Preliminary safety of Bcl-2 inhibitor BGB-11417 in relapsed/refractory multiple myeloma Harbouring t(11,14): Phase 1b/2 study

Background: B-cell lymphoma-2 (Bcl-2) proteins play an important role in multiple myeloma (MM) cell survival and represent an attractive therapeutic target. In prior trials, a subgroup analysis of patients with t(11;14)-positive relapsed/refractory (R/R) MM showed the combination of a Bcl-2 inhibitor, a proteasome inhibitor, and dexamethasone improved progression-free survival with no increased mortality. BGB-11417, a Bcl-2 inhibitor, is more potent and selective than venetoclax. BGB-11417- 105 (NCT04973605) is a phase 1b/2 study assessing the safety and efficacy of BGB-11417 monotherapy, in combination with dexamethasone, or with dexamethasone+carfilzomib in patients with t(11;14)-positive R/R MM. Preliminary safety results for the combination of BGB-11417 + dexamethasone are presented. Method(s): Eligible patients had t(11;14)-positive R/R MM and had been exposed to a proteasome inhibitor, immunomodulatory agent, and anti-CD38 therapy. Patients received 80-, 160-, 320-, or 640-mg BGB-11417 daily with 40-mg dexamethasone weekly until death, intolerability, or disease progression. Dose escalation was guided by a mTPI-2 design and overall review by a safety monitoring committee. Pharmacokinetics (PK) were also assessed. Result(s): As of 1 July 2022, 10 patients were enrolled in the 80-, 160-, and 320-mg (3 patients each) and 640-mg (1 patient) dose-escalation cohorts of BGB-11417 + dexamethasone. The median age was 69 years (range, 52-81) and median prior lines of therapy was 3 (range, 1-5). The median treatment duration was 3.2 months (range, 0.5-6.5). No patients experienced dose-limiting toxicity at any dose level. Three patients died whilst on study: 1 due to COVID-19 complications 157 days after treatment discontinuation (day 208), 1 due to progressive disease 50 days after treatment discontinuation (day 89), and 1 due to COVID-19 whilst on study treatment (day 78). No deaths were associated with study treatment. Two patients experienced Grade >= 3 treatment-emergent adverse events (TEAEs). One patient in the 160-mg cohort experienced Grade 3 increase in liver enzymes and lymphopenia. One patient in the 320-mg cohort experienced Grade 3 lymphopenia. The most common TEAEs were insomnia (50%), fatigue (30%), arthralgia (20%), back pain (20%), lymphopenia (20%), and nausea (20%). BGB-11417 exposure increased dose-dependently from 80 mg to 320 mg with high interpatient PK variability. BGB-11417 exposures after single and multiple doses appeared similar, indicating limited accumulation. Conclusion(s): BGB-11417 plus dexamethasone was generally well-tolerated in patients with R/R MM harbouring t(11;14) at doses <=640 mg. Efficacy data are forthcoming. Recruitment is ongoing in the US, Australia, and New Zealand;the BGB-11417, dexamethasone, and carfilzomib combination arm will open in the future.

Anaplastic extramedullary plasmacytoma resistant to novel therapies: A case report

The treatment of choice for extramedullary plasmacytoma (EMP) is radiotherapy (RT). It is under discussion whether the management of an anaplastic form of EMP requires the addition of systemic therapy. We present a case of a 66-year-old male who was diagnosed with anaplastic plasmacytoma of the maxillary sinus. After the exclusion of multiple myeloma, Dara-VMP (daratumumab, bortezomib, melphalan, and prednisolone) regimen was initiated. During the third cycle of Dara-VMP, a progression of the tumor was observed. RT and BRd (bendamustine, dexamethasone, and lenalidomide) regimen were initiated. After 4 cycles of BRd, disease progression was established. KRd (carfilzomib, lenalidomide, and dexamethasone) regimen was initiated. The first cycle of KRd was not completed, as the patient was diagnosed with COVID-19. After the infection, the progression of EMP was observed. In this case, the anaplastic EMP was resistant to RT and chemotherapy regimens with novel agents, including a monoclonal antibody, an immunomodulatory drug, and proteasome inhibitors. Copyright © 2023 the author(s), published by De Gruyter, Berlin/Boston.

Drug-induced pericarditis

Though not common, drug-induced pericarditis is a serious condition, since pericardial tamponade, should it develop, may be life-threatening. As the number of drugs is constantly expanding, so does the proportion of those capable of causing pericarditis. The authors reviewed the relevant literature in the PubMed database and complemented it with information from the VigiBase database. In their article, the authors present current knowledge about the mechanisms of origin and level of risk of drug-induced pericarditis and discuss relevant information on individual drugs divided into 7 classes. Some medicines are associated with a high risk of developing pericarditis, a fact to be taken into account when treating patients with these agents. © 2022 Czech Society of Cardiology Z.S. All rights reserved.

