**3. Discussion**

CD38 [5] is a transmembrane glycoprotein that is highly expressed on multiple myeloma cells and on normal lymphoid and myeloid cells albeit at low levels.

**89**

*Pleural Effusion Secondary to Multiple Myeloma: Is Daratumumab an Effective Treatment?…*

The mechanism of action is that of an ectoenzyme involved in the regulation of the intracytoplasmic concentration of calcium and of the catabolism of extracel-

The anti-CD38 fully human IgG1-k monoclonal antibody, daratumumab, carries out its cytotoxic effect through a series of mechanisms following binding to CD38, including antibody-dependent cell-mediated cytotoxicity (ADCC), complementdependent cytotoxicity (CDC), antibody-dependent cell-mediated phagocytosis (ADCP), and direct induction of apoptosis, which are its main mechanisms of action. Another effect of daratumumab recently described is its immunomodula-

A phase I/II dose escalation study in 104 patients with relapsed or refractory

Two phase [5] III studies are evaluating patients with relapsed or refractory disease; one of these studies is comparing daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone and the other is comparing daratumumab plus lenalidomide and dexamethasone versus lenalidomide and

Pending the final results of these studies, however, we want to underline how the CASTOR study (Velcade/dex vs. Dara/Velcade/dex) was interrupted early because at an interim analysis the study reached its final point with a ratio of very impressive risk of 0.39 in favor of the daratumumab arm. The POLLUX study (Rev/dex vs. Dara/Rev/dex) also showed similarly impressive results with a hazard ratio of 0.37 in favor of the Dara arm. Two further phase III studies are ongoing in patients with previously untreated multiple myeloma; one is comparing daratumumab plus bortezomib, melphalan, and prednisone with bortezomib, melphalan, and prednisone), and the other is evaluating daratumumab plus lenalidomide and dexamethasone

We wanted to report this clinical case only to hypothesize a possible role of daratumumab in the treatment of extramedullary recurrences and above all its possible

The selection of resistant clones is known in the course of myeloma recurrence, but the negativity/masking of CD 38 in the pleural fluid could demonstrate the

Obviously we have no previous data, but the phenotypic analysis of the marrow

But to date, the treatment of extramedullary plasmacytoma remains a therapeu-

Despite significant progress in the treatment of multiple myeloma, the disease

The approval of promising new agents will undoubtedly improve outcomes for

Most likely, we should have performed a PET/CT at the onset of staging for a better evaluation of any extramedullary localization and perhaps choose different

Molecular biology studies certainly in the near future will help us better understand which forms are most at risk and perhaps will guide us better in

The most common adverse events were grade 3 or 4 pneumonia and

multiple myeloma evaluated the safety of daratumumab.

*DOI: http://dx.doi.org/10.5772/intechopen.95659*

lular nucleotides.

tory action.

thrombocytopenia.

dexamethasone.

with lenalidomide and dexamethasone.

overcoming of the pleural barrier by daratumumab.

or more aggressive therapeutic treatments.

tic challenge even in the era of new drugs.

remains incurable in a vast majority of patients.

therapeutic choices.

**4. Conclusion**

myeloma patients.

and peripheral blood is the same for the other antigens evaluated.

overcoming of the pleural barrier.

*Pleural Effusion Secondary to Multiple Myeloma: Is Daratumumab an Effective Treatment?… DOI: http://dx.doi.org/10.5772/intechopen.95659*

The mechanism of action is that of an ectoenzyme involved in the regulation of the intracytoplasmic concentration of calcium and of the catabolism of extracellular nucleotides.

The anti-CD38 fully human IgG1-k monoclonal antibody, daratumumab, carries out its cytotoxic effect through a series of mechanisms following binding to CD38, including antibody-dependent cell-mediated cytotoxicity (ADCC), complementdependent cytotoxicity (CDC), antibody-dependent cell-mediated phagocytosis (ADCP), and direct induction of apoptosis, which are its main mechanisms of action.

Another effect of daratumumab recently described is its immunomodulatory action.

A phase I/II dose escalation study in 104 patients with relapsed or refractory multiple myeloma evaluated the safety of daratumumab.

The most common adverse events were grade 3 or 4 pneumonia and thrombocytopenia.

Two phase [5] III studies are evaluating patients with relapsed or refractory disease; one of these studies is comparing daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone and the other is comparing daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone.

