**3. Daratumumab in relapsed/refractory multiple myeloma**

Approval of daratumumab by regulatory bodies was made possible thanks to clinical trials evaluating its use in RRMM. Patients with RRMM still represent the patients best benefitting from this monoclonal antibody, both as single agent and in combination with other agents (**Table 1a**).

#### **3.1 Daratumumab in relapsed/refractory multiple myeloma as single agent**

GEN501 and SIRIUS are the two main trials who led to approval of monotherapy with daratumumab. Both studies enrolled patients with RRMM: patients in GEN501 had relapsed after or were refractory to ≥2 prior lines of therapy, including inhibitors of proteasome (PIs), immunomodulatory drugs (IMiDs), chemotherapy and autologous stem cell transplantation (ASCT); patients in SIRIUS had relapsed after ≥3 lines of therapy, including a PI and a IMiDs or were double refractory to the most recently received PI and IMiDs. The primary endpoint of GEN501 was evaluation of safety while SIRIUS was designed to first evaluate overall response rate (ORR). Data regarding 148 patients from pooled analysis of the two trials confirmed how daratumumab, at the dosage of 16 mg/kg, is effective and safe in a population of heavily pretreated patients [12]. With a median number of 12 infusions, the ORR was 31.1%. At the time of the analysis, after a median follow-up of 20.7 months, the progression free survival (PFS) was 4 months, with a 12-month PFS rate of 22%. Stratifying the patients by the response according to International Myeloma Working Group, the PFS and the overall survival (OS) went out to be 15 months and not reached respectively for responders, 3 months and 18.5 months for patients with a stable disease or minimal response, 0.9 months and 3.7 months for non-responders. The median duration of response was 7.6 months and it deepened and improved in patients continuing daratumumab.

*Multiple Myeloma*

**Figure 1.**

Daratumumab binds CD38, killing tumour cells via Fc-dependent immune effector

*Mechanism of action of daratumumab. Daratumumab binds CD38, killing myeloma cells via Fc-dependent immune effector mechanisms: CDC, ADCC and ADCP. Daratumumab also inhibits enzymatic activity of* 

The anti-tumour activity of Daratumumab does not depend only on the direct action on plasma cells but also on the interaction with other lymphoid and myeloid cells with a weak expression of CD38: NK cells, B and T regulatory cells and CD8+ effector cells. Krejcik et al. have demonstrated that bone marrow and peripheral blood from patients on treatment with Daratumumab present low levels of regulatory cells and high levels of NK and CD8+ effector cells. This monoclonal antibody may interfere with the immunosuppressive microenvironment in the multiple myeloma bone niche, in favour of major susceptibility for the plasma cells to the NK

Daratumumab is usually administered at the dosage of 16 mg/kg weekly for 8 weeks then every 2 weeks for 16 weeks and every 4 weeks thereafter until progression of disease. The administration on a mg/kg basis is due to the observation that distribution and clearance of daratumumab depends on bodyweight. It seems to be not influenced by age, gender, race, mild renal and liver impairment. To our knowledge, the extra-liver metabolism of daratumumab is the reason for the absence of

The efficacy and safety of this schedule have been demonstrated by two studies involving patients with relapsed/refractory multiple myeloma (RRMM) treated with the anti-CD38 monoclonal antibody as single agent: GEN501 and SIRIUS. GEN501 was a phase I/II, open-label, multicenter study. In the dose-escalation part, sequential cohorts of patients received intravenous doses of daratumumab ranging from 0.005 to 24 mg/kg, administered over 6–8 h. In the dose-expansion

mechanisms including complement-dependent cytotoxicity (CDC), antibodydependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) [5]. The complement activation seems to be the most effective mechanism used by Daratumumab [6]: the Fc tail of the drug binds the activating factor C1q leading both to ultimate activation of membrane attack complex and to deposition of C3b on the surface of multiple myeloma plasma cells. The activation of membrane attack complex causes osmotic lysis of cells while the deposition of complement factors attracts phagocytic cells. The recruitment of immune effector cells is also boosted by the

release of circulating factors such as C3 and C5a (**Figure 1**).

*CD38, downregulating intracellular Ca2+ trafficking.*

and CD8+ cells toxicity [7].

interactions with other drugs.

