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Patients with multiple myeloma (MM) mount suboptimal neutralizing antibodies (nAb) following 2 doses of SARS-CoV-2 mRNA vaccines. Currently, circulating SARS-CoV-2 variants of concern (VOC) carry the risk of breakthrough infections. We evaluated immune recognition of current VOC including BA.1, BA.2, and BA.5 in 331 racially representative patients with MM following 2 or 3 doses of mRNA vaccines. The third dose increased nAbs against WA1 in 82%, but against BA variants in only 33% to 44% of patients. Vaccine-induced nAbs correlated with receptor-binding domain (RBD)–specific class-switched memory B cells. Vaccine-induced spike-specific T cells were detected in patients without seroconversion and cross-recognized variant-specific peptides but were predominantly CD4+ T cells. Detailed clinical/immunophenotypic analysis identified features correlating with nAb/B/T-cell responses. Patients who developed breakthrough infections following 3 vaccine doses had lower live-virus nAbs, including against VOC. Patients with MM remain susceptible to SARS-CoV-2 variants following 3 vaccine doses and should be prioritized for emerging approaches to elicit variant-nAb and CD8+ T cells.Significance:Three doses of SARS-CoV-2 mRNA vaccines fail to yield detectable VOC nAbs in nearly 60% and spike-specific CD8+ T cells in >80% of myeloma patients. Patients who develop breakthrough infections following vaccination have low levels of live-virus nAb.This article is highlighted in the In This Issue feature, p. 101

This supplement to JADPRO provides an overview of several abstracts that were presented at the 2021 ASH Annual Meeting, along with expert commentary that aims to contextualize the information presented at ASH for the advanced practitioner. Kathryn T. Maples, PharmD, BCOP, of Emory University, evaluates data on antibody therapy, which has become a critical component in the treatment of multiple myeloma. Dr. Maples reviews outcomes of multiple myeloma patients after progressing on a bispecific antibody and the efficacy and safety profiles of two BCMA- and CD3-targeting bispecific antibodies, elranatamab and teclistamab.

This file contains supplementary figures 1-25

Suppl Table 1. Correlative analysis of breakthrough SARS CoV-2 infection following booster vaccination.

Supplementary Table 2: Antibodies used for immune-phenotyping (CyTOF analysis). Supplementary Table 3: Antibodies used for flow cytometry. Supplementary Table 4: Antibodies used for AIM Assay (CyTOF analysis).

Melphalan is an alkylating agent used in both autologous (ASCT) and allogeneic stem cell transplantation. It is a substrate of L-type amino acid transporter-1 (LAT-1) and LAT-2, which are involved in its tissue penetration and elimination. Gabapentin and pregabalin, common concomitant medications in patients with multiple myeloma undergoing ASCT, are also substrates of LAT transporters, raising concern for potential competitive inhibition of melphalan transport. We evaluated whether concurrent use of gabapentin or pregabalin in patients receiving high-dose melphalan (≥140 mg/mWe aimed to determine if concurrent administration of gabapentin or pregabalin and melphalan increased melphalan toxicity.This was a single-center, retrospective evaluation including patients ≥18 years of age who received high-dose melphalan as part of a conditioning regimen at the Winship Cancer Institute of Emory University between August 1, 2010 and April 1, 2020 and were followed through their transplant admission. After identification and inclusion of patients who received melphalan in combination with gabapentin or pregabalin, patient matching based on age (±5 years), sex, and melphalan dose (140 mg/mAmong 176 patients evaluated in each group, median hospital LOS was 16 days, median time to neutrophil engraftment was 14 days, and median time to platelet-20 engraftment was 16 days in both groups. In addition, there were no significant differences in supportive care requirements between groups.In this study, use of gabapentin or pregabalin in combination with melphalan did not impact safety of the conditioning regimen in patients undergoing ASCT.

