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    Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis

  • 1.

    Lousada I, et al. Light chain amyloidosis: Patient experience survey from the Amyloidosis Research Consortium. Adv Ther 2015; 32:920928. doi: 10.1007/s12325-015-0250-0

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Dispenzieri A, et al. Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood 2004; 104:18811887. doi: 10.1182/blood-2004-01-0390

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Palladini G, et al. A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood 2014; 124:23252332. doi: 10.1182/blood-2014-04-570010

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Venner CP, et al. Cyclophosphamide, bortezomib, and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival. Blood 2012; 119:43874390. doi: 10.1182/blood-2011-10-388462

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Mikhael JR, et al. Cyclophosphamide-bortezomibdexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood 2012; 119:43914394. doi: 10.1182/blood-2011-11-390930

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Palladini G, et al. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood 2015; 126:612615. doi: 10.1182/blood-2015-01-620302

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Kaufman GP, et al. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood 2017; 130:900902. doi: 10.1182/blood-2017-01-763599

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Sanchorawala V, et al. Safety, tolerability, and response rates of daratumumab in relapsed AL amyloidosis: Results of a phase 2 study. Blood 2020; 135:15411547. doi: 10.1182/blood.2019004436

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Kastritis E, et al. Daratumumab-based treatment for immunoglobulin light-chain amyloidosis. N Engl J Med 2021; 385:4658. doi: 10.1056/NEJMoa2028631

  • 10.

    Palladini G, et al. Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: Safety run-in results of ANDROMEDA. Blood 2020; 136:7180. doi: 10.1182/blood.2019004460

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Landau H, et al. Long-term event-free and overall survival after risk-adapted melphalan and SCT for systemic light chain amyloidosis. Leukemia 2017; 31:136142. doi: 10.1038/leu.2016.229

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    • Search Google Scholar
    • Export Citation

ANDROMEDA: Incorporating Daratumumab into Upfront Treatment for AL Amyloidosis Accelerates Therapeutic Progress by Light Years

  • 1 Heather Landau is Director of the Amyloidosis Program with the Adult Bone Marrow Transplant Service, an Associate Member of the Memorial Sloan Kettering Cancer Center, and Associate Professor of Clinical Medicine with Weill Cornell Medical College, New York, NY.
Full access

Monoclonal immunoglobulin (Ig)/light chain (AL)-associated systemic amyloidosis is caused by clonal plasma cells producing abnormal Ig light chains that misfold into amyloid fibrils, deposit in vital organs, disrupt organ function, and if left untreated, ultimately result in death. Given its insidious onset and nonspecific symptomatology, delay in AL amyloidosis diagnosis is unfortunately typical (1). The prognosis of patients is primarily driven by an advanced organ, specifically cardiac involvement (2). The kidney is affected in 70% of patients manifesting as proteinuria and progressive kidney dysfunction, which leads to the need for kidney replacement therapy in 15%–30% of patients (3). Rapid and deep hematologic responses to plasma cell-directed therapy are critical to preserve organ function and reverse organ deterioration.

The off-label standard-of-care treatment for newly diagnosed patients in the United States has been a combination of a proteasome inhibitor (bortezomib), an alkylator (cyclophosphamide), and steroids (dexamethasone) (VCD) (46). In the largest retrospective series of 230 patients treated with VCD, the hematologic overall response rate (ORR) was 60% (complete response [CR] 23%). Organ responses were suboptimal and often delayed (6). In 2015, the anti-CD38 monoclonal antibody daratumumab was approved by the US Food and Drug Administration (FDA) to treat relapsed/refractory multiple myeloma. Daratumumab, a human IgG1κ monoclonal antibody, binds to CD38-expressing cells and induces tumor cell death through various immune-mediated actions. CD38 is overexpressed on amyloidogenic plasma cells, making it a rational target.

In a small series of 25 patients, ORR was 76% with one-third of patients achieving CR (7). Since then, prospective studies of daratumumab in relapsed disease showed rapid (median time to response 1–4 weeks) and deep hematologic responses (8). Given impressive efficacy in the relapse setting, daratumumab was evaluated in a large randomized phase 3 study of almost 400 newly diagnosed patients treated with VCD, with or without daratumumab (ANDROMEDA, ClinicalTrials.gov: NCT03201965). The addition of the monoclonal antibody resulted in significant improvement in ORR (92% vs. 77%; CR 53% vs. 18%), and major organ deterioration progression-free survival favored the quadruplet arm (hazard ratio [HR] for major organ deterioration, hematologic progression, or death: 0.58; 95% confidence interval [CI], 0.36 to 0.93; p = 0.02) (Figure 1). The quadruplet was also associated with doubling of organ responses at 6 months (cardiac response 42% vs. 22%, renal response 53% vs. 24%) (9). Patients achieved responses faster and stayed on therapy longer in the quadruplet arm (10). Based on these data, the FDA endorsed daratumumab in combination with VCD (dara-VCD) in a historic approval as the first and only FDA-approved drug for AL amyloidosis on January 15, 2021.

Figure 1.
Figure 1.

Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis

Citation: Kidney News 13, 10/11

The ANDROMEDA trial represents therapeutic progress at warp speed. Prior to these data, a CR rate of 53% had only been achieved with high-dose melphalan followed by autologous hematopoietic cell transplant (AHCT) plus bortezomib-based consolidation, which is therapy available to only a very select patient population representing 25% of all patients (11). Even then, organ responses were typically appreciable over months to years. With the use of daratumumab upfront, more rapid organ recovery may increase the pool of AHCT candidates. Alternatively, if the goal is hematologic CR, and that can be achieved with daratumumab-based therapy, perhaps fewer patients will require AHCT and be spared the associated toxicity. Time will tell how durable the responses to dara-VCD will be.

The ANDROMEDA trial represents therapeutic progress at warp speed.

References

  • 1.

    Lousada I, et al. Light chain amyloidosis: Patient experience survey from the Amyloidosis Research Consortium. Adv Ther 2015; 32:920928. doi: 10.1007/s12325-015-0250-0

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Dispenzieri A, et al. Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood 2004; 104:18811887. doi: 10.1182/blood-2004-01-0390

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Palladini G, et al. A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood 2014; 124:23252332. doi: 10.1182/blood-2014-04-570010

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Venner CP, et al. Cyclophosphamide, bortezomib, and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival. Blood 2012; 119:43874390. doi: 10.1182/blood-2011-10-388462

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Mikhael JR, et al. Cyclophosphamide-bortezomibdexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood 2012; 119:43914394. doi: 10.1182/blood-2011-11-390930

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Palladini G, et al. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood 2015; 126:612615. doi: 10.1182/blood-2015-01-620302

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Kaufman GP, et al. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood 2017; 130:900902. doi: 10.1182/blood-2017-01-763599

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Sanchorawala V, et al. Safety, tolerability, and response rates of daratumumab in relapsed AL amyloidosis: Results of a phase 2 study. Blood 2020; 135:15411547. doi: 10.1182/blood.2019004436

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Kastritis E, et al. Daratumumab-based treatment for immunoglobulin light-chain amyloidosis. N Engl J Med 2021; 385:4658. doi: 10.1056/NEJMoa2028631

  • 10.

    Palladini G, et al. Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: Safety run-in results of ANDROMEDA. Blood 2020; 136:7180. doi: 10.1182/blood.2019004460

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Landau H, et al. Long-term event-free and overall survival after risk-adapted melphalan and SCT for systemic light chain amyloidosis. Leukemia 2017; 31:136142. doi: 10.1038/leu.2016.229

    • Crossref
    • Search Google Scholar
    • Export Citation
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