; Humans; Immunoglobulin Light-chain Amyloidosis; Kidney Function Tests; Liver Function Tests; Proteasome Inhibitors; Risk Assessment; Stem Cell Transplantation; Steroids
PubMed: 30650422
DOI: 10.1159/000495455 -
Annals of Hematology Apr 2023Subcutaneous daratumumab plus bortezomib/cyclophosphamide/dexamethasone (VCd; D-VCd) improved outcomes versus VCd for patients with newly diagnosed immunoglobulin... (Randomized Controlled Trial)
Randomized Controlled Trial
Subcutaneous daratumumab plus bortezomib/cyclophosphamide/dexamethasone (VCd; D-VCd) improved outcomes versus VCd for patients with newly diagnosed immunoglobulin light-chain (AL) amyloidosis in the phase 3 ANDROMEDA study. We report a subgroup analysis of Asian patients (Japan; Korea; China) from ANDROMEDA. Among 388 randomized patients, 60 were Asian (D-VCd, n = 29; VCd, n = 31). At a median follow-up of 11.4 months, the overall hematologic complete response rate was higher for D-VCd versus VCd (58.6% vs. 9.7%; odds ratio, 13.2; 95% confidence interval [CI], 3.3-53.7; P < 0.0001). Six-month cardiac and renal response rates were higher with D-VCd versus VCd (cardiac, 46.7% vs. 4.8%; P = 0.0036; renal, 57.1% vs. 37.5%; P = 0.4684). Major organ deterioration progression-free survival (MOD-PFS) and major organ deterioration event-free survival (MOD-EFS) were improved with D-VCd versus VCd (MOD-PFS: hazard ratio [HR], 0.21; 95% CI, 0.06-0.75; P = 0.0079; MOD-EFS: HR, 0.16; 95% CI, 0.05-0.54; P = 0.0007). Twelve deaths occurred (D-VCd, n = 3; VCd, n = 9). Twenty-two patients had baseline serologies indicating prior hepatitis B virus (HBV) exposure; no patient experienced HBV reactivation. Although grade 3/4 cytopenia rates were higher than in the global safety population, the safety profile of D-VCd in Asian patients was generally consistent with the global study population, regardless of body weight. These results support D-VCd use in Asian patients with newly diagnosed AL amyloidosis. ClinicalTrials.gov Identifier: NCT03201965.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cyclophosphamide; Dexamethasone; Immunoglobulin Light-chain Amyloidosis; Multiple Myeloma
PubMed: 36862168
DOI: 10.1007/s00277-023-05090-z -
Hematology/oncology Clinics of North... Dec 2020Stem cell transplantation was one of the first proven effective regimens for the management of immunoglobulin light-chain amyloidosis. Criteria for patient selection and... (Review)
Review
Stem cell transplantation was one of the first proven effective regimens for the management of immunoglobulin light-chain amyloidosis. Criteria for patient selection and the mobilization regimen become important features in ensuring a safe outcome. The technique of stem cell transplantation has evolved considerably in parallel with the development of new chemotherapeutic agents for the management of amyloidosis. Optimal outcomes require both the use of effective novel agent induction and appropriate application of high-dose chemotherapy with subsequent stem cell reconstitution.
Topics: Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Transplantation, Autologous
PubMed: 33099429
DOI: 10.1016/j.hoc.2020.07.007