**2. Pharmacokinetics**

**68**


*RRMM: Relapsed/Refractory Multiple Myeloma, IV: intravenous, SC: subcutaneous, Rd.: lenalidomidedexamethasone, Vd: bortezomib-dexamethasone, ORR: Overall Response Rate, Maximum CTrough: Maximum Concentration Trough, AEs: Advese Events, PFS: Progression Free Survival, NDMM: Newly Diagnosed Multiple Myeloma, VMP: bortezomib-melphalan-dexamethasone, VTd: bortezomib-thalidomide-dexamethasone, RVd: lenalidomide-botrezomib-dexamethasone, sCR: stringent Complete Response.*

#### **Table 1.**

*Overview of main trials using Daratumumab in (a) RRMM, (b) NDMM.*

#### *3.1.1 Daratumumab in relapsed/refractory multiple myeloma in combination therapies: with IMiDs*

Efficacy of daratumumab seems to be strengthened by other drugs used for multiple myeloma, given the synergic action on the immune system. As said before, the anti-CD38 may stimulate NK and T-cells, restoring "tumor suppressive immunological surveillance". Also IMiDs could increase the amount of regulatory cells in the bone niche, through inhibition of some transcriptional factors (Ikaros and Aialos) and the subsequent production of interleukin 2 [13]. Furthermore, some studies show that the main target of daratumumab is upregulated by action of IMiDs [14]. NCT01615029 was the first trial exploring the applicability of these laboratory observations, investigating efficacy of daratumumab in combination with lenalidomide and dexamethasone (Rd) [15]. It was a phase 1/2 study addressed to patients with relapsed multiple myeloma: phase 1 was a dose-escalation study in which the dose of 16 mg/kg for daratumumab was again determined; phase 2 was a dose-expansion study using the recommended dose of the first part. The three drugs were administered in cycle of 28 days: daratumumab was given according to the standard schedule, lenalidomide at 25 mg/day from days 1 to 21 of each cycle and dexamethasone at 40 mg/week. This combination revealed to be safe and very effective: the 18-months PFS rate was 72% and ORR was 81%, in this case too with an improvement of responses in time. To evaluate the advantage of adding daratumumab to a regimen with lenalidomide and dexamethasone, from 2014 to 2015, a phase III, randomized trial was carried out across Europe, Northern America and Asia [16]. The POLLUX trial enrolled 569 patients with multiple myeloma who had

**71**

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

received one or more previous lines of therapy: 286 were assigned to the daratumumab group (daratumumab plus lenalidomide and dexamethasone) and 283 to the control group (lenalidomide and dexamethasone). Also in this trial, each cycle was of 28 days, with daratumumab administered according to the usual schedule, lenalidomide at 25 mg/day from days 1 to 21 of each cycle and dexamethasone at a dose of 40 mg weekly. At 12 months, the PFS rate was 83.2% in the daratumumab group *vs* 60.1% in the control group. In a sub analysis, this extension of PFS in the experimental group went out to be independent from the number of previous lines of therapy and from the previous exposure to lenalidomide, even if the paucity of refractory patients to IMiDs enrolled in this trial may represent a bias. After a follow-up of 13.5 months, progression disease or death occurred in 53 patients in the daratumumab group *vs* 116 patients in the control arm, with a hazard ratio of 0.37 in favour of the first group. Also in this case, an improvement of deepness of molecular response was observed with continuation of therapy with the monoclonal antibody and it translated in a longer survival. Indeed, 22.4% of patients in the experimental group had results below the threshold for minimal residual disease (MRD), compared to 4.6% in the control group. Neutropenia, diarrhea and infusional reactions were the main adverse events reported in the experimental arm with a higher incidence than in the control group but, in spite of that, the rate of grade 3 and grade 4 infections was not so different. In conclusion, POLLUX trial confirmed the efficacy and safety of adding daratumumab to a regimen with IMiDs and high-dose steroid. Furthermore, the excellent results below the threshold for minimal residual disease suggest that minimal residual disease negativity could

