**7. Conclusions**

Daratumumab has showed proven efficacy and tolerability both in patients with RRMM and with NDMM, as confirmed in all the studies conducted during the last

*Multiple Myeloma*

**5.2 Daratumumab in SMM**

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

Smouldering myeloma is defined by a medullar infiltration of clonal plasmacells ≥10% in the absence of symptoms. According to the Mayo Clinic criteria, M-protein >2 g/dl, medullar infiltration ≥20% and free-light chain ratio > 20 define risk categories. Patients with one, two and three of these criteria are considered to be at low, intermediate and high risk with 5-year progression of 23% in the low risk, 47% in the intermediate risk and 82% in the high risk [41]. However, in spite of the important risk of transformation into symptomatic disease, current guidelines recommend "watch and wait" even in people with high and intermediate risk smouldering myeloma. Since the earlier intervention may delay progression, different studies are evaluating the use of new drugs in this subset of patients. Daratumumab could be the perfect drug, given the efficacy and the tolerability showed in other subsets. Based on the good results of the CENTAURUS trial, a phase II study for patients with intermediate and high risk smouldering multiple myeloma, randomly assigned, in a 1:1:1 ratio, to receive one of three different schedules of daratumumab [42], a phase III trial has been designed (NCT03301220). In this study, patients with high-risk smouldering myeloma are randomized either to receive subcutaneous daratumumab or to be just monitored. Daratumumab is administered according to the usual schedule, until 39 cycles or up to 36 months or until confirmed disease progression or unacceptable toxicity. This study recently completed the enrolment and the results are still awaited but all the most recent findings suggest that the anti-CD38 could be used with safety and efficacy also in smouldering myeloma.

the enrolment and the results are awaited (NCT03201965).

**6. The dark side of daratumumab: adverse events**

All pivotal studies leading to approval of daratumumab for the treatment of relapsed-refractory or newly diagnosed multiple myeloma showed a slight major susceptibility to infections in the studied populations. This risk seems to be due to the neutropenia and to the impairment of cellular immunity which is a direct consequence of targeting CD38 [43]. In the study by Nahi et al., nine patients out of 23 treated with daratumumab had viral and/or bacterial complications, mainly involving the respiratory tract. In these patients, assessment of circulating lymphocytes indicated a selective depletion of NK cells and viral reactivation after Daratumumab treatment. This finding is in line with data emerging from all the trials using anti-CD38-based regimens and suggest the necessity of screening for cytomegalovirus, Epstein–Barr virus and viral hepatitis before starting the treatment, therefore an adequate antiviral and antibacterial prophylaxis in the treated

**76**

years. A deep and durable response with easy-to-control side effects was obtained using this monoclonal antibody. The revolutionary power of this new drug could be also extended to patients with other plasma cell neoplasms, such as AL amyloidosis and SMM. Given the specific mechanisms of action of daratumumab targeting both clonal plasma-cells and bone-niche microenvironment, further studies are warranted to better understand the correct timing to introduce this monoclonal antibody in the context of a sequential therapy. On a side, the immune-mediated plasma-cell killing, induced by daratumumab in the early phase of treatment, acts as a debulking for the disease; on the other side, the restoration of the immune system may boost other metabolic effects of the monoclonal antibody, in a later phase of therapy, when the control of the disease is better [49]. Based on these hypothesis, the retreatment with daratumumab after a wash-out period may seem reasonable. Therefore, the anti-CD38 is a revolutionary weapon: understanding the best moment to use it in the battle against multiple myeloma is the great challenge of the future.