Objective: To review the available data for the efficacy and safety of daratumumab in the treatment of multiple myeloma (MM), both in the newly diagnosed and relapsed/refractory settings, as well as provide additional guidance to clinicians on operational, safety, and supportive care considerations. Data Sources: A literature search of PubMed (1966 to October 2021) was conducted using the keywords daratumumab, Darzalex, and myeloma. Data were also obtained from prescribing information and unpublished abstracts from meetings. Study Selection and Data Extraction: All relevant published articles, prescribing information, and unpublished meeting abstracts on daratumumab for the treatment of MM were reviewed. Data Synthesis: Daratumumab is an anti-CD38 monoclonal antibody indicated for the treatment of MM. The addition of daratumumab to proteasome inhibitor and immunomodulatory drug-based regimens has led to a consistent improvement in progression-free survival and response rates in relapsed/refractory MM as per the POLLUX, CASTOR, APOLLO, and CANDOR trials. The ALCYONE and MAIA phase III trials have demonstrated an overall survival benefit when adding daratumumab to frontline regimens for transplant-ineligible patients with newly diagnosed MM. In transplant-eligible patients, daratumumab-based quadruplet regimens have improved depth of response in the CASSIOPIEA and GRIFFIN trials. Relevance to Patient Care and Clinical Practice: Operational and safety considerations that clinicians need to account for do exist, including different administration and infusion strategies, infusion-related reactions, increased risk for infectious complications, and interference with blood transfusion management. Conclusions: Daratumumab has led to a shift in the treatment paradigm of both newly diagnosed and relapsed/refractory MM, leading to improvements in outcomes such as response rates, depth of response, and progression-free survival.

Antibody therapy, which has become a critical option in the treatment of multiple myeloma (MM), includes monoclonal antibodies, antibody-drug conjugates, and bispecific antibodies. Anti-CD38 and anti-SLAMF7 monoclonal antibodies were the first to enter the MM portfolio as treatment options for relapsed/ refractory MM. More recently, daratumumab has become important in the treatment of newly diagnosed MM, and a subcutaneous formulation has been approved. BCMA-targeted antibody-drug conjugates and bispecific antibodies, which are the newest antibody therapies to be investigated, provide additional therapeutic options for patients with heavily pretreated MM. This article reviews how antibody therapy has influenced the treatment of MM, describes the unique adverse event profiles of each relevant drug class, and explains how to incorporate antibody therapy into practice.

Allogeneic hematopoietic cell transplantation (HCT) is a curative option for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), but carries a high risk of relapse. This retrospective review evaluates the effectiveness of maintenance azacitidine in high-risk AML and MDS patients to reduce the probability of relapse. Twenty-five patients who received maintenance azacitidine were matched to historical controls in a two-to-one ratio based on diagnosis, donor type, conditioning regimen intensity, and age. Over 90% of patients received myeloablative conditioning. There was no difference in time to hematologic relapse, overall survival, or non-relapse mortality. Maintenance therapy was stopped early in 72% of patients due to graft-versus-host-disease, relapse, infection, and intolerance (13 of 25 patients received less than 4 cycles). There was a trend towards higher toxicity in the azacitidine group. The use of prophylactic azacitidine following myeloablative allogeneic HCT outside a clinical trial cannot be recommended at this time.