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

Some *in-vitro* studies have shown that not only IMiDs but also PIs interact with daratumumab in a synergic way, strengthening its effect. An assay performed by the Dutch group [14] evaluated the rate of lysis in samples of bone marrow mononuclear cells from 16 multiple myeloma patients incubated with medium containing either daratumumab, lenalidomide and bortezomib or just one drug. The rate of lysis went out to be higher in the samples with the addition of daratumumab, showing that not only lenalidomide but also bortezomib enhance the effect of this monoclonal antibody by sensitizing the cells to the antibody-mediated lysis. The "lysis effect" was even better in cells from patients who previously showed refractoriness to IMiDs or IPs, suggesting that immunomodulatory effects of daratumumab may restore host susceptibility to anti-myeloma agents. Based on a phase 1b trial in which daratumumab showed encouraging results in combination with PIs-based regimens in naive patients [17], a phase 3 trial randomized patients with relapsed and/or refractory multiple myeloma to a treatment with only bortezomib and dexamethasone or with the addition of daratumumab [18]. Of 498 patients, 251 were assigned to the daratumumab group and 247 to the control group. Each cycle had a duration of 21 days. Daratumumab was administered at the usual dosage of 16 mg/ kg once per week during cycles 1 to 3, once every 3 weeks during cycles 4 to 8 and once every 4 weeks thereafter until toxicity or progression disease. Dexamethasone was given for a total dose of 160 mg per cycle and bortezomib was administered in the subcutaneous formulation at the dosage of 1.3 mg per square meter on days 1, 4, 8 and 11 of cycles 1 to 8. The 12-month rate of PFS was 60.7% in the experimental group and 26.9% in the control group. After a follow up of 7.4 months, progression disease or death occurred in 67 patients in the daratumumab group *vs* 122 in the control group. Given the results of the interim analysis, the trial was unblended

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

represent a goal also for RRMM patients.

*therapies: with PIs*

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

received one or more previous lines of therapy: 286 were assigned to the daratumumab group (daratumumab plus lenalidomide and dexamethasone) and 283 to the control group (lenalidomide and dexamethasone). Also in this trial, each cycle was of 28 days, with daratumumab administered according to the usual schedule, lenalidomide at 25 mg/day from days 1 to 21 of each cycle and dexamethasone at a dose of 40 mg weekly. At 12 months, the PFS rate was 83.2% in the daratumumab group *vs* 60.1% in the control group. In a sub analysis, this extension of PFS in the experimental group went out to be independent from the number of previous lines of therapy and from the previous exposure to lenalidomide, even if the paucity of refractory patients to IMiDs enrolled in this trial may represent a bias. After a follow-up of 13.5 months, progression disease or death occurred in 53 patients in the daratumumab group *vs* 116 patients in the control arm, with a hazard ratio of 0.37 in favour of the first group. Also in this case, an improvement of deepness of molecular response was observed with continuation of therapy with the monoclonal antibody and it translated in a longer survival. Indeed, 22.4% of patients in the experimental group had results below the threshold for minimal residual disease (MRD), compared to 4.6% in the control group. Neutropenia, diarrhea and infusional reactions were the main adverse events reported in the experimental arm with a higher incidence than in the control group but, in spite of that, the rate of grade 3 and grade 4 infections was not so different. In conclusion, POLLUX trial confirmed the efficacy and safety of adding daratumumab to a regimen with IMiDs and high-dose steroid. Furthermore, the excellent results below the threshold for minimal residual disease suggest that minimal residual disease negativity could represent a goal also for RRMM patients.

