Proteasome Inhibitors to Treat AL Amyloidosis

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.

Download Full-text

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.

Download Full-text

A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis

Blood ◽

10.1182/blood-2016-12-756528 ◽

2017 ◽

Vol 129 (15) ◽

pp. 2120-2123 ◽

Cited By ~ 49

Author(s):

Giovanni Palladini ◽

Paolo Milani ◽

Andrea Foli ◽

Marco Basset ◽

Francesca Russo ◽

...

Keyword(s):

Proteasome Inhibitors ◽

Al Amyloidosis ◽

Phase 2 ◽

Phase 2 Trial ◽

Rescue Treatment ◽

Key Points

Key Points PDex can be a rescue regimen for patients with AL amyloidosis previously exposed to alkylators, proteasome inhibitors, and lenalidomide. Responses to PDex are frequent, rapid, and improve survival.

Download Full-text

Clinical Characteristics, Treatment Regimens and Survival in Elderly Patients with AL Amyloidosis in a Tertiary Referral Center

Blood ◽

10.1182/blood-2019-124980 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5447-5447

Author(s):

Jose Acevedo ◽

Gheorghe Doros ◽

Raphael Szalat ◽

John Mark Sloan ◽

Shayna Sarosiek ◽

...

Keyword(s):

Overall Survival ◽

Elderly Patients ◽

Research Funding ◽

Clinical Characteristics ◽

Proteasome Inhibitors ◽

Median Number ◽

Stage Ii ◽

High Dose ◽

Al Amyloidosis ◽

Treatment Regimens

Background AL amyloidosis is the most common form of systemic amyloidosis, characterized by an associated plasma cell dyscrasia leading to extracellular fibril deposition causing organ dysfunction. In these patients there is a fine balance between treatment toxicities and tolerability due to frailty and presence of multiorgan involvement. This balance is increasingly recognized in the elderly but treatment and outcomes have not been systematically studied, where co-morbidities and frailty may compound morbidity and mortality. Methods A retrospective analysis of all patients 70 years or older who were evaluated at the Boston University (BU) Amyloidosis Center from 2000 until 2018 was performed to determine demographics, clinical characteristics, treatments and outcome measures. Kaplan Meier method was used to perform an overall survival (OS) of all patients from the time of diagnosis. Further analysis of OS was performed based on whether treatment was received before or after 2010 (when proteasome inhibitors were incorporated in the treatment algorithm for AL amyloidosis), whether administered treatment regimens consisted of proteasome inhibitors (PI), and whether or not treatment with high dose melphalan and stem cell transplantation (HDM/SCT) was received. Results A total of 342 patients with AL amyloidosis who were older than 70 years of age at the time of diagnosis had their initial evaluation at BU Amyloidosis Center from 2000 to 2018. There were 215 (63%) men. The median age was 74 years (range, 70 - 90), and 55 (16%) were older than 80 years of age. The majority of patients were Caucasians (90%). The median number of organs involved by AL amyloidosis was 2 (range, 1- 7). The most common organ involvement was renal in 229 patients (68.3%), followed by cardiac in 167 patients (48.8%), and neurologic in 98 (29.2%). The majority of patients had renal stage II disease and BU cardiac stage II disease. Of the 342 patients, 223 (65%) received systemic treatment, the remainder (35%) received only supportive treatment. The median number of chemotherapy regimens administered was 1 (range 1-5), 116 patients (52%) received one regimen, 81 (36.1%) received two regimens, 35 (15.6%) patients received more than three treatment regimens. Of the 342 patients, 32 (9.4%) received treatment with HDM/SCT. The median age of patients undergoing HDM/SCT was 71 years (range, 70-75). The median overall survival was 3.4 years (95% CI 2.9-4.1) with a median follow-up of 2.6 years (range, 0.02-15.2). The median OS of patients treated with PI based therapy was 6.0 years vs 3.7 years for those not treated with PI based regimens (p=0.01) (Figure 1). The median OS of patients was 6.8 years for patients treated with HDM/SCT and 4.0 years for those not receiving HDM/SCT (p=0.08). Moreover, the median OS of patients diagnosed prior to 2010 was 3.4 years which is similar to 3.9 years for those diagnosed after 2010 (p=0.07). Conclusion In summary, the presentation of elderly patients with systemic AL amyloidosis is similar to that of younger patients in general. There are a higher proportion of patients with advanced cardiac and renal stage disease, perhaps reflecting delay in diagnosis. Compared to supportive care, overall survival in those receiving a PI based therapy is better with respect to survival, although this may reflect selection bias. In addition, HDM/SCT can be offered to highly selected patients with age older than 70 years. Prospective studies in older patients with novel agents with a better toxicity profile and ease of administration may allow a greater proportion of patients to benefit from treatment. Figure 1 Disclosures Sloan: Merck: Other: endpoint review commitee; Stemline: Consultancy; Abbvie: Other: Endpoint Review Committee. Sarosiek:Acrotech: Research Funding. Sanchorawala:Proclara: Consultancy, Honoraria; Caelum: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Takeda: Research Funding.

