Prospective phase 2 trial of daratumumab with dexamethasone in patients with relapsed/refractory multiple myeloma and severe renal impairment or on dialysis: The <scp>DARE</scp> study

Up to half of multiple myeloma (MM) patients present with renal impairment (RI) at the time of diagnosis and 2%–4% require dialysis.1 Anti-CD38 monoclonal antibodies have considerably improved outcomes of MM patients over the last decade; however, data for patients with MM and severe RI are limited. Therefore, we performed a prospective study to evaluate the safety and efficacy of daratumumab with dexamethasone in patients with relapsed/refractory MM (RRMM) and severe RI. This was a phase 2, multicenter, non-comparative, open-label trial (DAratumumab in patients with REnal impairment, DARE, ClinicalTrials.gov: NCT03450057). Eligible patients with MM had received at least two lines of prior treatment including bortezomib and lenalidomide, and they had documented evidence of disease progression at last line of therapy according to the IMWG criteria. All patients had severe RI defined as estimated glomerular filtration rate (eGFR) of <30 mL/min/1.73 m2 by CKD-EPI or they were in need for renal dialysis. The primary study endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), renal response rate (RRR), duration of response (DoR), time to next therapy (TNT), overall survival (OS), and safety (Supplement S1). All patients provided written informed consent before enrolment in the study. From February 22, 2018 to March 5, 2020, a total of 38 patients were enrolled across five sites in Greece and two sites in Italy (Supplement S1). The median (Q1–Q3) age of the enrolled patients was 72 years (64–76 years) and 29 (76%) were males. The median (Q1–Q3) eGFR per CKD-EPI at screening was 12.0 (7.0–22.0) mL/min/1.73 m2 and 17 (44.7%) patients were on dialysis. The median number of prior lines of therapy was 3 (range 2–6), whereas 31 patients (82%) were refractory to their last line of therapy. All patients had received bortezomib and lenalidomide, while 11 (28.9%) had received pomalidomide and 8 (21.1%) carfilzomib; 25 (65.8%) were refractory to both a PI and an IMiD. The median (Q1–Q3) follow-up was 11.3 months (3.3–22.5). Regarding the primary study endpoint, 8 patients (21.1%) died without prior documented disease progression, and 16 patients (42.1%) experienced disease progression on daratumumab. The median (95% CI) PFS was 11.8 (2.8–20.8) months. The 6-and 12-month PFS rates were 54.0% and 48.1%, respectively. For the whole study population, the ORR was 47.4% (95% CI: 31.5–63.2). Specifically, 13 (34.2%) patients achieved very good partial response (VGPR) and 5 (13.2%) patients achieved PR. Three patients (7.9%) achieved a minimal response (MR). The median (Q1–Q3) time to first response (PR or better) was 0.9 (0.9–1.0) months. The median (95% CI) DoR for patients achieving at least PR was 28.4 (15.1–not reached) months. Furthermore, the RRR (PRrenal or better) was 18.4% (95% CI: 7.7–34.3) and 31 patients (81.6%) had either MRrenal (2 patients) or no response (29 patients) (Supplement S1). Among the study participants, 16 (42.1%) patients died without receiving next-line therapy and 3 (7.9%) received subsequent systemic treatment. The median (95% CI) TNT was 18.0 (5.5–not reached) months. Overall, 17 patients (44.7%) died during the observation period of the study. The median (95% CI) OS was 24.5 (5.5–not reached) months. The 12- and 24-month OS rates were 62.7% and 51.7%, respectively. The median (95% CI) PFS was 2.8 (1.2–16.1) months for dialysis patients and 13.3 (3.9–not reached) months for non-dialysis patients (log-rank P-value = .358; HR [95% CI] for dialysis v. non-dialysis = 1.453 [0.649–3.249]; Figure 1A). The ORR (PR or better) was 47.1% (8/17) for dialysis patients and 47.6% (10/21) for non-dialysis patients. A best response of PR and VGPR was achieved by 3 (17.6%) and 5 (29.4%) of the dialysis patients, respectively. Among non-dialysis patients, 2 (9.5%) and 8 (38.1%) achieved PR and VGPR, respectively. The median (Q1–Q3) time to first response of PR or better was 0.9 (0.9–1.0) months for dialysis patients