COVID-19: From the Molecular Mechanisms to Treatment

The 2019 novel coronavirus (SARS-CoV-2) causes severe pneumonia called COVID-19 and leads to severe acute respiratory syndrome with a high mortality rate. The SARS-CoV-2 virus in the human body leads to jumpstarting immune reactions and multi-organ inflammation, which has poorer outcomes in the presence of predisposing conditions, including hypertension, dyslipidemia, dysglycemia, abnormal adiposity, and even endothelial dysfunction via biomolecular mechanisms. In addition, leucopenia, hypoxemia, and high levels of both cytokines and chemokines in the acute phase of this disease, as well as some abnormalities in chest CT images, were reported in most patients. The spike protein in SARS-CoV-2, the primary cell surface protein, helps the virus anchor and enter the human host cells. Additionally, new mutations have mainly happened for spike protein, which has promoted the infection's transmissibility and severity, which may influence manufactured vaccines' efficacy. The exact mechanisms of the pathogenesis, besides molecular aspects of COVID-19 related to the disease stages, are not well known. The altered molecular functions in the case of immune responses, including T CD4+, CD8+, and NK cells, besides the overactivity in other components and outstanding factors in cytokines like interleukin-2, were involved in severe cases of SARS-CoV-2. Accordingly, it is highly needed to identify the SARS-CoV-2 bio-molecular characteristics to help identify the pathogenesis of COVID-19. This study aimed to investigate the bio-molecular aspects of SARS-CoV-2 infection, focusing on novel SARS-CoV-2 variants and their effects on vaccine efficacy.Copyright © 2022 NRITLD, National Research Institute of Tuberculosis and Lung Disease, Iran.

Mechanism-based approaches of 1,3,4 thiadiazole scaffolds as potent enzyme inhibitors for cytotoxicity and antiviral activity

Significant progress in understanding cancer pathogenesis, it remains one of the leading causes of death after cardiovascular diseases. Similarly viral infections have emerged from wildlife or re-emerged, generating serious threats to the global health. As a result, there is an urgent need for the development of novel, more effective anticancer and antiviral therapeutics. Scientists, medicinal chemists and researchers are continuously finding novel targets, mechanisms and molecules against theses severe and dangerous infections. Therefore, ongoing extensively study and research emphasizes 1,3,4 thiadiazole pharmacophore have versatile pharmacological actions. Due to mesoionic behaviour of 1,3,4 thiadiazole pharmacophore allows to enter and easily cross biological membrane which allow to interact various biological proteins. In this review study an attempt has been made of various mechanisms involved in cancer and viral prevalence with updated studies done so far. This review study also findings the role of 1,3,4 thiadiazole motif in the management of various cancers and viral infection. This study also highlighting research statics on clinical trials and various patents containing 1,3,4 thiadiazole derivatives. © 2022 The Author(s)

DARATUMUMAB CARFILZOMIB LENALIDOMIDE AND DEXAMETHASONE AS INDUCTION THERAPY IN HIGH-RISK TRANSPLANT ELIGIBLE NEWLY DIAGNOSED MYELOMA PATIENTS: RESULTS OF THE PHASE 2 STUDY IFM 2018-04

