Treatment in AL Amyloidosis: Moving towards Individualized and Clone-Directed Therapy

Systemic amyloid light chain (AL) amyloidosis is a rare protein deposition disease caused by a clonal B cell disorder of the bone marrow. The underlying diseases can be plasma cell disorders (monoclonal gammopathy of clinical significance, smoldering or symptomatic myeloma) or B cell non-Hodgkin’s lymphoma (e.g., Waldenstrom’s disease or marginal zone lymphoma) with secretory activity. It is crucial to characterize the underlying disease very precisely as the treatment of AL amyloidosis is directed against the (often small) B cell clone. Finally, the detection of cytogenetic aberrations of the plasma cell clone will likely play an important role for choosing an effective drug in the near future.

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Evaluation of the Cytogenetic Aberration Pattern in AL Amyloidosis Compared to Monoclonal Gammopathies Not Requiring Treatment: Translocation t(11;14) Is More Frequent in AL Amyloidosis.

Blood ◽

10.1182/blood.v110.11.2500.2500 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2500-2500 ◽

Cited By ~ 1

Author(s):

Tilmann Bochtler ◽

Stefan O. Schonland ◽

Anna Jauch ◽

Christiane Heiss ◽

Axel Benner ◽

...

Keyword(s):

Plasma Cell ◽

Monoclonal Gammopathy ◽

Control Group ◽

Al Amyloidosis ◽

Fish Analysis ◽

Cell Content ◽

Cytogenetic Aberration ◽

Cytogenetic Aberrations ◽

Plasma Cell Disorders ◽

Unknown Significance

Abstract Introduction: Cytogenetic aberrations (CA) have emerged as important pathogenetic and prognostic factors in plasma cell disorders. However, in AL amyloidosis (AL) only a few reports with small numbers of patients have been published. Methods: Using interphase FISH analysis in CD138+ cells, we evaluated the role of CA in a series of 85 AL patients as compared to 146 patients with a monoclonal gammopathy without treatment requirement in a prospective manner. Our panel included IgH translocations t(11;14), t(4;14), t(14;16) and translocation of 14q32 with an unidentified partner, gains of 1q21, 11q23 and 19q13 as well as deletions of 8p21, 13q14 and 17p13. Using these probes we could detect at least one of these aberrations in 95% of AL and in 88% of the control group. Age, gender and plasma cell content were statistically equally distributed among both groups. Results: The most frequent aberration in AL was t(11;14), which was detected in 45% of AL patients as compared to 26% of the control group (p=0,056). It was strongly associated with the lack of an intact immunoglobulin (p<0,001), thus accounting for the frequent light chain only subtype in AL. Markedly, t(11;14) was more frequently found in combination with gain 11q23 in AL than in the control group (20% versus 6%, p = 0.005). Other frequent aberrations in AL included deletion 13q14 (32%) and gain 1q21 (21%), which were observed in the control group at comparable frequencies (34% and 20%). The overlapping character of the underlying plasma cell disorder in both disease entities was also emphasized by the similarities of branching patterns of the five major CA in cluster analysis applied in 169 patients (figure 1). The relation of clinical parameters and chromosomal aberrations was also evaluated. The analyzed CA had no impact on the organ involvement pattern in AL patients. Conclusions: We observed a high frequency for t(11;14) in AL. Apart from this finding, the cytogenetic patterns known in monoclonal gammopathy of unknown significance and multiple myeloma were widely shared by AL amyloidosis. Figure Figure

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Hyperdiploidy Is Rare in Patients with AL Amyloidosis – Identification of Major Cytogenetic Groups in Early Monoclonal Plasma Cell Disorders.

Blood ◽

10.1182/blood.v114.22.2823.2823 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2823-2823 ◽

Cited By ~ 1

Author(s):

Tilmann Bochtler ◽

Ute Hegenbart ◽

Christiane Heiss ◽

Axel Benner ◽

Stephanie Pschowski-Zuck ◽

...