Download Full-text

Neuropathy Associated with Systemic Amyloidosis

Seminars in Neurology ◽

10.1055/s-0039-1688994 ◽

2019 ◽

Vol 39 (05) ◽

pp. 578-588 ◽

Cited By ~ 7

Author(s):

Michelle Kaku ◽

John L. Berk

Keyword(s):

Proteasome Inhibitors ◽

Systemic Amyloidosis ◽

Al Amyloidosis ◽

Immunoglobulin Light Chain ◽

Transthyretin Amyloidosis ◽

Sensorimotor Polyneuropathy ◽

Clinical Presentations ◽

Tunnel Syndrome ◽

Amyloid Polyneuropathy ◽

Transthyretin Familial Amyloid Polyneuropathy

AbstractPeripheral neuropathy occurs in the setting of both hereditary and acquired amyloidosis. The most common form of hereditary amyloidosis is caused by 1 of 140 mutations in the transthyretin (TTR) gene, which can lead to neuropathic hereditary transthyretin amyloidosis (hATTR; previously referred to as transthyretin familial amyloid polyneuropathy), whereas acquired immunoglobulin light chain (AL) amyloidosis is the most common acquired form. Patients typically present with a sensorimotor polyneuropathy, focal neuropathy such as carpal tunnel syndrome, or autonomic neuropathy. When neuropathy is the sole or dominant presenting symptom, the diagnosis is commonly delayed. With the advent of new drug therapies for AL amyloidosis and hATTR amyloidosis, including proteasome inhibitors, TTR silencers, and TTR protein stabilizers, the neurologist is uniquely positioned to diagnose neurologic manifestations of systemic amyloidosis, leading to earlier disease identification and treatment. This article reviews the epidemiology, clinical presentations, pathophysiology, diagnostic workup, and treatment of neuropathy in the setting of amyloidosis.

Download Full-text

Proteasome inhibitors in AL amyloidosis: focus on mechanism of action and clinical activity

Hematological Oncology ◽

10.1002/hon.2351 ◽

2016 ◽

Vol 35 (4) ◽

pp. 408-419 ◽

Cited By ~ 7

Author(s):

T. Jelinek ◽

E. Kryukova ◽

Z. Kufova ◽

F. Kryukov ◽

R. Hajek

Keyword(s):

Mechanism Of Action ◽

Proteasome Inhibitors ◽

Clinical Activity ◽

Al Amyloidosis

Download Full-text

High-Dose Pomalidomide and Dexamethasone Induce Rapid Responses In Patients With AL Amyloidosis Exposed To Alkylators, Immune Modulatory Drugs, and Proteasome Inhibitors

Blood ◽

10.1182/blood.v122.21.288.288 ◽

2013 ◽

Vol 122 (21) ◽

pp. 288-288 ◽

Cited By ~ 2

Author(s):

Giovanni Palladini ◽

Paolo Milani ◽

Marta Vidus Rosin ◽

Andrea Foli ◽

Giampaolo Merlini

Keyword(s):

