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Key Points• FRD is a well-tolerated oral triplet regimen with durable responses in myeloma.• Correlative analysis identified MAGEA1 as a functional biomarker of resistance.Phase 3 studies combining histone deacetylase inhibitors with bortezomib were hampered by gastrointestinal (GI) intolerance, which was not observed when combined with immunomodulatory drugs. This study is a single-center phase 2 study of panobinostat with lenalidomide and dexamethasone (FRD). Twenty-seven relapsed multiple myeloma patients were enrolled. Twenty-two patients (81%) were lenalidomide refractory and 9 (33%), 14 (52%), and 7 (26%) were refractory to pomalidomide, bortezomib, and carfilzomib, respectively. High-risk molecular findings were present in 17 (63%) patients. Responses included 2 complete responses (CRs), 4 very good partial responses (VGPRs), 5 partial responses (PRs), and 9 minimal responses (MRs) for an overall response rate of 41%, clinical benefit rate of 74%, and a disease control rate of 96%. The median progression-free survival (PFS) was 7.1 months. In the 22 lenalidomide-refractory patients, there were 1 CR, 4 VGPRs, 3 PRs, and 7 MRs, with a median PFS of 6.5 months. Median overall survival was not reached.Grade 3/4 toxicities were primarily hematologic. Gene expression profiling of enrollment tumor samples revealed a set of 1989 genes associated with short (,90 days) PFS to therapy.MAGEA1 RNA and protein expression were correlated with short PFS, and laboratory studies demonstrated a role for MAGE-A in resistance to panobinostat-induced cell death.FRD demonstrates durable responses, even in high-risk, lenalidomide-refractory patients, indicating the essential role of panobinostat in attaining responses. MAGEA1 expression may represent a functional biomarker for resistance to panobinostat. In contrast to PANORAMA 1, there were no significant GI toxicities and primarily expected hematologic toxicities. This trial was registered at www.clinicaltrials.gov as #NCT00742027.

Background Daratumumab (DARA) is a human IgG1 kappa monoclonal antibody that targets cells expressing CD38, which is highly expressed in multiple myeloma (MM) cells. In the phase 2 MMY2002 (Sirius) trial, treatment with single agent DARA resulted in a 29% overall response rate, with a median PFS of 3.7 months in heavily pretreated MM patients (Lonial S. J Clin Oncol. 2015; 33(suppl): abstrLBA8512). However, CD38 is also expressed on red blood cells (RBCs) and DARA binding to RBCs results in pan-reactivity on RBC panel testing using an indirect antiglobulin test (IAT). Recently, it was reported that treating RBCs with dithiothreitol (DTT) removes DARA to allow for accurate antibody testing (Chapuy CI, et al. Transfusion. 2015;55(6pt2):1545-1554) but also denatures Kell antigen in the process. To date, little is known about the impact of DARA interference with IAT on the outcomes of patients requiring packed RBC (PRBC) transfusions. Methods The frequencies of PRBC transfusions and any transfusion-related adverse events from all 124 patients treated on the Sirius study were obtained from the clinical database as of the data cut off of January 9th, 2015. Although details of transfusions were not prospectively collected, surrogate outcomes of transfusion reactions within 4 weeks of the transfusion were analyzed including change in hemoglobin (Hb), elevated bilirubin, fever, and hypotension. In addition, we evaluated IAT results and transfusion outcomes of the 8 patients treated at our institution. Results During the study, 47 patients received 147 transfusions with a total of 235 units of PRBCs. To date, no transfusion-related reactions were noted. Of the 47 patients, 8 patients were treated at our institution. One patient showed multiple alloantibodies (anti-E, -K, -Jkb, -Fya, -Fy3, -S, Knops) on IAT prior to DARA. This individual and 6 others agglutinated all RBCs on panel testing with weak reactivity at the antihuman globulin phase of testing. Reactivity was enhanced by gel testing compared to reactivity in low ionic strength saline and was unaffected by enzymatic treatment with ficin. Six out of 7 patients had a negative autocontrol. The one patient with a positive autocontrol had a weakly positive direct antiglobulin test with IgG. Six out of these 7 patients with panagglutinin had a positive result on the first IAT after initiation of DARA, ranging from 7 to 175 days (median 49). One patient did not have an IAT after initiation of DARA. A total of 9 leuko-reduced, irradiated, phenotypically matched RBCs were given to 3 patients during DARA treatment, and additional 9 units were given to 3 patients after DARA completion while their IATs remained positive. All transfusions resulted in an appropriate rise in Hb (median 1.0 g/dL, range 0.5-2.7) without any associated transfusion reactions. None of the patients made new unexpected RBC alloantibodies while receiving phenotypically matched RBCs. Conclusion For the 7 patients at our site with IAT testing after DARA treatment, all demonstrated pan-reactivity on RBC panel testing. Treatment with DTT removes this interference but also denatures Kell antigen in the process. Most hospitals do not use DTT as part of routine immunohematology workups; therefore, we recommend obtaining a red cell phenotype prior to initiating DARA treatment and providing phenotypically matched blood thereafter to avoid resultant difficulties in new alloantibody identification and delays in providing compatible PRBCs. Based on a database query of all 124 patients as well as all patients at our site, PRBC transfusions did not appear to be associated with complications. In a MM patient population that will frequently require PRBC transfusion, blood bank and hematologist/oncologist awareness of these findings is important to minimize errors or delays in providing compatible PRBCs. Disclosures Chari: Novartis: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Consultancy, Research Funding; Biotest: Other: Institutional Research Funding; Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding. Jagannath:Celgene: Honoraria; BMS: Honoraria; MERCK: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria; Janssen: Honoraria. Catamero:Celgene: Honoraria, Other: Lecturer; Onyx: Other: Lecturer; Millennium/Takeda: Other: Lecturer. Verina:Celgene: Other: Lecturer. Doshi:Janssen: Employment. Feng:Janssen: Employment. Uhlar:Janssen: Employment. Khan:Janssen: Employment. Ahmadi:Janssen: Employment. Voorhees:Millennium/Takeda and Novartis: Honoraria; Array Biopharma, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, and Oncopeptides: Consultancy; Celgene, GlxoSmithKline, and Oncopeptides: Research Funding.

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Daratumumab, a human immunoglobulin G1 kappa monoclonal antibody that targets CD38, is currently approved as monotherapy and in varying combinations with approved anti-myeloma regimens in both newly diagnosed multiple myeloma and relapsed refractory multiple myeloma. Originally developed for intravenous administration, the subcutaneous formulation of daratumumab (daratumumab and hyaluronidase-fihj) was recently approved by the US Federal Drug Administration and European Commission in 2020. In clinical trials, compared with the intravenous formulation, subcutaneous daratumumab (Dara-SC) has significantly shorter administration time (median first dose 7 h versus 3–5 min, respectively), lower rates of infusion-related reactions (median first dose 50% versus less than 10%, respectively), and lower volume of infusion (median 500–1000 ml versus 15 ml, respectively). Otherwise, the pharmacokinetics, safety profile, and efficacy are comparable. This review summarizes the pivotal trials that led to the approval of Dara-SC, highlights important clinical considerations for the use of Dara-SC, and provides practical guidelines for the administration of Dara-SC in the clinic.