Keyword(s):

Plasma Cell ◽

Multiple Testing ◽

Conflicts Of Interest ◽

Cell Clone ◽

Plasma Cell Dyscrasia ◽

Al Amyloidosis ◽

Inverse Association ◽

Chromosome 11 ◽

Tree Model ◽

Cytogenetic Aberrations

Abstract Abstract 2823 Poster Board II-799 AL amyloidosis (AL) is characterized by the deposition of amyloid fibrils in diverse tissues due to an underlying monoclonal plasma cell dyscrasia. In a previous study (Bochtler et al, Blood 2008) we have demonstrated that in AL cytogenetic aberrations were detectable in about 90% of patients (pts). Translocation t(11;14) proved to be the most frequent aberration in AL found in 45% of the pts. In this study we evaluated whether the concept of hyperdiploidy and non-hyperdiploidy as major pathogenetic pathways in monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) is also applicable to AL. Our study was based on the largest patient group tested for cytogenetics in AL thus far including 184 pts with AL - among them 21 pts with concomitant MM I. They were assessed for their ploidy status by interphase fluorescence in situ hybridization (FISH). 179 MGUS and MM I pts not requiring therapy served as controls. We used a well established score (Wuilleme et al, Leukemia 2005), which requires extra copies for at least two out of the three probes 5p15/5q35, 9q34 and 15q22 as criterion for hyperdiploidy. The hyperdiploidy frequency was very low in AL with 14% as compared to 32% in MGUS / MM I (p<0.001). Among AL pts those with a concomitant MM I displayed a higher hyperdiploidy frequency than those without (43% versus 10%, p<0.001) suggesting that chromosomal gains reflect progression of the monoclonal plasma cell clone. Addressing hyperdiploidy probes in detail, we could show that both in the 184 pts. with AL and 179 pts. with MGUS / MM I gains of 11q23, 17p13 and 19q13.3 closely clustered with the three hyperdiploidy defining probes 5p15/5q35, 9q34 and 15q22 (p'0.01 for all probes after adjusting for multiple testing). However, gain of 11q23 was also frequently detected in association with t(11;14). The group with gain of 11q23 subdivides into a t(11;14) positive and a hyperdiploidy positive subgroup in both the AL (p<0.001) and the MGUS / MM I (p<0.001) entities. As revealed by additional probes for 11p15 and 11cen, gain of 11q23 in hyperdiploid pts reflected a gain of the whole chromosome 11 in all tested pts (10 AL and 31 MGUS / MM I). On the contrary, gain of 11q23 in t(11;14) positive pts was merely due to the translocation involving chromosome 11 (with 25 out of 26 AL and 5 out of 7 MGUS / MM I pts displaying a normal diploid status for 11p15 and 11cen). Therefore, gain of 11q23 is a poor indicator of hyperdiploidy in AL, where t(11;14) frequencies are particularly high and hyperdiploidy frequencies are particularly low. Addressing the cytogenetic clustering of hyperdiploidy with other cytogenetic aberrations we observed a strong inverse association of hyperdiploidy with t(11;14) in both AL and MGUS / MM I (p<0.001 in both entities). Accordingly, both aberrations were allocated to branches separating from each other already at the root in the oncogenetic tree model (see figure 1). Del13q14/t(4;14) and IgH translocations with an unknown partner also separated as distinct branches early from the root. These similar clustering patterns of both AL and MGUS / MM I with 4 major cytogenetic groups suggests common pathogenetic mechanisms in both entities despite their differing hyperdiploidy and t(11;14) frequencies. Disclosures: No relevant conflicts of interest to declare.

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Dose-Intensive Melphalan With Blood Stem-Cell Support for the Treatment of AL (Amyloid Light-Chain) Amyloidosis: Survival and Responses in 25 Patients

Blood ◽

10.1182/blood.v91.10.3662 ◽

1998 ◽

Vol 91 (10) ◽

pp. 3662-3670 ◽

Cited By ~ 247

Author(s):

Raymond L. Comenzo ◽

Evan Vosburgh ◽

Rodney H. Falk ◽

Vaishali Sanchorawala ◽

Johann Reisinger ◽

...