Background: High-risk (HR) cytogenetic is associated with poor outcome in transplant eligible (TE) newly diagnosed myeloma multiple myeloma (NDMM). The triplet combination carfilzomib lenalidomide and dexamethasone (KRD) plus transplantation demonstrated high efficacy with faorable safety profile in TE-NDMM patients (FORTE). The addition of daratumumab (Dara) to frontline therapy also improed response rate and progression free-surial in TE-NDMM patients (CASSIOPEIA, GRIFFIN). Double transplant also improed outcome of HR TE NDMM patients (EMN02, STAMINA). Aims: The phase 2 trial 2018-04 from the Intergroupe Francophone du Myelome (IFM) is ealuating an intensie strategy with Dara-KRD induction and consolidation plus double transplant in HR TE NDMM (NCT03606577). Methods: HR MM was defined by the presence of del17p, t(4;14) and/or t(14;16). Stategy includes Dara-KRD induction (6 cycles), autologous stem cell transplantation (ASCT), Dara-KRD consolidation (4 cycles), second ASCT, Dara-lenalidomide maintenance. The primary endpoint was the feasibility of this intensie strategy. Here, we report efficacy and safety analysis of Dara-KRD induction. Results: Fifty patients with preiously untreated NDMM were included from july 2019 to march 2021 in 11 IFM centers Median age was 57 (range 38 -65). ISS stage 3 was present in 12 (24%) patients. Based on inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n=20, 40%), t(4;14) (n=26, 52%) or t(14;16) (n=10,20%). Forty-six patients completed Dara-KRD induction. Two patients discontinued treatment due to seere aderse eent (COVID-19 infection, n=1 ;drug-induced hepatitis, n=1) and 2 patients discontinued treatment due to disease progression. Grade 3-4 treatment related aderse eent (>5% of patients) were neutropenia (38%), anemia (14%), thrombocytopenia (8%), infection (6%), renal insufficiency (6%) and deep-ein thrombosis (6%). Two patients (6%) experienced stem-cell collection failure. Oerall response rate was 96%, including 92 % > ery good partial response. Among 37/46 ealuable patients post induction, Minimal Residual Disease negatiity rate (NGS, 10-5) was 62%. Summary/Conclusion: Dara-KRD as induction prior ASCT is safe and allows deep responses in TE NDMM patients with high-risk cytogenetic profile. IFM 2018-04 study is ongoing and longer follow-up is needed to ealuate safety and efficacy of the oerall strategy with Dara-KRD induction and consolidation plus double transplant in this subset of HR patients.

Bortezomib- and carfilzomib-resistant myeloma cells show increased activity of all three arms of the unfolded protein response

Proteasome inhibitors are among the most potent classes of drugs in multiple myeloma treatment. One of the main challenges in myeloma therapy is acquired resistance to drugs. Several theories have been proposed to describe the mechanisms responsible for resistance to the most commonly used proteasome inhibitors bortezomib and carfilzomib. This study aimed to describe functional differences between sensitive myeloma cells (MM1S WT) and their daughter cell lines resistant to either bortezomib (MM1S/R BTZ) or carfilzomib (MM1S/R CFZ), as well as between both resistant cell lines. Bortezomib- and carfilzomib-resistant cell lines were successfully generated by continuous exposure to the drugs. When exposed to different drugs than during the resistance generation period, MM1S/R BTZ cells showed cross-resistance to carfilzomib, whereas MM1S/R CFZ cells were similarly sensitive to bortezomib as MM1S WT cells. Following proteomic profiling, unsupervised principal component analysis revealed that the MM1S/R BTZ and MM1S/R CFZ cell lines differed significantly from the MM1S WT cell line and from each other. Canonical pathway analysis showed similar pathways enriched in both comparisons - MM1S WT vs. MM1S/R CFZ and MM1S WT vs. MM1S/R BTZ. However, important differences were present in the statistical significance of particular pathways. Key alterations included the ubiquitin-proteasome system, metabolic pathways responsible for redox homeostasis and the unfolded protein response. In functional studies, both drugs continued to reduce chymotrypsin-like proteasome activity in resistant cells. However, the baseline activity of all three catalytic domains of the proteasome was higher in the resistant cells. Differences in generation of reactive oxygen species were identified in MM1S/R BTZ (decreased) and MM1S/CFZ cells (increased) in comparison to MM1S WT cells. Both baseline and drug-induced activity of the unfolded protein response were higher in resistant cells than in MM1S WT cells and included all three arms of this pathway: IRE1α/XBP1s, ATF6 and EIF2α/ATF4 (downstream effectors of PERK). In conclusion, contrary to some previous reports, resistant MM1S cells show upregulation of unfolded protein response activity, reflecting the heterogeneity of multiple myeloma and prompting further studies on the role of this pathway in resistance to proteasome inhibitors.

Daratumumab carfilzomib lenalidomide and dexamethasone as induction therapy in high-risk, transplant-eligible patients with newly diagnosed myeloma: Results of the phase 2 study IFM 2018-04

