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

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,

**75**

*The Modern Age of Monoclonal Antibodies: The Revolution of Daratumumab*

(MASTER trial). The results of all these studies are awaited.

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 smoulder-

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

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

ing myeloma (SMM).

**5.1 Daratumumab in amyloidosis**

but not in patients with a higher stage disease and a higher risk cytogenetics. Also in this trial the main adverse events were represented by infections but none of them represented a cause of treatment discontinuation. Surprisingly, daratumumab went out to be associated with a reduction of the amount of collected stem cells CD34+ and the subsequent use of plerixafor, even if this aspect did not translate into a worse performance of the transplant. Recently, Voorhees et al. published the results of another study evaluating the use of daratumumab as first line in transplant eligible patients, the GRIFFIN trial [30]. In this phase II randomized trial, 207 enrolled patients received four 21-day induction cycles and two 21-day consolidation cycles of oral lenalidomide (25 mg daily on days 1–14), subcutaneous bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11), and oral dexamethasone (VRD), followed by maintenance with lenalidomide until toxicity or progression disease. Patients in the experimental group received daratumumab (16 mg/kg) on days 1, 8, and 15 of cycles 1 through 4 and day 1 of consolidation cycles and of maintenance cycles. After the end of post-transplant consolidation, the primary end-point of sCR was achieved in 42 patients in the experimental group *vs* 31 patients in the control group. Also the secondary end-points of overall response rate and rate of VGPR or better resulted higher in the daratumumab group. These good results deepened over time. The observed benefit was maintained also in the older population but not again in patients with a higher disease stage and with high-risk cytogenetics. As usually observed, also in this trial the experimental arm recorded a high rate of not statistically significant infections. Several ongoing trials aim to evaluate the use of daratumumab as first-line in transplant eligible NDMM patients: among these, PERSEUS is a promising ongoing phase III trial evaluating efficacy of daratumumab plus VRD *vs* VRD in terms of PFS, utilizing subcutaneous daratumumab to minimize toxicity. There are also few ongoing trials evaluating induction with daratumumab irrespective of transplant eligibility and some of them are based on MRD-driven therapies

*DOI: http://dx.doi.org/10.5772/intechopen.95406*

#### *The Modern Age of Monoclonal Antibodies: The Revolution of Daratumumab DOI: http://dx.doi.org/10.5772/intechopen.95406*

but not in patients with a higher stage disease and a higher risk cytogenetics. Also in this trial the main adverse events were represented by infections but none of them represented a cause of treatment discontinuation. Surprisingly, daratumumab went out to be associated with a reduction of the amount of collected stem cells CD34+ and the subsequent use of plerixafor, even if this aspect did not translate into a worse performance of the transplant. Recently, Voorhees et al. published the results of another study evaluating the use of daratumumab as first line in transplant eligible patients, the GRIFFIN trial [30]. In this phase II randomized trial, 207 enrolled patients received four 21-day induction cycles and two 21-day consolidation cycles of oral lenalidomide (25 mg daily on days 1–14), subcutaneous bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11), and oral dexamethasone (VRD), followed by maintenance with lenalidomide until toxicity or progression disease. Patients in the experimental group received daratumumab (16 mg/kg) on days 1, 8, and 15 of cycles 1 through 4 and day 1 of consolidation cycles and of maintenance cycles. After the end of post-transplant consolidation, the primary end-point of sCR was achieved in 42 patients in the experimental group *vs* 31 patients in the control group. Also the secondary end-points of overall response rate and rate of VGPR or better resulted higher in the daratumumab group. These good results deepened over time. The observed benefit was maintained also in the older population but not again in patients with a higher disease stage and with high-risk cytogenetics. As usually observed, also in this trial the experimental arm recorded a high rate of not statistically significant infections. Several ongoing trials aim to evaluate the use of daratumumab as first-line in transplant eligible NDMM patients: among these, PERSEUS is a promising ongoing phase III trial evaluating efficacy of daratumumab plus VRD *vs* VRD in terms of PFS, utilizing subcutaneous daratumumab to minimize toxicity. There are also few ongoing trials evaluating induction with daratumumab irrespective of transplant eligibility and some of them are based on MRD-driven therapies (MASTER trial). The results of all these studies are awaited.