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Performance Status ◽

Al Amyloidosis ◽

Organ Systems ◽

Plasma Cell Disorders ◽

Plasma Cell Disorder ◽

Amyloid Light Chain ◽

Al Amyloid ◽

Cell Disorder

Abstract AL (amyloid light-chain) amyloidosis is an uncommon plasma cell disorder in which depositions of amyloid light-chain protein cause progressive organ failure and death in a median of 13 months. Autologous stem-cell transplantation is effective therapy for multiple myeloma and therefore, we evaluated its efficacy for AL amyloidosis. Patients with adequate cardiac, pulmonary, and renal function had stem cells mobilized with granulocyte-colony stimulating factor and were treated with dose-intensive intravenous melphalan (200 mg/m2). Response to therapy was determined by survival and improvement of performance status, complete response or persistence of the clonal plasma cell disorder, and change in the function of organs involved with amyloid at baseline. We enrolled 25 patients with a median age of 48 years (range, 29-60), all of whom had biopsy-proven amyloidosis with clonal plasma cell disorders. Twenty-two (88%) were Southwest Oncology Group performance status 1 or 2 within a year of diagnosis, and 16 (64%) had received no prior therapy. Predominant amyloid-related organ involvement was cardiac (n = 8), renal (n = 7), hepatic (n = 6), neuropathic (n = 3), and lymphatic (n = 1). Fifteen patients had one or two organ systems involved, whereas 10 had three or more involved. With a median follow-up of 24 months (12-38), 17 of 25 patients (68%) are alive, and the median survival has not been reached. Thirteen of 21 patients (62%) evaluated 3 months posttransplant had complete responses of their clonal plasma cell disorders. Currently, two thirds of the surviving patients (11 of 17) have experienced improvements of amyloid-related organ involvement in all systems, whereas 4 of 17 have stable disease. The improvement in the median performance status of the 17 survivors at follow-up (0 [range, 0-3]) is statistically significant versus baseline (2 [range, 1-3]; P < .01). Significant negative prognostic factors with respect to overall survival include amyloid involvement of more than two major organ systems and predominant cardiac involvement. Three patients have experienced relapses of the clonal plasma cell disorder at 12 and 24 months. Dose-intensive therapy should currently be considered as the preferred therapy for patients with AL amyloidosis who meet functional criteria for autologous transplantation.

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Learning from Patients: The Interplay between Clinical and Laboratory Research in AL Amyloidosis

Hemato ◽

10.3390/hemato3010002 ◽

2021 ◽

Vol 3 (1) ◽

pp. 3-16

Author(s):

Moshe E. Gatt ◽

Marjorie Pick

Keyword(s):

Patient Care ◽

Plasma Cell ◽

Light Chain ◽

Cell Clone ◽

Organ Injury ◽

Laboratory Research ◽

Al Amyloidosis ◽

Related Factors ◽

Amyloid Light Chain

Primary systemic light chain amyloidosis (AL) is a rare monoclonal plasma cell disorder. Much research has been performed to determine the factors that underly amyloidogenicity. However, there is increasing evidence that the primary clone, and also patient-related factors, influence the mechanism and rate of the process. The lessons learnt from patient care definitely imply that this is not solely due to the deposition of material in the tissues that cause organ injury but amyloid light chain precursors are likely to mediate cellular toxicity. The disease rarity, combined with the lack of in vitro tools, and that multi-organ failure has a wide clinical spectrum, result in investigative challenges and treatment limitations (due to AL patient frailty). All these characteristics make the disease difficult to diagnose and indicate the need to further study its origins and treatments. This review will focus on the various aspects of the amyloidogenic plasma cell clone, as learnt from the patient care and clinics, and its implications on basic as well as clinical trials of AL research. Details regarding the etiology of the plasma cell clone, understanding the diagnosis of AL, and improvement of patient care with specific consideration of the future perspectives of individualized patient therapy will be described.

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Dose-Intensive Melphalan With Blood Stem-Cell Support for the Treatment of AL (Amyloid Light-Chain) Amyloidosis: Survival and Responses in 25 Patients

Blood ◽

10.1182/blood.v91.10.3662.3662_3662_3670 ◽

1998 ◽

Vol 91 (10) ◽

pp. 3662-3670 ◽

Cited By ~ 3

Author(s):

Raymond L. Comenzo ◽

Evan Vosburgh ◽

Rodney H. Falk ◽

Vaishali Sanchorawala ◽

Johann Reisinger ◽

...