Background: Despite significant advances in therapeutic options for multiple myeloma (MM) patients, there is an ongoing need to identify effective treatment strategies in the relapsed space. The efficacy of daratumumab, pomalidomide and dexamethasone (DPD) in relapsed and/or refractory patients has been demonstrated in clinical trials, but there is limited data at first relapse in a real world setting. Here, we present a retrospective analysis utilizing our institutional data of multiple myeloma patients treated with DPD at first relapse at the Winship Cancer Institute of Emory University. Methods: Ninety relapsed and/or refractory myeloma (RRMM) patients were identified who had received only one prior line of therapy and subsequently treated with DPD at first relapse. Dose-adjustments were made based on the treating physician's discretion and patient tolerability. Demographic and outcomes data for the patients were obtained from our IRB approved myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: The median age of this cohort was 61.9 years (range, 38-85). Other notable patient characteristics include: M/F 44.4%/55.6%; W/AA/Asian 50%/46.7%/3.3%; ISS I/II/III 28.9%/31.1%/20%; Isotype IgG/IgA/FLC 62.2%/17.8%/16.7%; standard risk/high risk 21.1%/52.2%. High risk disease was defined as the presence of t(4;14), t(14;16), del(17p), and/or complex karyotype. A total of 69 patients (76.7%) underwent autologous stem cell transplant (ASCT) upfront after attaining at least a partial response with induction therapy. The most common induction regimen was RVD (78.9%). 81.1% of patients received maintenance therapy, with 50.5% receiving single-agent lenalidomide maintenance and 72.2% receiving a lenalidomide-based maintenance regimen (RVD: 8 pts; Rd: 4 pts; IRD: 7 pts, KRD: 1 pt). With a median follow up of 72 months, the median OS from diagnosis was 158.6 months (95% CI 126.7-190.5) for the entire cohort. The median PFS from time of initiation of DPD was 15.6 months (95% CI 9.9-21.2), and the median OS from time of initiation of DPD was 41.3 months. For high risk vs standard risk patients, the mPFS from time of initiation of DPD was 7.2 months (95% CI 3.6-10.7) vs 17.6 months (95% CI 10.9-24.3), respectively. Median PFS2 in patients 2 years from transplant was 8.6 months vs NR, respectively. Conclusions: These results illustrate the activity of DPD at first relapse in a predominantly len-refractory RRMM cohort of patients with impressive long-term outcomes. This benefit was particularly demonstrated in patients with time to relapse of >2 years post-transplant. Figure 1 Figure 1. Disclosures Joseph: GSK: Honoraria; BMS: Research Funding; Takeda: Research Funding; Karyopharm: Honoraria. Boise: AstraZeneca: Honoraria, Research Funding; AbbVie/Genentech: Membership on an entity's Board of Directors or advisory committees. Hofmeister: BlueBird Bio: Other: Non-CME speaker; Aptitude Health: Other: Non-pharma speaker for education, research, marketing; Verascity: Other: Non-pharma speaker for education, research, marketing; TRM Oncology: Other: Non-pharma speaker for education, research, marketing; DAVA Oncology: Other: Non-pharma speaker for education, research, marketing; Medscape: Other: Non-pharma speaker for education, research, marketing; Amgen: Other: Non-CME speaker; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Philips Gilmore: Other: CME speaker; Non-pharma speaker for education, research, marketing; BioAscend: Other: CME speaker; Imbrium: Membership on an entity's Board of Directors or advisory committees; Myeloma360: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Local PI of CST; Oncolytics: Other: National PI for CST; PI or co-PI IST; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; BMS/Celgene: Other: National PI for CST; PI or co-PI IST; Local PI of CST; Sanofi: Other: National PI for CST; PI or co-PI IST; Ohio State University: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: IP rights, Patents & Royalties. Kaufman: Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sutro, Takeda: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Fortis Therapeutics: Research Funding; Heidelberg Pharma: Research Funding; BMS: Consultancy, Research Funding; Amgen: Research Funding; Tecnofarma SAS, AbbVie: Honoraria; Incyte, celgene: Consultancy; Janssen: Honoraria; Novartis: Research Funding; Genentech, AbbVie, Janssen: Consultancy, Research Funding. Lonial: Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Merck: Honoraria; AMGEN: Consultancy, Honoraria. Nooka: GlaxoSmithKline: Consultancy, Other: Travel expenses; Amgen: Consultancy, Research Funding; Oncopeptides: Consultancy; Janssen Oncology: Consultancy, Research Funding; Sanofi: Consultancy; Karyopharm Therapeutics: Consultancy; Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Adaptive technologies: Consultancy.

