Consolidation with a Short Course of Daratumumab Improves Complete Response Rates in Patients with AL Amyloidosis or Lcdd
Authors: Kastritis Efstathios , Gavriatopoulou Maria , Despina Fotiou , Dialoupi Ioanna , Ziogas Dimitrios C. , Migkou Magdalini , Roussou Maria , Kanellias Nikolaos , Tselegkidi Maria Irini , Ntalianis Argyrios , Eleutherakis-Papaiakovou Evangelos , Papanota Aristea-Maria , Papanikolaou Asimina , Psimenou Erasmia , Gatou Anastasia , Gakiopoulou Charikleia , Spyropoulou-Vlachou Marilyn , Katopi Despina , Liacos Christine Ivy , Mparmparousi Despina , Terpos Evangelos , Dimopoulos Meletios A 
Published: October 2019

A deep hematologic response (i.e at least a very good partial hematologic response - hemVGPR or a complete hematologic response- hemCR) is associated with the highest probability of organ function and survival improvement in patients with AL amyloidosis. Bortezomib-based therapy is the mainstay of anti-clonal therapy for patients with AL amyloidosis and 70-80% of patients with previously untreated AL may achieve a hematologic response, however, hemVGPR or better is expected in less than 50%. Given that clones in AL are often small and indolent, further improvement of hematologic response may be achieved by consolidation strategies which may include high dose melphalan with autologous stem cell transplantation (HDM-ASCT); however, toxicity is significant and only a minority of patients is eligible for HDM-ASCT. New targets may provide new opportunities to eliminate the residual clonal plasma cells. Anti-CD38 targeting monoclonal antibody daratumumab has shown activity in myeloma and in AL amyloidosis with minimal toxicity. Specifically in AL, recent data indicate that even a short course of daratumumab was able to induce hematologic responses in several patients with relapsed or refractory AL. Thus, daratumumab may be a unique treatment to improve the outcomes of patients with AL amyloidosis. The endpoint was improvement of response 1 month In order to evaluate the feasibility and activity of a short course of daratumumab as a consolidation strategy, we administered 4 weekly infusions of daratumumab in consecutively treated patients at the Department of Clinical Therapeutics, Athens, Greece with AL or LCDD which had achieved either PR or VGPR after completing their primary therapy. Patients that had not achieved a response to primary therapy were excluded and received full dose salvage therapy. All patients received consolidation with 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 daratumumab that included low dose steroids (equivalent of 16 mg of methylprednisolone), H1 & H2 inhibitors and montelukast.

So far 17 patients (15 AL and 2 LCDD) have received daratumumab consolidation. Among patients with AL amyloidosis, median age is 67 (range and 73% were males, kidneys and heart were involved in 80% and in 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 (13/15 of AL patients were lambda). Median time from start of first line therapy to daratumumab consolidation was 9 months and all patients had completed the planned therapy of bortezomib-based treatment.

At the time of initiation of daratumumab, 16 patients were in VGPR and one in PR and the median level of dFLC was 12 mg/L, all had positive serum or urine immunofixation and in all patients next generation flow (NGF) according to Euroflow protocol was positive for the presence of MRD. Except for one patient, all the others received the planned 4 daratumumab infusion; the single patient that did not receive the planned therapy did so because of a severe infection that occurred 1 day after the first daratumumab infusion and was not considered daratumumab related. IRRs occurred in 3 patients and were mild (grade 1 in 2 and grade 2 in one patient); no IRRs occurred after the first infusion.

One month after completion of consolidation with daratumumab, median dFLC dropped to 5 mg/L and 41% of the patients improved their response: 37.5% from VGPR to hemCR and the one patients with PR to VGPR. Notably, small IgGkappa bands were found in 4 patients at one month post daratumumab. Among those that achieved a CR after daratumumab, 50% became MRD negative by NGF; however, further follow up is needed for the evaluation of organ responses after consolidation.

We conclude that consolidation with a short course of daratumumab can improve the depth of response in patients with AL or LCDD that have not achieved a hemCR after primary therapy. In addition, some patients may even achieve MRD negative disease status. 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.

Disclosures

Kastritis: Prothena: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Terpos:BMS: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; Novartis: Consultancy. Dimopoulos:Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria.