A deep hematologic response is associated with the highest probability of organ function and survival improvement in patients with AL amyloidosis. Bortezomib-based therapy is the primary therapy for patients with AL amyloidosis but less than 40% achieves a CR. Further improvement of hematologic response may be achieved by consolidation strategies but HDM-ASCT is associated with significant toxicity, and only a minority of AL patients is eligible for this treatment. Recent data indicate that even a short course of daratumumab (DARA) was able to induce hematologic responses in patients with relapsed or refractory AL. Thus, DARA may be a unique treatment to improve the outcomes of patients with AL amyloidosis.
To evaluate the feasibility and activity of a short course of daratumumab as a consolidation strategy, in patients with AL or LCDD which had achieved either PR or VGPR after completing their primary therapy, with bortezomib-based therapy.
The endpoint of this exploratory approach was improvement of response post completion of DARA consolidation. All patients received 4 weekly infusions of daratumumab 16 mg/kg with dexamethasone 20 mg. Pre-emptive therapy for IRR was given starting two days before the first infusion of DARA. In all patients next generation flow (NGF) according to Euroflow protocol was performed before and after consolidation
26 patients (23 AL and 3 with LCDD) received DARA consolidation. Median age is 67 and 73% were males. Kidneys and heart were involved in 80% and 73% respectively, baseline Mayo stage was 20%, 67% and 13% for stage 1,2 & 3 respectively. Baseline immunofixation in serum or urine was positive in all patients (19/23 of AL patients were lambda). Median time from start of first line therapy to DARA consolidation was 8 months and all patients had completed the planned bortezomib-based treatment. Before consolidation all patients were in either VGPR (23/23 AL patients and 2/3 LCDD patients) or in PR (1/3 LCDD patients); all patients had positive serum and/or urine immunofixation with or without abnormal FLC ratio. All but one patient received the planned 4 infusion of DARA. Mild IRR (Gr1) were observed in 3 patients. After consolidation with DARA, 42% of the patients (10/23 with AL and 1/3 with LCDD) achieved a CR. In 9/26 patients small monoclonal IgGk was observed 1 month post DARA and in all but one patient IgGk resolved at 2–3 months post DARA. The patient that received only one dose of daratumumab also achieved a CR. In all patients MRD by NGF was positive before DARA consolidation while DARA 6/11 patients in CR became MRDnegative. All patients that did not achieve a VGPR remained MRD positive. One patient with IgGk AL that remained with positive immunofixation after DARA was MRD(neg). Because of interference with daratumumab we repeated immunofixation, which 2 months after daratumumab became negative.
Consolidation with a short course of DARA can improve the depth of response in patients with AL or LCDD that have not achieved a CR after primary therapy, including MRD negative disease in some.
We will further explore this strategy in a formal clinical trial with a longer duration of daratumumab therapy so that CR and MRD negative rates may improve further.