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

Palladini, Giovanni; Milani, Paolo; Foli, Andrea; Basset, Marco; Russo, Francesca; Perlini, Stefano; Merlini, Giampaolo

doi:10.1182/blood-2016-12-756528

Cited by 82 publications

(57 citation statements)

References 15 publications

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“…43,44 Renal response criteria, based on a 30% or more decrease in proteinuria or below 0.5 g/24 h without renal progression, were defined after the start of this study and applied retrospectively. 36 Preliminary data indicated hematologic (ORR, 52% in the RP2/3D cohort) as well as early organ responses (56% in the RP2/3D cohort) in this heavily pretreated population (median, 3 prior lines of therapy [range, [1][2][3][4][5][6][7][8]). Importantly, responses appeared durable, with 60% of patients treated at the RP2/3D remaining in response at 1 year.…”

Section: Discussionmentioning

confidence: 99%

“…4 Although there are no currently approved therapies for patients with relapsed or refractory disease, bortezomib, lenalidomide, and pomalidomide, all of which are approved for the treatment of MM, are effective. 5,[7][8][9][10][11][12] Achievement of a hematologic response is required and predictive of an organ response (which can take up to a year), 13 as well as prolonged survival. 14,15 Response criteria were established in 2005 16 and updated in 2012 based on the difference between levels of involved and uninvolved free light chains (dFLC) 17 ; these updated criteria were later validated.…”

Section: Introductionmentioning

confidence: 99%

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A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis

Sanchorawala

Palladini

Kukreti

et al. 2017

Blood

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116

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This phase 1/2 study assessed the safety, tolerability, and preliminary efficacy of the oral proteasome inhibitor (PI) ixazomib in patients with relapsed/refractory immunoglobulin light chain (AL) amyloidosis. Ixazomib was administered to adult patients with relapsed/refractory AL amyloidosis after 1 or more prior lines of therapy (including bortezomib) on days 1, 8, and 15 of 28-day cycles, for up to 12 cycles. Patients with less than partial response after 3 cycles received oral dexamethasone (40 mg, days 1-4) from cycle 4. A 3+3 dose-escalation phase was followed by 2 expansion cohorts (PI-naive and PI-exposed patients) at the maximum tolerated dose (MTD). Twenty-seven patients were enrolled: 11 during dose escalation (6 at 4.0 mg and 5 at 5.5 mg) and 16 during dose expansion (4.0 mg). Three patients experienced dose-limiting toxicities: 1 at 4.0 mg and 2 at 5.5 mg; the MTD was determined as 4.0 mg. Most common adverse events (AEs) included nausea, skin and subcutaneous tissue disorders (SSTD), diarrhea, and fatigue; grade 3 or higher AEs included dyspnea, fatigue, and SSTD. Overall, the hematologic response rate was 52% in patients treated at the MTD (n = 21). Organ responses were seen in 56% of patients (5 cardiac, 5 renal). Median hematologic progression-free survival was 14.8 months; 1-year progression-free and overall survival rates were 60% and 85%, respectively (median follow-up, 16.9 months). Weekly oral ixazomib appears to be active in patients with relapsed/refractory AL amyloidosis, with a generally manageable safety profile. The study was registered at clinicaltrials.gov as #NCT01318902. A phase 3 study is ongoing (#NCT01659658).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis

Sanchorawala

Palladini

Kukreti

et al. 2017

Blood

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116

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“…In the relapsed refractory population, treatment with IMiDs demonstrated ORR in the range of 50 to 70%, although a smaller proportion of patients achieved CR 42, 43 . However, IMiD-based regimens should be used with caution in patients with proteinuria.…”

Section: Treatmentmentioning

confidence: 98%

“…Immunomodulatory agents (IMiDs), including thalidomide 41 , lenalidomide 42 , and pomalidomide 43 , have shown significant activity in patients with relapsed refractory AL amyloidosis with the hypothesis that these drugs can overcome the resistance to alkylating agent therapy. In the relapsed refractory population, treatment with IMiDs demonstrated ORR in the range of 50 to 70%, although a smaller proportion of patients achieved CR 42, 43 .…”

Section: Treatmentmentioning

confidence: 99%

Recent advances in understanding and treating immunoglobulin light chain amyloidosis

2018

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Immunoglobulin (Ig) light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by misfolded Ig light chain deposition in vital organs of the body, resulting in proteotoxicity and organ dysfunction. Owing to its diverse clinical presentations and a tendency to mimic common medical conditions, AL amyloidosis is often diagnosed late and results in dismal outcomes. Early referral to a specialized center with expertise in management of AL amyloidosis is always recommended. The availability of sensitive biomarkers and novel therapies is reforming our approach to how we manage AL amyloidosis. Treatment for patients with AL amyloidosis should be risk-adapted and customized on the basis of individual patient characteristics. In the future, approaches directed at amyloid fibril clearance in combination with agents that target plasma cells will be needed both to eradicate the malignant clone and to establish organ responses.

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“…The median OS and PFS were 26 and 16 months, respectively. The median time to response was 1 month [94]. …”

Section: Immunomodulatory Drugsmentioning

confidence: 99%

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

Vaxman

Gertz

2019

Acta Haematol

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

Abstract: 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.

Cited by 82 publications

References 15 publications

A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis

A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis

Recent advances in understanding and treating immunoglobulin light chain amyloidosis

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

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