and 0.9 (0.9–2.7) months for non-dialysis patients. The median (95% CI) DoR was not reached (1.8–not reached) for dialysis patients and was 28.4 (3.5–not reached) months for non-dialysis patients (Figure 1B). The RRR was 5.9% (1/17) for dialysis patients (one became dialysis independent) and 28.6% (6/21) for non-dialysis patients. The respective median (95% CI) OS was 12.5 (2.2-not reached) months and 24.5 (10.1–not reached) months for dialysis and non-dialysis patients, respectively (log-rank P-value = .223; HR for dialysis vs. non-dialysis = 1.798 [0.690–4.682]; Figure 1C). Overall, 12 serious adverse events (SAE) were reported in 11 patients (28.9%) during the study period (Supplement S1). The most common SAE was septic shock (N = 4, 10.5%), of which three cases were fatal. Regarding infections, one patient experienced a grade 3 pneumonia requiring hospitalization, whereas a fatal peritonitis in a patient on peritoneal dialysis and a fatal lower respiratory tract infection were reported in other two patients, respectively. Antivirals (acyclovir or valacyclovir) and antibiotics were administered as prophylaxis against viral and bacterial infections in 33 (86.8%) and 26 (68.4%) patients, respectively. There was only one acute kidney injury SAE which was not related to study drugs. Also, three patients required dialysis during treatment due to disease progression. The relatively favorable results in the current study compared with previous studies with daratumumab monotherapy must be interpreted with caution, since we used a doublet (daratumumab with dexamethasone) and not monotherapy. However, our population had some high-risk characteristics with the most prominent being the presence of severe renal dysfunction, requiring dialysis in almost half of the patients. Until today there are small case series and case reports showing that daratumumab-based regimens can be safely administered in patients with MM and RI without need for dose modifications.2 Kuzume et al. retrospectively reported the outcomes of 13 MM patients with eGFR ≤15 mL/min/1.73 m2 who received daratumumab as induction or intensification therapy for patients with suboptimal (less than CR) disease response to upfront therapy.3 Daratumumab resulted in a rapid reduction of free light chain levels in 10 out of 13 patients, which is important to reverse RI in MM. Half of dialysis-dependent patients (3/6) achieved dialysis independence during daratumumab treatment. Another retrospective study has reported the outcomes of daratumumab monotherapy in 15 patients with end-stage RI requiring dialysis.4 Although the ORR was 40% and the disease control rate reached 87%, no patient managed to become independent from hemodialysis.4 Other case reports have also shown that daratumumab-based combinations can be safely administered and may even reverse the need for hemodialysis in patients with severe RI due to underlying MM. Furthermore, daratumumab-based treatment is a feasible option in patients with MGRS.5 Daratumumab resulted in a high ORR of 74% among 25 patients; previously untreated patients, those who received daratumumab-based combinations and those who were dialysis-independent at the start of daratumumab had improved hematological and renal responses.5 In addition, subgroup analyses of pivotal clinical trials have shown the efficacy and safety of daratumumab- and isatuximab-based combinations in MM patients with moderate RI.2 The median OS of patients on dialysis was almost half of that for non-dialysis patients (12.5 and 24.5 months, respectively) and the RRR for dialysis-dependent patients was almost five-fold lower than the RRR for dialysis-independent patients. These findings are aligned with earlier reports on the OS of such patients and indicative of the poor prognosis of patients requiring dialysis, at any stage of the disease, whereas independence from dialysis may be associated with improved survival.6 The major limitation of our study lies in the relatively small number of enrolled patients and the lack of PK data. Because of the small number of patients in each category, the assessment of secondary study outcomes and subgroup