Safety, tolerability, and response rates of daratumumab in relapsed AL amyloidosis: results of a phase 2 study

Sanchorawala, Vaishali; Sarosiek, Shayna; Schulman, Amanda; Mistark, Meredith; Migre, Mary Ellen; Cruz, Ramon; Sloan, J. Mark; Brauneis, Dina; Shelton, Anthony C

doi:10.1182/blood.2019004436

Cited by 122 publications

(120 citation statements)

References 24 publications

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“…In the near future, anti-plasma-cell immunotherapy, particularly daratumumab, will likely be added to these combinations in the search for a novel standard of care. It is possible that combinations of potent IMiDs and daratumumab and/or ixazomib will soon improve the treatment of relapsed/refractory patients [58-61].…”

Section: Resultsmentioning

confidence: 99%

Conventional Therapy for Amyloid Light-Chain Amyloidosis

Milani¹,

Palladini²

2020

Acta Haematol

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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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Section: Resultsmentioning

confidence: 99%

Conventional Therapy for Amyloid Light-Chain Amyloidosis

Milani¹,

Palladini²

2020

Acta Haematol

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“…Thus, the utility of sFLCR as a criterion for CR has been correctly questioned, 9 since extreme ratios are seen in the setting of highly immunosuppressive chemotherapy and a normal ratio does exclude residual disease. In addition, daratumumab, a therapeutic monoclonal antibody which is increasingly being used in patients with AL amyloidosis, 21‐23 results in substantial immunoparesis and impacts response evaluation using sFLCR despite low iFLC, as already recognized 22,23 . Individual studies have tested the prognostic role of several FLC measures as a marker for very deep responses, including how to deal with those patients with low baseline dFLC 14‐16 .…”

Section: Discussionmentioning

confidence: 99%

Refining amyloid complete hematological response: Quantitative serum free light chains superior to ratio

et al. 2020

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Response assessment in light chain (AL) amyloidosis is based on serum and urine monoclonal protein studies. Newly diagnosed patients (n = 373) who achieved very good partial response or complete response (CR) to first line therapy were assessed for the survival impact of each of the monoclonal protein studies. At end of therapy (EOT), negative serum/urine immunofixation (IFE) was achieved in 61% of patients, 72% achieved normal serum free light chain ratio (sFLCR), and the median involved free light chain (iFLC) and difference between involved to uninvolved light chain (dFLC) were 17 mg/L and 5 mg/L, respectively. Overall, 46% of patients achieved a CR at EOT. At EOT, iFLC ≤20 mg/L and dFLC ≤10 mg/L were additive in survival discrimination to negative serum/urine IFE and were independent predictors of overall survival. In contrast, normalization of sFLCR did not add survival discrimination to serum/urine IFE and was not independent predictor of survival. We propose a new definition for hematological CR to include serum/urine IFE negativity plus iFLC ≤20 mg/L or dFLC ≤10 mg/L, instead of the current definition of serum/urine IFE negativity and normal sFLCR. Complete response using dFLC ≤10 mg/L had the best performance in those with significant renal dysfunction and by light chain isotype, making it the preferred partner to IFE. Validation of these results in a multicenter cohort is warranted.

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“…These findings are also supported by our multivariate analysis demonstrating independent predictive value of immunofixation electrophoresis and iFLC. Free light chain levels can be affected by a number of clinical factors, including impaired renal function 11 , underlying inflammatory or infectious conditions 12 , and new monoclonal antibody therapies such as daratumumab and isatuximab 13 . Therefore free light chain measurements may not accurately reflect an individual's hematologic response.…”

Section: Discussionmentioning

confidence: 99%

Comparing measures of hematologic response after high-dose melphalan and stem cell transplantation in AL amyloidosis

et al. 2020

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Hematologic complete response (hemCR) in AL amyloidosis requires absence of monoclonal protein by immunofixation electrophoreses (IFE) and normal serum free light chain ratio (FLCR). Recent literature suggests that an involved free light chain (iFLC) <20 mg/L or difference in free light chains (dFLC) <10 mg/L may more accurately predict outcomes after treatment. We evaluated overall survival in 340 patients treated with high-dose melphalan and stem cell transplantation (SCT). Of 305 patients evaluable 6 months after SCT, 90 (30%) achieved hemCR, 132 (43%) dFLC <10 mg/L, 118 (39%) iFLC <20 mg/L, and 176 (58%) normal FLCR. Of 215 patients without hemCR, 65 (30%) had dFLC <10 mg/L and 86 (40%) had normal FLCR. Overall survival (OS) in those achieving dFLC <10 mg/L or normal FLCR without hemCR was inferior to those achieving hemCR (p = 0.013 and p = 0.001). OS was not significantly different in patients achieving iFLC <20 mg/L without hemCR compared with hemCR (p = 0.243). Of those with hemCR, OS was not significantly improved if dFLC <10 mg/L was also achieved (p = 0.852), but OS was improved for those with hemCR who also attained iFLC <20 mg/L (p = 0.009). Multivariate analysis demonstrated absence of monoclonal protein in IFE and iFLC <20 mg/L as independent predictors of survival. Attainment of hemCR remains a treatment goal, although achieving iFLC <20 mg/L may also predict improved OS.

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Safety, tolerability, and response rates of daratumumab in relapsed AL amyloidosis: results of a phase 2 study

Cited by 122 publications

References 24 publications

Conventional Therapy for Amyloid Light-Chain Amyloidosis

Conventional Therapy for Amyloid Light-Chain Amyloidosis

Refining amyloid complete hematological response: Quantitative serum free light chains superior to ratio

Comparing measures of hematologic response after high-dose melphalan and stem cell transplantation in AL amyloidosis

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