Pending the final results of these studies, however, we want to underline how the CASTOR study (Velcade/dex vs. Dara/Velcade/dex) was interrupted early because at an interim analysis the study reached its final point with a ratio of very impressive risk of 0.39 in favor of the daratumumab arm. The POLLUX study (Rev/dex vs. Dara/Rev/dex) also showed similarly impressive results with a hazard ratio of 0.37 in favor of the Dara arm. Two further phase III studies are ongoing in patients with previously untreated multiple myeloma; one is comparing daratumumab plus bortezomib, melphalan, and prednisone with bortezomib, melphalan, and prednisone), and the other is evaluating daratumumab plus lenalidomide and dexamethasone with lenalidomide and dexamethasone.

We wanted to report this clinical case only to hypothesize a possible role of daratumumab in the treatment of extramedullary recurrences and above all its possible overcoming of the pleural barrier.

The selection of resistant clones is known in the course of myeloma recurrence, but the negativity/masking of CD 38 in the pleural fluid could demonstrate the overcoming of the pleural barrier by daratumumab.

Obviously we have no previous data, but the phenotypic analysis of the marrow and peripheral blood is the same for the other antigens evaluated.

Most likely, we should have performed a PET/CT at the onset of staging for a better evaluation of any extramedullary localization and perhaps choose different or more aggressive therapeutic treatments.

Molecular biology studies certainly in the near future will help us better understand which forms are most at risk and perhaps will guide us better in therapeutic choices.

But to date, the treatment of extramedullary plasmacytoma remains a therapeutic challenge even in the era of new drugs.

#### **4. Conclusion**

Despite significant progress in the treatment of multiple myeloma, the disease remains incurable in a vast majority of patients.

The approval of promising new agents will undoubtedly improve outcomes for myeloma patients.

*Multiple Myeloma*

restriction = 13%

*Phenotypic analysis on bone marrow blood.*

chains kappa and lambda

*Phenotypic analysis of pleural effusion.*

\*Therapy with Daratumumab

*Phenotypic analysis of pleural effusion.*

**Table 4.**

**Table 5.**

**Table 6.**

After one cycle of Dara Rd. therapy, for new reappearance of pleural effusion,

**Immunophenotypic study in flow cytometry Method used direct immunofluorescence**

Result Mature lymphocytes = 20% Clonal myeloma plasma cells: CD 138+ CD 38++CD19-CD56+ bright, CD 45 low with kappa clonal

**Immunophenotypic study in flow cytometry Method used direct immunofluorescence** Antigens studied: CD3, CD3/4, CD 3/CD8, CD19, CD16–56, CD117, CD 138, CD38, CD45, intracytoplasmatic

> Result Mature lymphocytes = 60%

**Immunophenotypic study in flow cytometry Method used direct immunofluorescence**

> RESULT Mature lymphocytes = 40%

Clonal myeloma plasma cells: CD 138+ CD 38-, CD56+, CD 45 + heterogeneous, cy kappa + = 10%

Antigens studied: CD19, CD 138, CD38, CD 56, chains kappa and lambda

While the plasma cells are absent for the reevaluation of the phenotypic study on

the patient underwent thoracentesis, this time by performing the phenotypic

Clonal myeloma plasma cells: CD 138+ CD 38-\*, CD56 + bright, cyvs38c+, CD 19- = 7.5%

After four cycles of therapy, we repeated PET/CT that was unfortunately

The PET/CT showed persistence of a large area of hyperaccumulation of the tracer in coincidence of pathological tissue from D3 to L5 that incorporates the

Persistence of pathological accumulation in the anterior mediastinum, in the pleuro-pericardial region in increase compared to the previous examination, extending from the xiphoid to the anterior costophrenic recess, area of hyperaccumulation in the right parasternal and at the level of the mediastinal pleura close to the ascending aorta. Despite the progression of disease, the CD38 negativity remained to the pheno-

CD38 [5] is a transmembrane glycoprotein that is highly expressed on multiple

myeloma cells and on normal lymphoid and myeloid cells albeit at low levels.

peripheral blood, we continued the treatment until the fourth cycle.

**88**

**3. Discussion**

analysis (**Table 5**).

compatible with persistence of disease.

posterior mediastinal structures in its course.

Antigens studied: CD 19, CD 56, CD 138, CD38, CD45, cyVS38c.

typic reevaluation of the pleural fluid (**Table 6**).

Daratumumab is a monoclonal antibody that is now approved for treatment of multiple myeloma patients and has shown significant response in the real-world setting.

Our case illustrates the potential to overcome the pleural membrane and therefore a possible role also in the treatment of extramedullary localizations of multiple myeloma.