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Performance Status ◽

Al Amyloidosis ◽

Organ Systems ◽

Plasma Cell Disorders ◽

Plasma Cell Disorder ◽

Amyloid Light Chain ◽

Al Amyloid ◽

Cell Disorder

AL (amyloid light-chain) amyloidosis is an uncommon plasma cell disorder in which depositions of amyloid light-chain protein cause progressive organ failure and death in a median of 13 months. Autologous stem-cell transplantation is effective therapy for multiple myeloma and therefore, we evaluated its efficacy for AL amyloidosis. Patients with adequate cardiac, pulmonary, and renal function had stem cells mobilized with granulocyte-colony stimulating factor and were treated with dose-intensive intravenous melphalan (200 mg/m2). Response to therapy was determined by survival and improvement of performance status, complete response or persistence of the clonal plasma cell disorder, and change in the function of organs involved with amyloid at baseline. We enrolled 25 patients with a median age of 48 years (range, 29-60), all of whom had biopsy-proven amyloidosis with clonal plasma cell disorders. Twenty-two (88%) were Southwest Oncology Group performance status 1 or 2 within a year of diagnosis, and 16 (64%) had received no prior therapy. Predominant amyloid-related organ involvement was cardiac (n = 8), renal (n = 7), hepatic (n = 6), neuropathic (n = 3), and lymphatic (n = 1). Fifteen patients had one or two organ systems involved, whereas 10 had three or more involved. With a median follow-up of 24 months (12-38), 17 of 25 patients (68%) are alive, and the median survival has not been reached. Thirteen of 21 patients (62%) evaluated 3 months posttransplant had complete responses of their clonal plasma cell disorders. Currently, two thirds of the surviving patients (11 of 17) have experienced improvements of amyloid-related organ involvement in all systems, whereas 4 of 17 have stable disease. The improvement in the median performance status of the 17 survivors at follow-up (0 [range, 0-3]) is statistically significant versus baseline (2 [range, 1-3]; P < .01). Significant negative prognostic factors with respect to overall survival include amyloid involvement of more than two major organ systems and predominant cardiac involvement. Three patients have experienced relapses of the clonal plasma cell disorder at 12 and 24 months. Dose-intensive therapy should currently be considered as the preferred therapy for patients with AL amyloidosis who meet functional criteria for autologous transplantation.

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Detection and Characterization of Plasma Cell and B Cell Clones in Patients with Systemic Light Chain Amyloidosis Using Flow Cytometry

Blood ◽

10.1182/blood.v124.21.2068.2068 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2068-2068

Author(s):

Stefan Schönland ◽

Ute Hegenbart ◽

Christoph Kimmich ◽

Katarina Lisenko ◽

Dirk Hose ◽

...

Keyword(s):

