Daratumumab combined with dexamethasone and lenalidomide or bortezomib in relapsed/refractory multiple myeloma (RRMM) patients: Report from the multiple myeloma GIMEMA Lazio group

Abstract The multiple myeloma (MM) treatment has changed over the last years due to the introduction of novel drugs. Despite improvements in the MM outcome, MM remains an incurable disease. Daratumumab is a human IgGK monoclonal antibody targeting CD38 with tumor activity associated with immunomodulatory mechanism. In combination with standard of care regimens, including bortezomib (Vd) or lenalidomide (Rd), daratumumab prolonged progression‐free survival (PFS) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) and in new diagnosis MM. We report the data of the MM GIMEMA Lazio group in 171 heavily treated pts who received daratumumab, lenalidomide and dexamethasone (DRd) or daratumumab, velcade and dexamethasone (DVd). The overall response rate was 80%, and the overall survival (OS) and PFS were 84% and 77%, respectively. In addition, pts treated with DRd showed a better median PFS compared to pts treated with DVd, at 12 and 24 months, respectively. The most common hematologic treatment‐emergent adverse events (TAEs) were neutropenia, thrombocytopenia, and anemia. The most common nonhematologic TAEs were peripheral sensory neuropathy and infections. Our data confirmed that DRd or DVd therapy is effective and safe in RRMM pts, and our real‐life analysis could support the physicians regarding the choice of optimal therapy in this setting of pts.

We report the data of the MM GIMEMA Lazio group in 171 heavily treated pts who received daratumumab, lenalidomide and dexamethasone (DRd) or daratumumab, velcade and dexamethasone (DVd). The overall response rate was 80%, and the overall survival (OS) and PFS were 84% and 77%, respectively. In addition, pts treated with DRd showed a better median PFS compared to pts treated with DVd, at 12 and 24 months, respectively. The most common hematologic treatment-emergent adverse events (TAEs) were neutropenia, thrombocytopenia, and anemia. The most common nonhematologic TAEs were peripheral sensory neuropathy and infections. Our data confirmed that DRd or DVd therapy is effective and safe in RRMM pts, and our real-life analysis could support the physicians regarding the choice of optimal therapy in this setting of pts.

K E Y W O R D S
immunotherapy, multiple myeloma, relapsed refractory

INTRODUCTION
The treatment of multiple myeloma (MM) has changed over the last decade, and the therapeutic armamentarium of effective anti-plasma cell drugs has expanded including several novel molecules, such as proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) [1,2].The incorporation of these novel agents into the standard of care regimens and use of high-dose chemotherapy, followed by autologous hematopoietic stem-cells transplantation (ASCT), has improved median overall survival (OS) by 6-8 years in newly diagnosed MM (NDMM) patients eligible for ASCT. Currently, 50% of MM patients are still alive 5 years after the diagnosis, and one third of patients live more than 10 years, according to disease risk staging and cytogenetic abnormalities (revised international staging system [R-ISS]) that have an impact on prognosis [3][4][5]. Nevertheless, despite the initial response after first line treatment, most of them experience relapse. Therefore,  [8,9]. Daratumumab shows direct and indirect anti-tumor activity and the specific mechanisms of action comprise immune-mediated effects, such as complement-dependent and antibody-dependent cellmediated cytotoxic effects, antibody-dependent cellular phagocytosis, and apoptosis by means of cross-linking [10][11][12][13][14]. Moreover, daratumumab presents an immumodulatory function that targets and depletes CD38 positive regulator immune suppressor cells, which leads to T cells clonal expansion and activation in MM patient who have a hematological response to treatment [15]. Initial approval by Food and Drug Administration (FDA) and European Medicines Agency (EMA) of daratumumab as monotherapy for MM patients heavily treated (at least 3 lines of therapy) was based on the phase I and II GEN501 and SIRIUS trials [16,17]. Subsequently, daratumumab in combination with standard of care regimen showed clinical benefit in two different phase III trials involving patients with relapsed or refractory myeloma. The addition of daratumumab to the standard of care regimen, including bortezomib and dexamethasone (CASTOR trial), or lenalidomide and dexamethasone (POLLUX trial), was associated with a significantly prolonged progression free survival (PFS), lower risk of disease progression, or death, a higher percentage of overall response rate (ORR), and minimal residual disease negativity (MRD) with a good safety profile [17,18]. This led to approval by FDA and EMA for pts with RRMM, as well as in newly diagnosed

MM.
We report the experience of the multiple myeloma Lazio group in 171 heavily treated patients treated in real-life with daratumumab, in combination with bortezomib (DVd) or with lenalidomide plus dexamethasone (DRd). criteria [19].

METHODS
The safety assessment was based on evaluation of hematological and nonhematological toxicity, and all adverse events were recorded using the Common Terminology Criteria for Adverse Events version 5.0.
The primary endpoint of this observational and retrospective study was to evaluate safety and efficacy of daratumumab-based treatment, in terms of toxicity, ORR, PFS, and OS. Response to therapy was assessed according to the IMWG criteria [13], and an ORR was calculated considering the achievement of at least a partial response (PR).
Patients' characteristics were compared by chi-squared or Fisher's exact test for categorical variables. Differences in distributions were assessed by Wilcoxon test for continuous data. Survival curves were estimated by the Kaplan-Meier product-limit method and compared using the log-rank test. Cox proportional hazards regression models were used in univariate analyses to estimate the risk on survival outcomes.
All tests were two-sided, accepting p < .05 as index of statistical significance. All analyses relied on the R software. Study data were collected and managed using REDCap electronic data capture tools hosted at the Sapienza University [20,21].

RESULTS
The baseline characteristics of the 171 patients are summarized in  with ≥3 lines of therapy with daratumumab (p = .003) ( Figure S5).
Finally, no statistical difference was found in OS at 12 and 24 months, respectively, according to the lines of therapy (p = .152) ( Figure S6).
The elevated LDH at diagnosis, a bad performance status either at diagnosis or at the time of starting therapy with daratumumab, and anemia were found to negatively affect the OS. In addition, the reduced level of white blood cell and elevated level of LDH at diagnosis, anemia, and a bad performance status at the time of starting therapy with daratumumab were found to negatively affect the PFS. We further demonstrated that a DVd scheme of therapy, a hematological response lower than VGPR, and daratumumab in fourth, or more lines of therapy, negatively influence the PFS.
All patients included were analyzed on safety. The most common  These data were consistent with our analysis, except for the higher rate of CR compared to our study. Nevertheless, a higher number of our pts were exposed to lenalidomide as induction or maintenance therapy compared to Antonioli's study. The analysis of the safety data showed that DRd or DVd was well tolerated with a low rate of treatment discontinuation due to toxicity (15 pts