Deep sustained response to daratumumab monotherapy associated with T-cell expansion in triple refractory myeloma

Abstract

Background: Daratumumab, a human CD38 monoclonal antibody that has direct on-tumor and immunomodulatory mechanisms of action, demonstrated clinical benefit as monotherapy or in combination with established regimens in patients with multiple myeloma with one or more prior lines of therapy.

Case presentation: A male patient, who was 70 years of age at the time of diagnosis of multiple myeloma in 2011, relapsed after five lines of therapy, including autologous stem cell transplantation. The patient's disease, which was considered high risk with a deletion of chromosome 17p, advanced quickly and was triple refractory 2 years after diagnosis leaving few treatment options. He was treated with daratumumab monotherapy in the SIRIUS clinical trial resulting in a stringent complete response and clearance of minimal residual disease. The duration of the patient's clinical response is now over 3.5 years without relapse, compared with a median of 7.6 months for similarly treated patients. The patient's immunophenotype revealed CD8+ T-cell expansion, clonal expansion of the T-cell receptor repertoire, and decreases in regulatory T cells during daratumumab therapy, suggesting a robust adaptive immune response. This immune response was still present 32 months into daratumumab therapy.

Conclusions: The results from this case report showed that a patient with advanced multiple myeloma, who had exhausted all treatment options with existing regimens, mounted an ongoing, deep, and durable response to daratumumab monotherapy. Further investigation of the immunologic profile provided additional patient-level evidence of an immunomodulatory mechanism of action of daratumumab.Trial registration ClinicalTrials.gov Identifier number NCT01985126. Submitted 22 July 2013.

Keywords: Daratumumab; Immune response; Minimal residual disease; Multiple myeloma; Stringent complete response; Sustained response; T-cell expansion; Triple refractory.

Figures

Fig. 1

M-protein levels over time. After initial presentation in 2010, the patient received five rounds of treatment and relapsed each time. The patient received the first dose of daratumumab (16 mg/kg) in October 2013 when he enrolled in the SIRIUS study. M-protein levels were measured at the local laboratory and then centrally after the first dose of daratumumab

Fig. 2

Change in immune cell populations and properties. A diagram of the T-cell receptor sequencing protocol is shown in a. DNA was extracted from peripheral blood mononuclear cells and subjected to 2 rounds of PCR amplification. During the first round, primers specific for the variable (forward) and joining (reverse) were used to amplify somatically recombined T-cell receptors. During the second round, each amplicon was amplified using primers containing barcode and adapter sequences to facilitate T-cell receptor sequencing via the Illumina platform in the next step of the protocol. The sequencing data were used to evaluate T-cell receptor clonality, diversity, and changes from baseline. Percent changes in CD8 T cells from baseline among patients in the SIRIUS study are shown in b. The patient, indicated by the red line, showed a rapid expansion of CD8+ T cells that was maintained over time. c The percent change from baseline of regulatory T cells over time. d T-cell receptor clonality at baseline versus on-treatment time points. For all patients in black, the on-treatment time point was 3 months. For the patient, the sample time points were 3 and 32 months, in orange and red, respectively. e The T-cell receptor clonality in the case study patient at baseline, 3, and 32 months. PBMCs peripheral blood mononuclear cells, V variable region, D diversity region, J joining region, PCR polymerase chain reaction, TCR T-cell receptor

Fig. 3

Minimal residual disease. A diagram of the protocol used to assess minimal residual disease shown in a. Bone marrow aspirates subjected to bulk red blood cell lysis and separated into 2 tubes. Each tube was incubated with an 8-marker antibody combination. Tube 1 was stained for surface markers only and tube 2 surface and intracellular markers. Minimal residual disease was then measured by flow cytometry merging data from each tube into one analysis. As shown in b plasma cells (PC) displayed a CD38high CD138int phenotype with low CD19 and CD45 expression indicative of an immature plasmablast (PC) population. By applying a cutoff value of 1 abnormal/clonal plasma cell per million nucleated event for MRD positivity (i.e., 10−6 sensitivity threshold of MRD positivity), the bone marrow aspirate tested MRD negative. BM bone marrow, RBCs red blood cells, MRD minimal residual disease