Introduction: Daratumumab (dara) and hyaluronidase-fihj was FDA approved for the treatment of newly diagnosed (NDMM) and relapsed/refractory multiple myeloma (RRMM) in May 2020, which offers a novel subcutaneous (SQ) administration for dara. The COLUMBA trial investigated the efficacy and safety of SQ dara (n=263) versus intravenous (IV) dara (n=259) in RRMM patients. The ORR was 41% with SQ dara versus 37% with IV dara (RR 1.11, 95% CI: 0.89-1.37). All-grade infusion-related reactions (IRR) were lower at 13% with SQ dara compared to 34% with IV dara. Other grade 3/4 adverse events were similar across both groups, with neutropenia being slightly higher with SQ (13% vs 8%). SQ dara was non-inferior to IV dara in terms of efficacy and offers MM patients a quicker administration with less risk for reactions. Since this approval, we have implemented all new patients to receive dara SQ and have transitioned IV dara patients to receive SQ formulation in efforts to improvise patient safety, without losing the efficacy. Additional advantages of reduced chair time and patient convenience made this an appealing option. The relative effect of patient satisfaction with this transition is unknown. Methods: We identified MM patients who received dara off-trial across our institution, which encompasses 150 infusion chairs across five ambulatory infusion centers, from June 1, 2020 through July 29, 2020. All patients on IV dara were switched to SQ for their next cycle after being seen at their regularly scheduled clinic visit where the change was discussed. SQ dara was administered via a 5-min SQ push and no observation period was implemented for patients who had previously received IV dara. A 3.5 hour observation was only utilized for cycle 1, day 1 SQ dara patients, based on the median time to IRR on COLUMBA trial. We analyzed the number of SQ and IV doses dispensed on a daily basis in order to capture the overall adoption rate of the SQ formulation. We also aimed to have our organization model a quick and safe transition between formulations for similarly sized cancer centers, Further, a five question patient satisfaction questionnaire was developed to administer to patients who switched from IV to SQ dara to assess their satisfaction with the new product. Results: From June 1 through July 29, 2020, a total of 417 doses of daratumumab were dispensed across all facilities at our intuition. The first patient treated with SQ dara was on June 17 after CPOE orderset development and staff education were completed. The number of SQ versus IV doses dispensed per day are displayed in Figure 1 and demonstrate the decrease in IV doses and subsequent increase in SQ doses over time. The adoption rate for the month of June was 90.5% IV dara and 9.5% SQ dara. Through July 29, the adoption rate shifted to 39.9% IV dara and 60.1% SQ dara. The patient questionnaire is ongoing and results will be presented at the time of the meeting. The economic implication of this conversion has resulted in 300 hours of reduced infusion chair usage. Updated formulary transition data will also be presented at the time of the meeting, as the formulary switch is ongoing. Conclusion: Our current adoption rate of 60.1% highlights the success of a large, academic medical institution in switching patients to the novel SQ dara formulation over a 6-week period from the first SQ patient. Our strategy of switching on a rolling basis allowed for patients to be counseled by a PharmD on this upcoming change. The daily dispense report assisted with drug ordering to ensure significant cost savings by reducing our purchases of IV dara and confirming adequate supply of SQ dara. Our goal is greater than 95% conversion to the SQ formulation, with minimal IV use reserved for patient preference or uncommon clinical needs. The patient satisfaction questionnaire results will inform providers of any concerns with this change. The implementation of SQ dara has streamlined drug administration and allowed for an increase in infusion-chair availability. Disclosures Maples: The Lynx Group LLC: Consultancy; GlaxoSmithKline: Consultancy. Kaufman:Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Tecnopharma: Consultancy, Honoraria; Sanofi/Genyzme: Consultancy, Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; AbbVie: Consultancy. Hofmeister:Janssen: Honoraria, Research Funding; Oncolytics Biotech: Research Funding; Oncopeptides: Honoraria; Nektar: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Imbrium: Honoraria; Sanofi: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Dhodapkar:Lava Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other; Amgen: Membership on an entity's Board of Directors or advisory committees, Other; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Other; Janssen: Membership on an entity's Board of Directors or advisory committees, Other; Kite: Membership on an entity's Board of Directors or advisory committees, Other; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other. Lonial:Merck: Consultancy, Honoraria, Other: Personal fees; Millennium: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; JUNO Therapeutics: Consultancy; Abbvie: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; Onyx: Honoraria; Amgen: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; GSK: Consultancy, Honoraria, Other: Personal fees; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding. Nooka:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Adaptive Technologies: Consultancy, Honoraria; Spectrum Pharmaceuticals: Consultancy; Oncopeptides: Consultancy, Honoraria; Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Daratumumab and hyaluronidase-fihj was approved for the treatment of multiple myeloma in specific combinations. Our abstract describes the conversion from daratumumab to daratumumab and hyaluronidase-fihj for all patients which will include some off-label combinations.

e20524 Background: The BELLINI trial investigated the efficacy and safety of venetoclax (ven)/bortezomib (bort)/dexamethasone (dex) vs placebo/bort/dex in patients with bort-sensitive, early relapsed myeloma. The median PFS favored the ven arm (22.4 vs 11.5 months); however, a higher death rate in the ven arm led to study discontinuation. A subgroup of patients with t(11;14) not only had improved PFS but a positive trend in OS with ven, suggesting biomarker-driven patient selection may mitigate the safety concern. BELLIINI results raised concern regarding the natural history of myeloma progressing on ven. We aimed to investigate the clinical outcomes of ven refractory myeloma patients. Methods: We identified 70 refractory myeloma patients at our institution prescribed ven alone or in combination between 03/2014 -11/2019. Our group has published the functional profiling of BCL2 family members to predict responses to ven (Matulis, S et al. Leukemia), and most patients had functional profiling available prior to starting ven. Demographic and outcomes data were obtained from our IRB approved myeloma database and responses were evaluated per IMWG criteria. Results: Patients received a median of 3 (1-13) lines of therapy (LOT), with 37% receiving ≥4prior LOT and 86% had t(11;14) by FISH/CTG. Most patients received ASCT (86%) and were refractory to len and bort (97%), dara (41.4%), car (43%), or pom (53%). The most common combinations with ven were dex (83%), PI and dex (8.5%), or dara and dex (8.5%). At a median follow up of 16.8 months, 38 patients progressed on ven. Median duration of therapy was 9.5 (1-63) months. Median PFS for the entire cohort was 13 (7.9-18.2) months. Use of ven as an early LOT provided PFS benefit ( < 3 vs > 3 LOT: 23.2 vs 10.4 months). Notably, patients who received > 6 LOT also had a PFS benefit of 7.23 (0-15.6) months, and ‘penta-refractory’ patients had a PFS of 7.2 (0-17.2) months. Among the 38 patients that progressed on ven, dara-based combinations (30%) and clinical trials (24%) were the most common subsequent LOT. At a median follow up of 15.4 months, the median OS for the cohort from the time of ven refractoriness was 31.4 months. Patients who received > 6 LOT had an OS of 15.1 (0-14.2) months and ‘penta-refractory’ patients at ven refractoriness had an OS of 13.7 (0-30.6) months. Conclusions: Patients with ven refractory myeloma can still experience good long term outcomes, and our experience does not support the hypothesis that ven resistance leads to a more refractory myeloma phenotype. These data support the early use of ven or ven combinations in the t(11;14) cohort of patients.