Adverse Events ◽

Proteasome Inhibitors ◽

Median Number ◽

Fluid Retention ◽

Cardiac Response ◽

High Dose ◽

Al Amyloidosis ◽

Cell Transplant ◽

Heart Involvement ◽

Rapid Responses

Abstract In the present trial (NCT01510613) we treated with the combination of pomalidomide and dexamethasone (PDex) 27 patients previously exposed to alkylators and bortezomib. All the patients were refractory to the last line of therapy performed. The median number of prior treatments was 2 (range: 1-7). Seven patients (26%) also received lenalidomide, 4 (15%) thalidomide, 3 (11%) ixazomib, 2 (7%) bendamustine, and six (22%) underwent autologous stem cell transplant. Pomalidomide was administered continuously in 28-day cycles. A standard 3 + 3 dose escalation scheme was adopted: since no dose limiting toxicity was observed in the first 3 patients treated with pomalidomide 2 mg/day, the remaining received 4 mg/day. Dexamethasone was administered at 40 mg weekly, and at 20 mg in 13 subjects who had baseline fluid retention >3% of body weight and / or repetitive ventricular arrhythmias at Holter electrocardiography. Prophylactic aspirin was also administered. Nineteen (68%) patients had heart involvement and 8 (29%) were stage 3. The kidney was involved in 11 patients (39%), the soft tissues in 5 (18%), and 4 subjects (14%) had peripheral neuropathy. The median number of PDex cycles performed was 3 (range: 1-9), and treatment is ongoing in 20 patients. Overall 18 patients (67%) experienced severe (grade 3-4) adverse events: neutropenia (8, 30%), fluid retention (7, 26%, all with heart involvement), infection (3, 11%), worsening neuropathy (2, 7%, all with peripheral nervous system involvement), and rash (2, 7%). Five patients (18%) discontinued treatment due to adverse events. Overall, 18 patients (67%) achieved a hematological response, with 5 (18%) very good partial responses. Importantly, the median times to first response and to best response were 1.1 and 3.0 months, respectively. Moreover, of the 7 patients previously exposed to lenalidomide 5 responded to pomalidomide, and the 3 patients who were refractory to ixazomib responded, indicating that pomalidomide can overcome resistance to other immune modulatory drugs and a second-generation proteasome inhibitor. As previously reported with other immune modulatory drugs, pomalidomide was associated with a median 116% increase in NT-proBNP during cycle 1, preventing the assessment of cardiac response according to current criteria. A renal response was achieved in 3 of the 11 patients (27%) with kidney involvement. With a median follow-up of 6 months, 1 patient died 5 months after enrollment due to heart failure. “High-dose” (4 mg/day) pomalidomide combined with dexamethasone induces a high rate of rapid responses in patients previously exposed to alkylators, other immune modulatory drugs, and proteasome inhibitors, representing a powerful and rapid rescue treatment in AL amyloidosis. Further studies are warranted to elucidate whether different dosing schedules based on high-dose induction followed by low-dose (2 mg/day) maintenance might retain the high response rates and rapid action, while improving tolerability. Disclosures: Off Label Use: Pomalidomide in AL amyloidosis. Merlini:Millennium-Takeda: Honoraria; Pfizer: Honoraria.

Download Full-text

Profile of Long-Term Survivors in Multiple Myeloma

Blood ◽

10.1182/blood-2019-127519 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5522-5522

Author(s):

Florence Sabirou ◽

Gautier Defossez ◽

Pierre Ingrand ◽

Isabelle Azais ◽

Geraldine Durand ◽

...

