Daratumumab proves safe and highly effective in AL amyloidosis

Daratumumab (DARA) is a first in class anti-CD38 human antibody (IgG1κ) with efficacy in relapsed/refractory multiple myeloma (MM) as monotherapy and in combination with proteasome inhibitors and immunomodulatory drugs (IMiDs) (Dimopoulos et al, 2016; Palumbo et al, 2016). The current therapeutic approach for AL amyloidosis (AL) is to target the toxic amyloidogenic light chain-producing plasma cells. Achieving a reduction in the involved free light chains (i.e., a haematological response) is considered a critical endpoint as it is crucial to prevent further organ damage (Comenzo et al, 2012). The clonal plasma cells in AL express CD38, making DARA a potentially active treatment. Three reports have been published to date describing the tolerability and efficacy of DARA in previously treated AL patients (Kaufman et al, 2017; Sher et al, 2016; Gran et al, 2018). Herein, we report our experience with DARA in 20 consecutive patients with previously treated AL. Our study was approved by the Institutional Review Boards of the Cleveland Clinic (CC) and Karmanos Cancer Institute (KCI). We identified 20 consecutive patients (15 CC, 5 KCI) with relapsed AL treated with DARA monotherapy between December 2015 and December 2017. All patients had biopsy-proven AL amyloidosis. DARA was administered at a dose of 16 mg/kg weekly for eight doses, then every other week for eight doses, followed by every 4 weeks until disease progression. Premedication with acetaminophen, antihistamines and corticosteroids was administered to all patients to minimize the risk of DARA-associated infusion reactions. Montelukast was given at the discretion of the treating physician. Safety and efficacy data for all patients are presented in a descriptive fashion. No statistical analysis was conducted. The median age was 67 years (40–88) and 50% of the patients were male. Ten patients (50%) had cardiac involvement and seven patients had renal involvement (35%). Fifteen patients (75%) were assessable for haematological response by light chain criteria difference between involved and uninvolved light chains (dFLC) >50 mg/l. Three patients had symptomatic MM as defined by the current International Myeloma Working Group criteria (IMWG) with concurrent AL amyloidosis (Rajkumar et al, 2014). The median number of prior lines of therapy was three (1–10). The majority of our patients (65%) had previously undergone high dose melphalan and autologous haematopoietic cell transplantation (AHCT). Fifty-five percent of patients had had at least a partial haematological response (PR) as best response to prior therapy. Table 1 summarises baseline patient and disease characteristics. Haematological response was assessed according to consensus guidelines (Comenzo et al, 2012). At a median follow-up of 10 months, the overall haematological response rate was 86% in the 15 patients assessable for haematological response. Five patients (33%) achieved a complete response (CR) and eight patients (53%) attained a very good partial response (VGPR). One patient who was not considered to have measurable baseline disease (because both the involved and uninvolved light chains were elevated) had a decrease in the involved free light chain from 61·2 mg/l to 13·4 mg/l after 2 cycles of DARA. The median time to haematological response (≥PR) was 4 weeks. The overall survival was 80% (16 patients). At the time of this report, 13 patients (65%) remain on DARA monotherapy. The two patients who did not have a meaningful haematological response to DARA died of complications of their cardiac amyloidosis. One patient who achieved VGPR with DARA opted to discontinue therapy and passed away shortly after, due to complications of amyloid-related renal failure. One patient achieved haematological CR but a rise in N-terminal pro B-type natriuretic peptide (NT-pro BNP) on DARA prompted its discontinuation with subsequent improvement of his NT-pro BNP. One patient remains on observation off DARA for 8 months with stable kidney and haematological response. One of our patients with co-existent myeloma developed progressive bone disease, necessitating change of therapy. The median number of DARA infusions was 17 (6–34) with most patients tolerating therapy well. The most common adverse event was infusion reactions with two patients experiencing a grade 3 infusion reaction that did not recur upon further infusions. No grade 4 or 5 adverse events were recorded. There were few infections (all respiratory), owing partly to the low incidence of therapy-related myelosuppression. Table 2 lists the most common toxicities seen in our patient cohort according to the worst grade documented in each patient. Relapsed AL amyloidosis is challenging to treat given the tenuous clinical status of many patients, particularly those with cardiac involvement. Often, advanced symptoms preclude the use of certain anti-plasma cell therapies, particularly AHCT. Most patients are treated with alkylating agents and/or bortezomib initially. Treatment is more variable for relapsed disease. IMiDs as well as the proteasome inhibitor, ixazomib, are used in this setting, with response rates ranging between 40% to 60% in small prospective studies (Dispenzieri et al, 2012; Sanchorawala et al, 2017). Each of these drugs is associated with myelosuppression, and IMiDs are associated with cardiac side effects in AL Comenzo et al, 2012. Given its efficacy and tolerability in relapsed/refractory myeloma, daratumumab is an attractive potential therapy for AL amyloidosis. The one previously published series of consecutively treated AL patients demonstrated an overall haematological response rate of 76% (Kaufman et al, 2017). Two other reports, each describing two AL patients treated with DARA, provide further evidence of the potential utility of this agent (Sher et al, 2016; Gran et al, 2018). Our retrospective series of 20 consecutive relapsed AL patients treated with DARA monotherapy confirms its efficacy and tolerability in previously treated AL. It is apparent that the single agent activity of DARA in relapsed AL exceeds that seen in relapsed myeloma (Kaufman et al, 2017; Sher et al, 2016; Gran et al, 2018). The reason for this is unclear, but it may be related to either the lower plasma cell burden in AL compared to MM or to intracellular metabolic perturbations related to the inherent toxicity of misfolded light chain production (Sitia et al, 2007). Our study is limited by its retrospective design and relatively small size, though randomized trials are currently lacking for this patient population. Driven largely by the observed efficacy in relapsed AL, there is an ongoing randomized trial comparing standard chemotherapy (cyclophosphamide, bortezomib and dexamethasone) to chemotherapy plus DARA in newly diagnosed AL (NCT 03201965). Based on our initial experience and that of others, monoclonal antibody therapy targeting CD38 seems likely to herald a promising era in AL amyloidosis therapy. JK, AK, FJR, NB, JZ and JV: Research design. JK, AK, BT, NB, CJS, HDL, MAK, JR, SM, BMF, GD, JZ and JV: Acquisition of data. JK, AK, BT, JZ and JV: Analysis and interpretation of data. JK, AK: Drafting the paper. CJS, HDL, BMF, NB, GD, JZ and JV: Revising paper critically. JK, AK, JZ and JV: Approval of the submitted and final versions.