Bang E Dara Part 2 Pdf Download

[Kathy Douds]

Extramedullarymultiple myeloma (EMD) is an aggressive subentity of multiple myeloma (MM), characterized by the ability of a subclone to grow outside of the bone marrow, resulting in a high-risk state associated with increased proliferation, evasion of apoptosis and treatment resistance. Despite the improvements in survival for most patients with MM over recent decades with development of newer immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), treatment outcomes remain less than satisfactory for EMD [1, 2].

Unfortunately, for bortezomib refractory patients with EMD there is no standard of care. Daratumumab (DARA), the first human anti-CD38 IgG1 monoclonal antibody, has shown some promising efficacy in patients with EMD. In GEN501 [10] and SIRIUS [11] studies, daratumumab monotherapy showed responses across all subgroups including patients with extramedullary plasmacytoma and those with triple- or quadruple-refractory disease or high-risk cytogenetics. Collectively, the reported overall response rate (ORR) of daratumumab monotherapy for heavily pretreated MM patients with EMD is around 20% [11,12,13,14,15,16].

To address the unmet medical needs in treatment of relapsed/refractory (R/R) MM with EMD, we conducted this phase II study combining DARA with chemotherapy DCEP (dexamethasone, cyclophosphamide, etoposide and cisplatin). Considering (1) the success of immunochemotherapy in B-cell non-Hodgkin lymphoma treatment and (2) the clinical and morphological resemblances between lymphoma and mass-forming MM [17, 18], we hypothesized that DARA-DCEP can induce synergy to effectively control R/R MM with EMD. To mitigate the concerns regarding hematologic adverse events of cytotoxic chemotherapy, prophylactic granulocyte colony-stimulating factor (G-CSF) was used and liberal DCEP dose reduction was allowed.

This open-label, multicenter, non-randomized phase II trial was carried out in 6 tertiary hospitals in Korea between August 2019 (first patient in after ClinicalTrials.gov registration) to January 2020 (ClinicalTrials.gov identifier: NCT04065308). The study was conducted according to the Declaration of Helsinki and was approved by the institutional review board of each hospital. Informed consent was taken from all patients before participating in any study-related procedure.

After 3 cycles of induction, bone marrow examination and imaging evaluation were done for response assessment. If partial response (PR) or better response was achieved per IMWG crtieria [19, 20], the patient was able to undergo either autologous stem cell transplantation (ASCT) followed by DARA maintenance or DARA maintenance depending on the circumstances. For patients undergoing ASCT, DARA maintenance had to be administered within 12 weeks of ASCT. During the maintenance phase, daratumumab was given at 16 mg/kg biweekly for 6 doses then 16 mg/kg monthly for 2 doses outpatient based.

The response evaluation was carried out according to the IMWG criteria [19]. EMD CR was confirmed by PET-CT in all cases. ORR was defined as PR or better response. The PFS was defined as time from study drug administration to relapse or death from any cause. The OS was defined from study drug administration to death of any cause. Patients were followed up until January 2022. The AE were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.

Daratumumab infusion-related reaction (IRR) was noted in 48.4% of the patients during the first cycle of DARA-DCEP. Three patients had grade 3 IRR (9.7%) with symptomatic bronchospasm, but recovered without sequelae. These 3 patients received prophylactic acetaminophen, H2-blocker and steroids for subsequent doses: 1 patient experienced grade 1 IRR during cycle 2 while other 2 patients did not have any more IRR events.

There were 2 deaths during the study (Table 2). One died due to underlying MM progression, while the other patient died due to combined bacterial and cytomegalovirus pneumonia. The latter patient was classified as treatment related mortality since the patient was in PR at the time of event (Table 4).

In this study, we combined daratumumab with conventional chemotherapy DCEP for the treatment of R/R MM with EMD and report ORR of 67.7% (21/31) with durable remission in 19.4% (6/31) of the treated patients. The importance of this trial lies on that 1) this is one of the very few prospective trials focusing on EMD and 2) we successfully laid grounds for implementing immunochemotherapy in MM treatment.

Despite its increasing incidence [21], the EMD responses in clinical trials have not been extensively analyzed thus there is no evidence-based consensus on the standard of care of EMD. The most validated modality is radiotherapy, but beyond radiotherapy patients are treated with multiple agents as per lymphoma treatment. DCEP regimen has been around for a while as a salvage treatment option for R/R MM patients, especially as bridge to high-dose therapy and stem cell transplantation or as a means of rapid tumor debulking [22,23,24,25,26,27]. The reported ORR of DCEP ranges from 45 to 58%, and more specifically, Park et al. reported ORR of 44.4% in Korean R/R MM with EMD (Additional file 1: Table 3). Daratumumab, on the other hand, is a more novel immunotherapeutic agent with reported ORR of 29.2% to 42.1% when used as monotherapy (Additional file 1: Table 3). When combined, we saw that DARA-DCEP indeed work synergistically as hypothesized, bringing the ORR up to 67.7%.

Another interesting point is that all of the attending physicians chose PET-CT over CT as means of EMD response evaluation. This is not surprising as PET-CT is considered the more suitable assessment tool of metabolically active EMD [28], and recent studies have demonstrated the negative correlation between abnormal PET-CT results and patient outcomes [29]. It is important to note that all EMD response evaluation in this study was corroborated by PET-CT results.

All in all, DARA-DCEP is an effective regimen for controlling R/R MM with EMD after bortezomib failure. Adequate dose adjustments and primary prophylactic G-CSF use can maximize efficacy while minimizing toxicities.

Youngil Koh was responsible for conceptualization, resources, investigation, writing the original draft and writing, reviewing and editing. Ja Min Byun was involved in investigation, data analysis, writing the original draft and writing, reviewing and editing. A. All authors took part in investigation and writing, reviewing and editing. All authors read and approved the final manuscript.

The study was conducted according to the Declaration of Helsinki and was approved by the institutional review board of each hospital. Informed consent was taken from all patients before participating in any study-related procedure.

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