Keyword(s):

Multiple Myeloma ◽

Single Agent ◽

Proteasome Inhibitors ◽

Al Amyloidosis ◽

First Line ◽

Term Survival ◽

Incident Cases ◽

Long Term Survivors

Background: The treatment revolution of multiple myeloma (MM) with the advent of novel therapies, proteasome inhibitors, immunomodulators and newer drugs lead to increased survival. Clinical characteristics at diagnosis of Long-term survivor (>5 years after the start of treatment) were described; however data regarding the profile of lines of treatment is very limited. The aim of this study was to describe the profiles of response of this population. Methods: The Poitou‐Charentes cancer registry has exhaustively registered incident cases of MM from 2008 to 2010. The follow-up date was December 31st, 2018. Patients (pts) alive after 5 years from the start of first line treatment were considered long-term survivors and their data were collected from their medical files. Three pts profiles were studied, very long responder (VLR) treated with a single line; long responder (LR) treated with [2-3] lines; and advanced (AdMM) [4 lines +[. Smoldering Myeloma, AL amyloidosis, lost to follow-up pts were excluded from the analysis. Results: Among the 396 MM registered, 177 were alive after 5 years, and 158 were included in the study. The mean age was 62.3 +/-11, sex ratio 1.2, 51% IgG, 25% IgA and 20% Light Chain isotype. ISS1 was 42%, 34% ISS2 and 14% ISS3. The median follow-up after the 5-year landmark was 39.9 +/-13 months and 52% pts died during follow-up. Overall, the median number of lines was 2.9 +/-2, 44% had at least one ASCT, 83% received Bortezomib, 72% Lenalidomide, 48% Thalidomide, 22% Pomalidomide, 20% Daratumumab (usually 3 lines+). VLR represented 19%, 27% LR, and 54% AdMM. In VLR group, 43% received a Bortezomib-based regimen (2 or 3 drugs) followed by ASCT, 47% a Melphalan-based regimen plus Thalidomide (MPT) or Bortezomib (MPV). In LR group, first line comprised: 39% Bortezomib-based regimen and ASCT versus 24% MPT and 15% MPV. Second line for LR group: 75% had Lenalidomide single agent or combination, 22% had a Bortezomib-based regimen, 17% had an ASCT. In the LR group, 45% received a third line: 40% Lenalidomide, mostly single agent, 25% a Bortezomib-based regimen and 3% had an ASCT. The AdMM group had a mean of 5.9 +/-1.6 lines (range 4 -11) and 56% of RR patients had at least one ASCT. Conclusion: Approximately 40% of MM were long-term survivors at 5 years from start of therapy in 2010, mainly on the basis of proteasome inhibitors and immunomodulators-based regimens plus use of ASCT. The vast majority of pts reached the 5 years cut-off with [4;+[ lines, and very few pts were real long-term survivors with an early prolonged control of Myeloma. Future perspective will look into 10 years long-term survival, including novel drug developments with the advent of immunotherapy. Disclosures Sabirou: AbbVie: Research Funding. Leleu:Janssen: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Merck: Honoraria; BMS: Honoraria.

Download Full-text

Autologous Stem Cell Transplant for AL Amyloidosis

Bone Marrow Research ◽

10.1155/2012/238961 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5 ◽

Cited By ~ 5

Author(s):

Vivek Roy

Keyword(s):

Stem Cell ◽

Amyloid Fibrils ◽

Stem Cell Transplant ◽

Plasma Cells ◽

Cell Clone ◽

Treatment Options ◽

Proteasome Inhibitors ◽

Autologous Stem Cell Transplant ◽

Al Amyloidosis ◽

Cell Transplant

AL amyloidosis is caused by clonal plasma cells that produce immunoglobulin light chains which misfold and get deposited as amyloid fibrils. Therapy directed against the plasma cell clone leads to clinical benefit. Melphalan and corticosteroids have been the mainstay of treatment for a number of years and the recent availability of other effective agents (IMiDs and proteasome inhibitors) has increased treatment options. Autologous stem cell transplant (ASCT) has been used in the treatment of AL amyloidosis for many years. It is associated with high rates of hematologic response and improvement in organ function. However, transplant carries considerable risks. Careful patient selection is important to minimize transplant related morbidity and mortality and ensure optimal patient outcomes. As newer more affective therapies become available the role and timing of ASCT in the overall treatment strategy of AL amyloidosis will need to be continually reassessed.

Download Full-text