**5. Daratumumab in other plasma cell neoplasms**

Given the promising results in the treatment of multiple myeloma with daratumumab, its use is being investigating also in the treatment of other plasma cell neoplasms, especially immunoglobulin light chain (AL) amyloidosis and smouldering myeloma (SMM).

### **5.1 Daratumumab in amyloidosis**

AL amyloidosis is due to the production of misfolded immunoglobulin light chain by an aberrant plasma-cells clone. This pathologic protein deposits in a variety of organs, usually heart and kidney, causing serious dysfunction. In spite of good results showed by treatment of this disease with PIs and IMiDs [31, 32], there is still a significant proportion of patients that do not respond to these agents. Based on a variety of reports showing safety and efficacy of daratumumab in patients with relapsed/refractory AL amyloidosis [33–36], some perspective trials have been recently conducted. NCT028441033 is a phase II study led at Boston Medical Center and aimed to evaluate safety and tolerability of daratumumab in a cohort of 25 participants with relapsed/ refractory AL amyloidosis. The preliminary results were encouraging, with only infusion reactions being reported as main side effect [37]. The ORR is instead the primary outcome of a multi-center phase II study across France and Italy (NCT02816476): it enrolled 35 patients with AL amyloidosis not in VGPR or better after previous treatment. The preliminary results showed an ORR of 59% with 44% of patients achieving

*Multiple Myeloma*

an event of disease progression or death had occurred in 88 (25.1%) patients in the daratumumab group *vs* 143 (40.2%) patients in the control group, with a hazardratio of 0.50 in favour of the first group. The superiority was even confirmed in the older patients, in those with a poor performance status and worse stage. It seemed to be also independent from impairment of renal and liver function which were quite frequent in the enrolled population. In spite of this general advantage given adding daratumumab, a prespecified subgroup analysis of progression-free survival showed that the D-VMP combination is not so effective in the overcome of the bad prognosis given by the high-risk cytogenetics (defined by t (4;14), t (14;16), del17p). The main adverse effect was represented by infections of the respiratory tract but they were not a cause of discontinuation of treatment. MAIA compared Rd. to daratumumab-Rd [27]. The trial enrolled 737 naïve patients: in cycles of 28 days, all of them received oral lenalidomide 25 mg on days 1 through 21 and oral dexamethasone 40 mg per week, until disease progression or toxicity. In the experimental group, daratumumab was added at a dose of 16 mg/kg once weekly during cycles 1 and 2, every 2 weeks during cycles 3 through 6, and every 4 weeks thereafter. At the median follow-up of 28 months, PFS was not reached in the daratumumab group and was 31.9 months in the control group. Disease progression or death occurred in 97 patients in the experimental group *vs* 143 in the control group, with a hazard-ratio of 0.56. Also in this trial, the benefit was maintained in older patients with worse performance status but not in the patients with high-risk cytogenetics. Pneumonia was recorded as the most frequent side effect in the experimental group but it did not influence the general outcome. Based on the exciting results of ALCYONE and MAIA, several ongoing trials throughout the world aim to evaluate the benefit of adding both subcutaneous and intravenous daratumumab to the different combinations of drugs used for the induction of multiple myeloma in naïve unfit patients (NCT03993912, NCT03742297, NCT03652064, NCT03217812, NCT04052880, NCT04009109, NCT03695744, NCT02918331). Some of these are designed to study possibility of combining the monoclonal antibody with the newest generations of IMiDs and IPs: NCT4009109 is a phase II trial with two arms based on induction with lenalidomide, ixazomib, daratumumab and dexamethasone; maintenance in arm 1 is with the only lenalidomide, in the arm 2 it is with lenalidomide, ixazomib and daratumumab. Ixazomib is a last-generation IPs which recently received the approval to be used in combination with lenalidomide and steroid in RRMM. The interim analysis of this phase II trial showed an overall

response rate (ORR) of 70%, with good molecular response [28].

**4.2 Daratumumab in untreated newly diagnosed multiple myeloma: transplant** 

The excellent results achieved in the population of unfit NDMM patients led to evaluate the efficacy of daratumumab also in the population of NDMM transplant eligible patients. CASSIOPEIA trial is the first largest study going in this direction: it enrolled 1085 patients across Europe, randomly assigned to the control arm with the use of VTD triplet or to the experimental arm adding daratumumab [29]. All patients received up to four 28-day, pre-transplant induction cycles and two 28-day, post-transplant consolidation cycles of subcutaneous bortezomib (administered according to the usual schedule), oral thalidomide (100 mg daily in all cycles), and oral or intravenous dexamethasone. Daratumumab was administered intravenously at a dose of 16 mg/kg of bodyweight once weekly in induction cycles 1 and 2 and once every 2 weeks during induction cycles 3 and 4 and consolidation. At 100 days post-transplant, the rate of sCR was higher in the daratumumab group than in the control group (29% *vs* 20%) and this superiority was maintained in older patients,

**74**

**eligible patients**

at least a VGPR [38]. These good results are confirmed by a report with the collaboration of our group [39]: 59 patients out of 72 with relapsed/refractory AL amyloidosis achieved a hematologic response after eight infusions of daratumumab, single agent or combined with bortezomib and lenalidomide, and the quality of this response improved with the continuation of therapy. The demonstration of the efficacy of daratumumab in the treatment of AL amyloidosis provided the rationale for exploring its use earlier in the disease course. Hossein Taghizadeh MA et al. presented the case of two patients with advanced cardiac involvement who achieved a normalization of light chain levels within one cycle of therapy with the anti-CD38, without any serious adverse events in spite of the cardiac dysfunction [40]. A phase III trial comparing cyclophosphamide, bortezomib and dexamethasone with or without daratumumab in the first-line treatment of AL amyloidosis has recently completed the enrolment and the results are awaited (NCT03201965).
