**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

**77**

**7. Conclusions**

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

to mobilized CD34 + progenitor cells from myeloma patients [48].

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

population. In the consensus document by ESCMID Study Group for Infections in Compromised Hosts (ESGICH), based on the pooled analysis of the two trials GEN501 an SIRIUS, daratumumab is associated also with an increased risk of varicella-zoster virus (VZV) infections, especially in the presence of combination therapy with protease inhibitors and/or corticosteroids [44]. Anti-herpesvirus prophylaxis with (val)acyclovir should be administered to VZV-seropositive patients at least 1 week before starting daratumumab therapy and for at least 12 weeks after its discontinuation. The consensus document also recommends seasonal-influenza vaccination. In the review of the drug conducted under the EMA's accelerated assessment program for drugs that are of major interest for public health, also thrombocytopenia and anemia are reported as the most common side effects, besides neutropenia [45]. In this same report, half of all patients experienced infusion-related reactions, mainly occurring at the first infusion. These reactions usually presented with nasal congestion, cough, throat irritation, chills, vomiting and nausea. Serious adverse reactions with bronchospasm, dyspnea, laryngeal edema, pulmonary edema and hypoxia have been also reported but in a few cases. Based on this phenomenon, EMA gave indication to premedicate every infusion with antihistamines, antipyretics and corticosteroids. Furthermore, oral corticorsteroids should be taken by all patients on the first and second day after all infusions. Patients on therapy with Daratumumab may present with positive indirect and direct Coombs test, due to the CD38 expression also on the red blood cells. This interference could complicate the safe provision of blood products to people on treatment with this drug. Chapuy et al. demonstrated that this "laboratory side effect" might be solved by incubating red blood cells with dithiothreitol (DTT) or trypsin [46]. These reagents remove the CD38 on the surface of red blood cells, easing routine compatibility testing. Evaluation of disease response in patients with multiple myeloma on treatment with daratumumab could also be complicated by this antibody. Given its proteic nature (IgG1), the drug can be confused with the endogenous monoclonal component during the interpretation of serum immunofixation electrophoresis (IFE). McCudden et al. proposed a daratumumab-specific immunofixation electrophoresis reflex assay (DIRA) using a mouse anti-daratumumab antibody in order to discriminate between endogenous myeloma protein and daratumumab [47]. Both Castor and Pollux trials showed a slight increase of rates of secondary primary cancers in the experimental arms, within 6 months after the initiation of trials [16, 18]. Most of the cases were non-melanocytes related cutaneous tumours and occurred in patients already treated with IMiDs and alkylating agents. Further studies and longer follow-up are needed to clarify the potential carcinogenicity of Daratumumab. Another concern, regarding the use of daratumumab, is due to the expression of CD38 on the surface of CD34+ hematopoietic progenitor cells. This could theoretically translate into a delay in stem cells collection for eligible patients to ASCT on treatment with the monoclonal antibody. Xun Ma et al. conducted an assay in which specimens of mobilized peripheral blood CD34 + cells from myeloma patients were evaluated to determine percentage of CD38 expression and later incubated with daratumumab and complement-rich human serum. First, CD38 is minimally expressed on CD34+ cells, compared to the control cell lines used. Furthermore, CDC did not occur, showing that, in vitro, daratumumab is not toxic

*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*

population. In the consensus document by ESCMID Study Group for Infections in Compromised Hosts (ESGICH), based on the pooled analysis of the two trials GEN501 an SIRIUS, daratumumab is associated also with an increased risk of varicella-zoster virus (VZV) infections, especially in the presence of combination therapy with protease inhibitors and/or corticosteroids [44]. Anti-herpesvirus prophylaxis with (val)acyclovir should be administered to VZV-seropositive patients at least 1 week before starting daratumumab therapy and for at least 12 weeks after its discontinuation. The consensus document also recommends seasonal-influenza vaccination. In the review of the drug conducted under the EMA's accelerated assessment program for drugs that are of major interest for public health, also thrombocytopenia and anemia are reported as the most common side effects, besides neutropenia [45]. In this same report, half of all patients experienced infusion-related reactions, mainly occurring at the first infusion. These reactions usually presented with nasal congestion, cough, throat irritation, chills, vomiting and nausea. Serious adverse reactions with bronchospasm, dyspnea, laryngeal edema, pulmonary edema and hypoxia have been also reported but in a few cases. Based on this phenomenon, EMA gave indication to premedicate every infusion with antihistamines, antipyretics and corticosteroids. Furthermore, oral corticorsteroids should be taken by all patients on the first and second day after all infusions. Patients on therapy with Daratumumab may present with positive indirect and direct Coombs test, due to the CD38 expression also on the red blood cells. This interference could complicate the safe provision of blood products to people on treatment with this drug. Chapuy et al. demonstrated that this "laboratory side effect" might be solved by incubating red blood cells with dithiothreitol (DTT) or trypsin [46]. These reagents remove the CD38 on the surface of red blood cells, easing routine compatibility testing. Evaluation of disease response in patients with multiple myeloma on treatment with daratumumab could also be complicated by this antibody. Given its proteic nature (IgG1), the drug can be confused with the endogenous monoclonal component during the interpretation of serum immunofixation electrophoresis (IFE). McCudden et al. proposed a daratumumab-specific immunofixation electrophoresis reflex assay (DIRA) using a mouse anti-daratumumab antibody in order to discriminate between endogenous myeloma protein and daratumumab [47]. Both Castor and Pollux trials showed a slight increase of rates of secondary primary cancers in the experimental arms, within 6 months after the initiation of trials [16, 18]. Most of the cases were non-melanocytes related cutaneous tumours and occurred in patients already treated with IMiDs and alkylating agents. Further studies and longer follow-up are needed to clarify the potential carcinogenicity of Daratumumab. Another concern, regarding the use of daratumumab, is due to the expression of CD38 on the surface of CD34+ hematopoietic progenitor cells. This could theoretically translate into a delay in stem cells collection for eligible patients to ASCT on treatment with the monoclonal antibody. Xun Ma et al. conducted an assay in which specimens of mobilized peripheral blood CD34 + cells from myeloma patients were evaluated to determine percentage of CD38 expression and later incubated with daratumumab and complement-rich human serum. First, CD38 is minimally expressed on CD34+ cells, compared to the control cell lines used. Furthermore, CDC did not occur, showing that, in vitro, daratumumab is not toxic to mobilized CD34 + progenitor cells from myeloma patients [48].