Flow Cytometry ◽

B Cell ◽

Cell Count ◽

Plasma Cell ◽

Light Chain ◽

Plasma Cells ◽

Cell Clone ◽

Flow Analysis ◽

Al Amyloidosis ◽

Cell Clones

Abstract Introduction: AL amyloidosis is a rare and life-threatening protein-deposition disorder caused by a small B cell (mostly plasma cell) clone which produces amyloidogenic light chains. The goal of therapy is to target this clone and halt the uncontrolled release of free light chain, which might subsequently lead to improvement of organ function. In routine diagnostic some of these B cell clones are missed as they might be extremely small. However, specific treatment can only be applied if the clone is well characterized. Hardly any data on the characteristics of these cells using flow cytometry have been reported. (e.g. Paiva et al., Blood 2011). Study design: We performed a retrospective analysis of consecutive patients who were referred to our amyloidosis center (March to July 2014) and have been thoroughly studied (immunhistology of amyloid, free light chain assay, immunofixation, bone marrow diagnostic: cytology, flow cytometry and interphase-FISH cytogenetics (iFISH)). Patients and Methods: Twenty-two patients were included (all untreated, 21 AL patients, one pt with monoclonal gammopathy of renal significance (MGRS)). Plasma cells were detected by their co-expression of CD38 and CD138 antigens. Differentiation between malignant and normal plasma cells was achieved by analysis of aberrant CD45 and CD19 expressions and proof of intracellular light chain restriction (see Figure 1). To evaluate potential targets for an antibody-based immunotherapy, we stained CD20, CD22, CD30, CD52 and CS-1 on these plasma cells. Overall, positivity was defined as >20% expression of the antigen. iFISH was done after CD138 selection as previously described (Bochtler et al., Blood 2011). Results: Main characteristics and results are shown in Table 1. Median dFLC was 304 mg/l, three patients had a dFLC of less than 50 mg/l. Median plasma cell count in cytology was 10%, 3 patients had less than 5%. Median plasma cell count by flow was 3.8%, three patients had less than 1%. Correlation between dFLC, plasma cell count in cytology and flow was low (FLC vs. flow: spearman=0.25, p=0.26; FLC vs. cytology: spearman=0.49, p=0.02; flow vs. cytology, spearman=0.36, p=0.1). Detection of the amyloidogenic clone by flow was possible in all but one patient (95%). In this patient we were not able to show a light chain restriction although we detected a relevant aberrant plasma cell clone (CD45low, CD19low). In one patient we found a B cell lymphoma as underlying disease for MGRS type IgG lambda (CD19+, CD20+, lambda+, CD5-, CD22+, FMC7-, CD23-, CD25+, CD103-, CD38+ typical for marginal zone lymphoma). In all 21 patients the light chain restriction demonstrated by flow was confirmed by immunofixation, FLC, and immunohistology of the amyloid. All patients analyzed for the expression of CS-1 were positive. 25% were also positive for CD20 and none was positive for CD22, CD30 and CD52. Detection of the plasma cell clone by iFISH was possible in all 21 patients (see Table 1). Conclusion: Flow cytometric analysis of the bone marrow is a very sensitive method to detect and characterize the amyloidogenic clone in AL amyloidosis. B cell lymphomas can easily be distinguished from pure plasma cell clones. Secondly, flow provides useful information to specify immune-chemotherapy in AL amyloidosis and related disorders. Table 1: Patients (n=22) Characteristics and Results Age in yrs (median / range) 67 (41 – 77) Sex: female / male 9 / 13 Type of light chain: kappa / lambda 4 / 18 Median dFLC in mg/l (range) 304 (22 - 6621) Median % of plasma cells in BM cytology (range) 10 (0 – 68) Underlying disease leading to AL amyloidosis“MG” / MM III / B-NHL 20 / 1 / 1 Median % of PC by flow (range) 3.8 (0.2 - 34) Detection of the amyloidogenic clone by flow 21 / 22 Flow analysis of clonal plasma cells (% of pts)CD20+ / CD22+ / CD30+ / CD52+ / CD56+ / CS-1+ 25 / 0 / 0 / 0 / 75 / 100 Detection of a clone by iFISH 21/21 % of pts with t(11;14) / Gain of 1q21 / Hyperdiploidy / High-risk cytogenetic (del 17p13, t(4;14)) 52 / 10 / 14 / 10 Figure 1: Representative flow analysis of one pt. with a lambda+, CD38+, CD138+ plasma cell clone (green). Polyclonal CD19+ B cells in red. Figure 1:. Representative flow analysis of one pt. with a lambda+, CD38+, CD138+ plasma cell clone (green). Polyclonal CD19+ B cells in red. Disclosures Schönland: Janssen: Honoraria; Celgene: Honoraria. Hegenbart:Janssen: Honoraria; Celgene: Honoraria. Hose:Novartis: Research Funding. Hundemer:Celgene: Honoraria, Research Funding.

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Single Arm, Prospective, Open-Label Phase II Trial to Evaluate the Efficacy of Isatuximab in Patients with Monoclonal Gammopathy of Renal Significance

Blood ◽

10.1182/blood-2019-123496 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3161-3161 ◽

Cited By ~ 1

Author(s):

Vikram Premkumar ◽

Suzanne Lentzsch ◽

Divaya Bhutani

Keyword(s):