analyses may have been underpowered to reach statistical significance. Lack of PK data does allow to evaluate the impact of dialysis and severe RI in the pharmacokinetic and pharmacodynamics of daratumumab, however, being an IgGk antibody, it is not expected to be affected significantly and filtered in the dialysate. In our study, we used the IV formulation, which was available at the time of study design and the SC formulation became available later. Nevertheless, PK data and the results of prospective studies show that there is no significant difference in the efficacy and safety of SC formulation. Notably, in the DARE study, a high proportion of patients who remained on therapy beyond trial completion, continued with SC formulation. Finally, DIRA test was not available, which potentially may have led to underestimating the CR rate, especially among patients with IgGk myeloma. Given that daratumumab has now been approved in multiple different combinations from the first line of therapy and beyond, our study may seem outdated. However, prospective data on the use of daratumumab in patients with severe RI or those on dialysis are not available and we only have subgroup analyses for these studies that included patients with only moderate RI. The DARE study provides data to support the use of daratumumab as a safe and effective partner of combination therapies for patients with RI of any degree, including those requiring dialysis. In this regard, we believe that daratumumab should be part of initial and salvage regimens for MM patients presenting with RI, in combination with bortezomib, carfilzomib or pomalidomide depending on the setting, refractoriness status and availability. Conceptualization: Efstathios Kastritis, Meletios A. Dimopoulos; Investigation: All authors; Formal analysis: Giorgos Cheliotis, Kyriaki Manousou; Funding acquisition: Efstathios Kastritis, Meletios A. Dimopoulos; Methodology: Efstathios Kastritis, Argiris Symeonidis; Supervision: Efstathios Kastritis, Meletios A. Dimopoulos; Writing – original draft: Efstathios Kastritis, Kyriaki Manousou; All authors reviewed and provided their approval for the final version of the manuscript. We thank all the investigators and the study staff who participated in this study, as well as the study participants. Kastritis: Consultancy and Honoraria: Janssen, Takeda, Pfizer, Genesis Pharma, Amgen, GSK; Research support: Amgen, Pfizer, Janssen; Terpos: Honoraria: Novartis, Takeda, Sanofi, Genesis, GSK, Janssen-Cilag, BMS, Amgen, Genesis, EUSA Pharma; Research funding: Amgen, Genesis, GSK, Janssen-Cilag, Takeda, Sanofi; Travel expenses: Amgen, EUSA Pharma, Takeda; Symeonidis: Consultancy and Honoraria: AbbVie, BMS, Sanofi, Sanofi/Genzyme, GSK, MSD, Takeda, Gilead, Roche, Demo, Astellas, Novartis, Amgen, Pfizer, Win Medica, Genesis Pharma, Janssen; Labropoulou: Consultancy and Honoraria: Genesis Pharma, Amgen, GSK, Sanofi, Abbvie, Demo S.A, Accord HealthCare Greece, Genepharm S.A.; Delimpasi: Honoraria: Janssen, Takeda, Amgen, GSK; Consultancy: Janssen, Takeda, Amgen, GSK, Sobi; Mancuso: Honoraria: Amgen, Bristol-MyersSquibb/Celgene, Janssen, Takeda, Sanofi, GlaxoSmithKline, Pfizer; Zamagni: Honoraria: Janssen, Bristol-Myers-Squibb, Takeda, Amgen; Katodritou: GSK, Amgen, Karyopharm, Abbvie, Janssen-Cilag, Genesis Pharma, Sanofi; Kyrtsonis: Honoraria: Janssen, Amgen, Celgene/Genesis Pharma, Takeda, Sanofi; Hatjiharissi: Consultancy and Honoraria: Servier, Janssen-Cilag, AstraZeneca, Abbvie; Migkou: Honoraria: Janssen-Cilag, Glaxo Smith Klein; Cheliotis: Health Data Specialists: Current Employment; Manousou: Health Data Specialists: Current Employment; Gavriatopoulou: Honoraria: GSK, Karyopharm, Takeda, Janssen, Amgen, Genesis, Sanofi; Dimopoulos: Honoraria: Beigene, Janssen, BMS, Amgen, Takeda. All other authors declare no conflicts of interest. All patients provided written informed consent before enrolment in the study. The data that support the findings of this study are available from the corresponding author and the Hellenic Society of Hematology (HSH) upon reasonable request. Data S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.