Prevalent molecular alterations of the phosphoinositide 3-kinase (PI3K) pathway are found on solid tumors and are expressed in leukocytes, making it a desirable target in both solid and hematologic malignancies. In recent years, two agents targeting this pathway have been approved by the United States Food and Drug Administration, idelalisib and copanlisib, with many others under investigation. Due to the off-target effects seen with these agents, those under development have varying isoform specificity that mitigates toxicity. In this review, we attempt to illustrate the varying differences among these agents, both mechanistically as well as highlight differences in their respective adverse effect profiles.

Introduction Triazole anti-fungal drugs have been important in preventing fungal infections in immunosuppressed pts who have received an allogeneic hematopoietic cell transplant (allo-HSCT). These agents inhibit fungal cytochrome P450 (CYP) enzymes, preventing ergosterol formation that is essential for fungal wall synthesis. However they also inhibit human CYP enzymes which are responsible for metabolism of certain drugs, notably immunosuppressants (IS) commonly used in allo-HSCT. This study is a retrospective analysis of the effect of the new triazole anti-fungal, isavuconazonium sulfate (ISV), on the serum blood levels of tacrolimus (Tac), cyclosporine (CsA), and Sirolimus (Siro) in pts who have received allo-HSCT. Patients and Methods This retrospective analysis included 78 pts who received a conventional, double-umbilical cord, or haplo-identical allogeneic stem cell transplant who received Tac, CsA, or Siro and were initiated on ISV for fungal prophylaxis. The pre-ISV serum blood level of IS was compared to the serum level 48 hrs after the start of the ISV loading dose. We also examined how IS were converted from IV to oral by comparing the IS level on the day of IV to PO conversion to the IS level 48 hrs after PO was initiated while pts received ISV. Results There were 85 instances of ISV initiation in 78 pts on IS. Of the 85 instances of ISV initiation 23 (27%) received CsA, 55 (65%) received Tac, and 7 (8%) received Siro. The median age was 56 (range 21-75) and 25 (32%) of the pts were female. Pts receiving IV CsA (n = 23) had a median percent dose change (%DC) of -10% on initiation of ISV and the median 48hr percent level change (%LC) was -5.7%, with a median net difference (%ND) of +6%. For the pts who were converted from IV CsA to PO CsA (n = 20) the empiric %DC from IV to PO was +25% with a %LC of +1.71% with a %ND of -18.51%. This corresponds to an IV:PO of 1:1.2. For pts receiving IV Tac (n = 55) the median %DC was -16.7% and the %LC was -3.4% with a %ND of +12.4 %. The pts who were converted from IV Tac to PO (n = 41) had a median empiric %DC of +200% with a corresponding %LC of -30.26, with a %ND of +228.49%. This corresponds to a IV:PO of 1:2.3. For the pts receiving Siro (n = 7) the median %DC was 0% and the median %LC of +17.8% with a %ND of +23.8%. Conclusion Initiation of ISV did result in serum level elevations in patients receiving CsA, Tac, and Siro. For CsA the increase in level was minimal, however for Tac and Siro the level increased 12.4% and 23.8% respectively which may be clinically important and dose reductions should be considered in select patients. This study also showed how ISV affects the IV to PO conversion of Tac and CsA with IV:PO ratios of 1:2.3 and 1:1.2 respectively. This demonstrates that ISV affects first-pass metabolism of Tac and CsA and this should be taken into consideration when making IV to PO conversions.