Multiple Myeloma ◽

B Cell ◽

Plasma Cell ◽

Monoclonal Gammopathy ◽

Plasma Cells ◽

Cell Clone ◽

Advisory Committees ◽

Renal Response ◽

Hematologic Response ◽

Stable Renal Function

Background: Monoclonal gammopathy of renal significance (MGRS) is a monoclonal B cell disorder, not meeting the definition of lymphoma or myeloma, that produces monoclonal proteins which deposit in the kidneys. Permanent renal damage can occur either as a consequence of direct deposition of toxic proteins or by an induced inflammatory response. Due to the low burden of the plasma cell clone, patients do not otherwise qualify for potentially toxic anti-plasma cell treatments and treatment is generally based on consensus opinion. To date there are no clinical trials exploring treatment options. Isatuximab is a chimeric mouse/human IgG1k monoclonal antibody which targets CD38 on both malignant and normal plasma cells and exhibits it antitumor effects primarily by antibody-dependent cellular toxicity. Isatuximab has recently been shown to be an active drug in the treatment of multiple myeloma, with improvements seen in hematologic and renal markers, and has been shown to have manageable toxicity. Given the efficacy of isatuximab in multiple myeloma, we propose a trial evaluating isatuximab monotherapy to treat the small plasma cell clone in MGRS with the hopes of maximizing response and minimizing toxicity. Study Design and Methods: The primary objective of this study is to evaluate efficacy of isatuximab monotherapy in patients with MGRS in order to establish a standard of care treatment for patients with this disease. Adult patients with proteinuria of at least 1 gram in 24 hours and a histopathological diagnosis of MGRS on renal biopsy in the last 24 months will be eligible for the trial. Patients will be excluded if their estimated GFR is below 30 mL/min, they have multiple myeloma, high risk smoldering myeloma, other B cell neoplasm meeting criteria for treatment, concurrent diabetic nephropathy, or require dialysis. Patients will be screened for B cell disorders with bone marrow biopsy and aspirate, serum protein electrophoresis (SPEP) with immunofixation (IFE), 24-hour urine protein electrophoresis (UPEP), free light chain (FLC) testing and screening PET/CT at time of enrollment. Enrolled patients will be administered isatuximab 20 mg/kg IV weekly for 4 weeks and then will receive the same dose every 2 weeks thereafter for a total of 6 months. Patients may be continued on treatment following completion of the 6 months at the discretion of the provider. To reduce the risk of infusion related reactions, patients will receive premedications with corticosteroids, diphenhydramine, H2 blockade and acetaminophen at least 60 minutes prior to infusion. Patients will have repeat SPEP + IFE, 24-hour UPEP + IFE and FLC testing every 4 weeks. There will be an optional repeat kidney biopsy 9-12 months following treatment initiation to assess pathologic response in the kidneys. Statistical Methods: The study will be comprised of 20 patients being treated with isatuximab over a span of 24-30 months. Ten patients will be initiated on the therapy for a period of 6 months. Interim analysis will be done after these patients have completed all the treatment cycles. If 4 out of 10 patients show response in form of improved/stable renal function, the study will proceed to include next 10 patients. If >50% of the first group of 10 patients show doubling of creatinine while on therapy, that would be considered as an indication to discontinue the therapy and the study due to drug toxicity. Endpoints: The primary endpoint will be efficacy as measured by renal response and hematologic response. Renal response will be measured by assessing the amount of proteinuria in a 24 hour urine sample. A sustained reduction in proteinuria by 30% from the patient's baseline amount of proteinuria with stable renal function (serum eGFR within 20% of baseline) will be considered a positive renal response. Hematologic response will be quantified per the 2016 International Myeloma Working Group (IMWG) uniform response criteria for multiple myeloma. An important secondary endpoint will be safety and will be analyzed from all patients who receive any study drug. Adverse events will be characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Other endpoints include time to dialysis and rate of minimal residual disease (MRD) negativity. Disclosures Lentzsch: Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy. Bhutani:Sanofi: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Our trial will be evaluating the efficacy of targeting CD38 on plasma cells with isatuximab in patients with monoclonal gammopathy of renal significance (MGRS). We will evaluate the effects of this drug on 24 hour proteinuria and hematologic response.

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Conventional Therapy for Amyloid Light-Chain Amyloidosis

Acta Haematologica ◽

10.1159/000507072 ◽

2020 ◽

Vol 143 (4) ◽

pp. 365-372

Author(s):

Paolo Milani ◽

Giovanni Palladini

Keyword(s):

Stem Cell ◽

Plasma Cell ◽

Light Chain ◽

Cell Clone ◽

Alkylating Agents ◽

Proteasome Inhibitors ◽

Response Rates ◽

Al Amyloidosis ◽

Cell Transplant ◽

Conventional Chemotherapy

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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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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