## *3.1.2 Daratumumab in relapsed/refractory multiple myeloma in combination therapies: with PIs*

Some *in-vitro* studies have shown that not only IMiDs but also PIs interact with daratumumab in a synergic way, strengthening its effect. An assay performed by the Dutch group [14] evaluated the rate of lysis in samples of bone marrow mononuclear cells from 16 multiple myeloma patients incubated with medium containing either daratumumab, lenalidomide and bortezomib or just one drug. The rate of lysis went out to be higher in the samples with the addition of daratumumab, showing that not only lenalidomide but also bortezomib enhance the effect of this monoclonal antibody by sensitizing the cells to the antibody-mediated lysis. The "lysis effect" was even better in cells from patients who previously showed refractoriness to IMiDs or IPs, suggesting that immunomodulatory effects of daratumumab may restore host susceptibility to anti-myeloma agents. Based on a phase 1b trial in which daratumumab showed encouraging results in combination with PIs-based regimens in naive patients [17], a phase 3 trial randomized patients with relapsed and/or refractory multiple myeloma to a treatment with only bortezomib and dexamethasone or with the addition of daratumumab [18]. Of 498 patients, 251 were assigned to the daratumumab group and 247 to the control group. Each cycle had a duration of 21 days. Daratumumab was administered at the usual dosage of 16 mg/ kg once per week during cycles 1 to 3, once every 3 weeks during cycles 4 to 8 and once every 4 weeks thereafter until toxicity or progression disease. Dexamethasone was given for a total dose of 160 mg per cycle and bortezomib was administered in the subcutaneous formulation at the dosage of 1.3 mg per square meter on days 1, 4, 8 and 11 of cycles 1 to 8. The 12-month rate of PFS was 60.7% in the experimental group and 26.9% in the control group. After a follow up of 7.4 months, progression disease or death occurred in 67 patients in the daratumumab group *vs* 122 in the control group. Given the results of the interim analysis, the trial was unblended

*Multiple Myeloma*

**(a) RRMM**

**(b) NDMM**

**Table 1.**

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

Efficacy of daratumumab seems to be strengthened by other drugs used for multiple myeloma, given the synergic action on the immune system. As said before, the anti-CD38 may stimulate NK and T-cells, restoring "tumor suppressive immunological surveillance". Also IMiDs could increase the amount of regulatory cells in the bone niche, through inhibition of some transcriptional factors (Ikaros and Aialos) and the subsequent production of interleukin 2 [13]. Furthermore, some studies show that the main target of daratumumab is upregulated by action of IMiDs [14]. NCT01615029 was the first trial exploring the applicability of these laboratory observations, investigating efficacy of daratumumab in combination with lenalidomide and dexamethasone (Rd) [15]. It was a phase 1/2 study addressed to patients with relapsed multiple myeloma: phase 1 was a dose-escalation study in which the dose of 16 mg/kg for daratumumab was again determined; phase 2 was a dose-expansion study using the recommended dose of the first part. The three drugs were administered in cycle of 28 days: daratumumab was given according to the standard schedule, lenalidomide at 25 mg/day from days 1 to 21 of each cycle and dexamethasone at 40 mg/week. This combination revealed to be safe and very effective: the 18-months PFS rate was 72% and ORR was 81%, in this case too with an improvement of responses in time. To evaluate the advantage of adding daratumumab to a regimen with lenalidomide and dexamethasone, from 2014 to 2015, a phase III, randomized trial was carried out across Europe, Northern America and Asia [16]. The POLLUX trial enrolled 569 patients with multiple myeloma who had

**Trial Phase Therapy Primary outcome**

GEN501 1/2 IV daratumumab single agent evaluation of safety SIRIUS 2 IV daratumumab single agent ORR PAVO 1B SC daratumumab Maximum ctrough

NCT01615029 1 / 2 DARA-Rd ORR CASTOR 3 DARA-Vd *vs* Vd PFS POLLUX 3 DARA-Rd *vs* Rd PFS

ALCYONE 3 DARA-VMP *vs* VMP PFS MAIA 3 DARA-Rd *vs* DARA-Rd PFS

PERSEUS 3 DARA-RVd *vs* RVd PFS *RRMM: Relapsed/Refractory Multiple Myeloma, IV: intravenous, SC: subcutaneous, Rd.: lenalidomidedexamethasone, Vd: bortezomib-dexamethasone, ORR: Overall Response Rate, Maximum CTrough: Maximum Concentration Trough, AEs: Advese Events, PFS: Progression Free Survival, NDMM: Newly Diagnosed Multiple Myeloma, VMP: bortezomib-melphalan-dexamethasone, VTd: bortezomib-thalidomide-dexamethasone, RVd:* 

CASSIOPEIA 3 DARA-VTd *vs* VTd sCR after consolidation

GRIFFIN 2 DARA-RVd *vs* RVd sCR after consolidation

daratumumab

COLUMBA 3 IV daratumumab *vs* SC

*lenalidomide-botrezomib-dexamethasone, sCR: stringent Complete Response.*

*Overview of main trials using Daratumumab in (a) RRMM, (b) NDMM.*

N° of patients with AEs

ORR Maximum ctrough

PFS

*therapies: with IMiDs*

**70**

#### *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 treatment discontinuation higher than in the control group.
