**4.1 Daratumumab in untreated newly diagnosed multiple myeloma: transplant ineligible patients**

ALCYONE and MAIA are the two main trials which evaluated the efficacy of adding daratumumab in the standard treatment of untreated patients with multiple myeloma ineligible to transplant. ALCYONE enrolled 706 naive patients randomized to receive VMP alone or with daratumumab [26]. Each cycle had a duration of 42 days. In the control group, all the patients received up to nine cycles of subcutaneous bortezomib, administered at the dosage of 1.3 mg per square meter of body-surface area (twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2 through 9), oral melphalan (9 mg per square meter, once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg per square meter, once daily on days 1 through 4 of each cycle). In the experimental group, intravenous daratumumab at the usual dose of 16 mg/kg was administered with oral or intravenous dexamethasone at a dose of 20 mg once weekly in cycle 1, every 3 weeks in cycles 2 through 9, and every 4 weeks thereafter until disease progression or toxicity. Dexamethasone at a dose of 20 mg was substituted for prednisone on day 1 of each cycle. At 12 months, the PFS was 86.7% in the daratumumab group *vs* 76.0% in the control group. At the clinical data cut-off,

*Multiple Myeloma*

earlier and patients in the control group with a progression disease were offered daratumumab monotherapy. This may represent a bias in the interpretation of all the long-term results. Nevertheless, this trial showed how daratumumab could give an advantage also in combination with PIs-based regimens. The recorded responses are deep and durable. The main adverse events reported in the daratumumab group were thrombocytopenia and infusion-related reactions but none of them led to a

*3.1.3 Daratumumab in relapsed/refractory multiple myeloma in combination* 

*therapies: the experience from the Multiple Myeloma GIMEMA Lazio Group*

Fazio et al. performed a multicentre retrospective analysis of patients with relapsed/refractory multiple myeloma treated with IMiDs or IPs-based regimens containing daratumumab in the hospitals of the GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) network in the Italian region of Lazio [19]. Of 188 patients, sixty-five performed at least one cycle of therapy and were evaluable for hematologic response. The ORR was 81.97%; with four patients (6.56%) achieving a stringent complete response (sCR), 20 (32.79%) patients a complete response (CR), 5 (8.2%) patients a non-complete response (NCR), 13 (21.31%) patients a very good partial response (VGPR) and 8 (13.11%) patients a partial response (PR). After a median follow-up of 8.8 (range 0.23–22.3) months, 50 (42.37%) patients were alive maintaining response, eight (13.11%) patients presented a progression disease and one (1.64%) patients died. The overall survival and progression-free survival were 86.3% (95% CI, 79.2–94) and 70.8% (95% CI, 61.2–82), respectively. The most common grade 3 or 4 hematologic treatment-emergent adverse events (TAEs) included neutropenia, anemia and thrombocytopenia. The most common non-hematologic TAEs, of any grade, were infections, peripheral sensory neuropathy (7.6%) and fatigue (7.6%). Among the cases of infection, 17 (26%) patients presented pneumonia, eight (12%) patients FUO and five (7.7%) patients viral reactivation. Our preliminary results confirm data from POLLUX and CASTOR trial, suggesting that treatment with daratumumab in combination with lenalidomide or bortezomib plus dexamethasone is a highly effective and well-tolerated regimen to

treatment discontinuation higher than in the control group.

be considered for multiple myeloma patients after first relapse.

*therapies: with other novel agents*

RRMM to obtain the best response.

**young patients?**

*3.1.4 Daratumumab in relapsed/refractory multiple myeloma in combination* 

In the setting of heavily pretreated myeloma patients, daratumumab has shown good results also in association with novel drugs belonging to the last generations of IMiDs and IPs. Both combination of daratumumab with pomalidomide and dexamethasone and with carfilzomib and dexamethasone allowed to obtain deep and durable responses with a tolerable toxicity profile [20, 21]. Therefore, it seems reasonable to use daratumumab in combination with triplets or quadruplets in

**3.2 Daratumumab in relapsed/refractory multiple myeloma in combination therapy: after or before allogenic hematopoietic cell-transplantation for** 

Despite improvements in the MM outcome and in the depth and response duration following subsequent lines of therapy, MM remains an incurable disease. It is reasonable to consider allogenic (allo) hematopoietic cell transplantation (HCT) as a treatment strategy for young patients with high-risk disease and an available

**72**

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].