Background Letermovir (LET) is approved for the prophylaxis of cytomegalovirus (CMV) in allogeneic hematopoietic cell transplantation (allo-HCT) patients. LET is a weak-moderate CYP3A4 inhibitor, which may impact calcineurin inhibitor (CNI) levels. In the phase 1 trial, LET caused an increase in maximum plasma concentrations (Cmax) of CSA and tacrolimus by 37% and 70%, respectively. There are no data to correlate how the Cmax increase in the presence of LET may affect CNI trough levels. Methods A retrospective review was conducted to evaluate the effect of LET on CNI trough levels and determine if empiric dose adjustments are needed. Patients ≥ 18 years were included if they received an allo-HCT with a CNI from February to June 2018 and received LET 480 mg daily or 240mg daily for tacrolimus- or CSA-based GVHD prophylaxis, respectively. The primary endpoint was percent change in concentration to dose (C/D) ratio over the 7-day period after initiation of LET. The C/D ratio allows for an analysis of the effect on trough levels at any given dose, which we would expect to rise upon initiation of LET due to CYP inhibition. LET reaches steady state in 36-60 hours; therefore, C/D percent changes were evaluated both from baseline to 4 days post-LET and from day 4 to day 7. Results Thirty-four patients (median age 53, range 24-75) were included in the analysis, with 24 (70.6%) patients receiving a tacrolimus-based graft-versus-host disease (GVHD) prophylaxis and 10 (29.4%) patients receiving CSA-based GVHD prophylaxis. There were 8 (24%) umbilical cord blood transplants, 10 (29%) haploidentical HCTs, and 16 (47%) conventional HCTs, with 14 patients (41%) receiving myeloablative conditioning. LET was initiated on a median of day 7 (range 6-30) post-HCT, and 23 patients (68%) received the drug orally. In the 10 patients who received CSA, there was an average of 3.8 (range 1-6) dose changes over 7 days. From baseline to 4 days post-LET, the mean percent change in C/D ratio was +15.9%, with a subsequent -10.0% change in C/D ratio from day 4 to day 7. In the 24 patients who received tacrolimus, there was an average of 2.2 (range 0-5) dose changes over 7 days. From baseline to 4 days post-LET, the mean percent change in C/D ratio was +20.4%, with a subsequent -18.9% change in C/D ratio from day 4 to day 7. Days 0 to 7 trough levels for all patients are displayed in Figures 1 and 2. Conclusion An empiric dose reduction in CNIs upon initiation of LET does not appear to be warranted based on this pilot study. An increase in trough levels is seen within 4 days after initiation of LET; however, the increase seems marginal and is compensated for by adjusting doses based on levels, which is the standard of care. Larger studies are needed to assess additional factors that may affect this drug-drug interaction.

Objective: To review the pharmacology, pharmacokinetics, efficacy, safety, dosage and administration, and formulary considerations for dinutuximab. Data Sources: MEDLINE was searched (1964 to January 2016) using the terms ch14.18, dinutuximab, immunotherapy, and neuroblastoma. Other information was identified from package insert, Biologics License Application, abstracts, news releases, and ClinicalTrials.gov. Study Selection and Data Extraction: Identified English-language articles were reviewed. Selected studies included phase I through III. Data Synthesis: High-risk neuroblastoma is primarily a childhood cancer with 5-year survival rates of 40% to 50%. Treatment for high-risk neuroblastoma includes induction chemotherapy, surgery, myeloablative chemotherapy with autologous hematopoietic stem cell transplant, and radiation therapy. For patients achieving clinical remission, limited treatments exist for preventing relapse. Dinutuximab is a chimeric, human-murine, anti-GD2 monoclonal antibody approved in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), aldesleukin (interleukin-2 [IL-2]), and isotretinoin (13-cis-retinoic acid [RA]) for maintenance treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to first-line multiagent, multimodality therapy. In phase III trials, dinutuximab increased 2-year event-free survival and overall survival when compared to standard treatment. Severe adverse effects of dinutuximab include pain, hypersensitivity reactions, capillary leak syndrome, and hypotension. Conclusions: Dinutuximab is the first anti-GD2 monoclonal antibody approved in combination with GM-CSF, IL-2, and RA for maintenance treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to first-line multiagent, multimodality therapy. Ongoing research will determine if dinutuximab could be used earlier in treatment, in nonresponders to initial therapies, in combination with chemotherapy, or in other cancers.