Résumé
Introduction: Systemic Light-chain amyloidosis (AL) is a clonal plasma-cell disorder, and has therefore benefited from the numerous therapeutic advances in multiple myeloma (MM). Nonetheless, outcome of refractory AL patients remains dire, especially in patients with severe end-organ damage. Daratumumab, a monoclonal antibody directed against CD38, has yielded significant results in MM, but data in AL, although promising, are scarce.
Methods: Between November 2016 and July 2018, 15 relapsed or refractory patients with histologically proven AL from five different French centres from the Hauts-de-France region received ongoing daratumumab at the dose of 16 mg/kg, weekly for the first two cycles, twice a month from cycle 3-6, and monthly after cycle seven. All patients had, at least, previously received a proteasome inhibitor (PI) or immunomodulatory drug (IMiD). Efficacy and safety data were assessed retrospectively after required authorization (CNIL registration n°2197989).
Results: Fifteen patients with a median number of previous lines of two [1-5] were included. Overall, the population was frail, with a median ECOG of one [range: 0 - 3], CIRS comorbidity score of 14 [8 - 27] and Charlson score of four [1 - 8]. Three of the patients had symptomatic MM according to International Myeloma Working Group criteria. All had elevated free light chains (mean 536 mg/L [38 - 1411]). The mean number of organ involved per patient was three [1-6]; 67% had evidence of cardiac involvement, including Mayo-Clinic stage III in all patients but one; 60% had kidney involvement, including two patients on chronic haemodialysis. Patients received a median of six cycles [1 - 17]. The overall haematological response was 73%, with at least a very good partial response (VGPR) in 33% of cases. Best haematological response was achieved after one cycle [1 - 10]. Eleven patients were evaluable for organ response, which was achieved in 36% of patients, after a median 3.5 cycles [3 - 5]. Infusion-related reactions occurred in 33% of patients, all were grade I-II. Infection occurred in 47% of patients, 60% being grade III or greater. At last follow-up, 67% of patients were still on daratumumab; two patients died, one from progressive disease and another from infection.
Discussion: As previous results suggest, daratumumab yields promising results in relapsed AL patients in terms of both haematological and organ-response. Short-time to response is particularly striking in this study as it is a well-known determinant of outcome in AL. These results are particularly remarkable given the frailty and the severity of our population. Frailty indexes have long been used in haematology especially in MM where it is now established that an ECOG score ≥2 or a Charlson score ≥2 impairs overall survival. CIRS score has also been used in cancer patients, where the cut-off to predict mortality varies between 3-4 and 6-7 in chronic lymphocytic leukaemia and acute myeloid leukaemia, respectively. In our cohort, the median Charlson index was over two in 83% of patients and the CIRS was greater than six in all patients, emphasizing the frailty of this real-life AL-population. This may be explained by the extent of organ involvement and the multiple prior treatment received. All but one cardiac patients had Mayo stage III disease, 93% had two or more organs involved, and had dFLC>60mg/L at diagnosis. This indicates high-risk patients, who are less inclined to respond to treatment. Despite these high-risk characteristics, even with a short follow-up, we observed organ responses. As expected, the deeper the haematological response was, the more likely organ response was observed. Even though the general toxicity profile was favourable, the incidence of high-grade infection ought to be noted. Although it may be explained by a combination of factors (i.e. previous treatment, frailty, co-morbidities), infection could outweigh any benefit in terms of overall survival. Shorter treatment course, response or frailty-driven treatment strategies alongside prophylactic measures should therefore be evaluated prospectively in this high-risk population.
Conclusion: Single agent daratumumab shows promising results, yielding rapid and deep haematological responses, with an acceptable safety profile, in a frail real-life AL population. Nonetheless, close attention should be paid in the future to infection and its relation to frailty in this specific group of patients.