Background: High-risk (HR) cytogenetic is associated with poor outcome in transplant eligible (TE) newly diagnosed myeloma multiple myeloma (NDMM). The triplet combination carfilzomib lenalidomide and dexamethasone (KRD) plus transplantation demonstrated high efficacy with favorable safety profile in TE-NDMM patients (FORTE). The addition of daratumumab (Dara) to frontline therapy also improved response rate and progression free-survival in TE-NDMM patients (CASSIOPEIA, GRIFFIN). Double transplant also improved outcome of HR TE NDMM patients (EMN02, STAMINA). The phase 2 trial 2018-04 from the Intergroupe Francophone du Myelome (IFM) is evaluating an intensive strategy with Dara-KRD induction and consolidation plus double transplant in HR TE NDMM (NCT03606577). Methods: HR MM was defined by the presence of del17p, t(4;14) and/or t(14;16). Stategy includes Dara-KRD induction (6 cycles), autologous stem cell transplantation (ASCT), Dara- KRD consolidation (4 cycles), second ASCT, Dara-lenalidomide maintenance. The primary endpoint was the feasibility of this intensive strategy. Here, we report efficacy and safety analysis of Dara-KRD induction. Results: Fifty patients with previously untreated NDMM were included from july 2019 to march 2021 in 11 IFM centers Median age was 57 (range 38 -65). ISS stage 3 was present in 12 (24%) patients. Based on inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n = 20, 40%), t(4;14) (n = 26, 52%) or t(14;16) (n = 10,20%). Forty-six patients completed Dara-KRD induction. Two patients discontinued treatment due to severe adverse event (COVID-19 infection, n = 1 ;drug-induced hepatitis, n = 1) and 2 patients discontinued treatment due to disease progression. Grade 3-4 treatment related adverse event (> 5% of patients) were neutropenia (38%), anemia (14%), thrombocytopenia (8%), infection (6%), renal insufficiency (6%) and deep-vein thrombosis (6%). Two patients (6%) experienced stem-cell collection failure. Overall response rate was 96%, including 92 % > very good partial response. Among 37 (/46) evaluable patients post induction, Minimal Residual Disease negativity rate (NGS, 10-5) was 62%. Conclusions: Dara-KRD as induction prior ASCT is safe and allows deep responses in TE NDMM patients with high-risk cytogenetic profile. IFM 2018-04 study is ongoing and longer follow-up is needed to evaluate safety and efficacy of the overall strategy with Dara- KRD induction and consolidation plus double transplant in this subset of HR patients.

CONTINUOUS THERAPY WITH CARFILZOMIB-LENALIDOMIDE-DEXAMETHASONE (KRD): A MULTICENTRIC EXPERIENCE IN REAL-LIFE

The irreversible proteasome inhibitor Carfilzomib has a proven efficacy in doublet and triplet combinations for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) as shown in the ENDEAVOR and ASPIRE trials. Here we retrospectively analyzed a series of RRMM patients treated with KRd regimen over 18 cycles to evaluate efficacy and tolerability of continuous treatment (Table 1). Data were elaborated using SPSS Statistics Version 26. Overall survival (OS) was calculated from the time of the beginning of treatment until the date of death for any cause or last follow-up visit. Progression free survival (PFS) was defined as the time from the beginning of treatment to documented progression. OS and PFS were analysed by the Kaplan-Meier test. The statistical significance level was set at the 95th percentile. 36 patients were enrolled at one Calabrian and three Sicilian centres on behalf of the Sicilian Myeloma Network from June 2016 to November 2021. 24 of them were on first relapse (66,6%). Median number of cycles was 31.5 (range 18-61). Overall response rate (ORR) at first response to KRd was 92%: 3 patients (8%) achieved a complete response (CR), 14 patients (39%) achieved a very good partial response (VGPR), 16 (45%) achieved PR, 2 (5%) a minimal response (MR) and 1 (3%) had a stable disease (SD). ORR at best response was 97% (56% CR, 30% VGPR, 4% PR), 1 patient (3%) had SD. At last follow up ORR was 53%: (36% CR, 8% VGPR, 8% PR), one (3%) had a SD. Progression disease (PD) occurred in 16 patients (44%), 15 of them were exposed to another treatment, among them 9 patients were exposed to at least two more treatments including novel agents (Daratumumab, Pomalidomide, Belantamab- Mafodotin). Median PFS was not reached and so was median OS calculated from the beginning of KRd. 9 patients (25%) reported grade 3-4 hematological AEs, 13 patients experienced (36%) grade 3-4 nonhematological AEs, only 3 (8%) cardiovascular AEs. Lenalidomide was reduced in 21 (58%), interrupted in 9 (25%) patients due to serious adverse events (SAEs). During Sars-Cov-2 pandemic waves, to reduce hospital admission, 8 patients who achieved at least VGPR continue halved Carfilzomib administration schedule (total dose 27 mg/m2 once every 2 weeks instead of twice) maintaining previous response except for 1 patient who experienced PD (at cycle 32, after one more year of KRD treatment). Real-world experiences often significantly diverge from randomized clinical trials for patients selection resulting into differences in terms of efficacy and tolerability. In our study KRd combination deepened response over time without relevant toxicity as showed also in a subgroup analysis of ASPIRE and ENDEAVOR. In addition, schedule modification during Sars-Cov-2 pandemic reduced the number of hospital admissions without losing quality of response, thus opening the question of which is the best administration regimen of Carfilzomib as maintenance. (Table Presented).

Acute respiratory distress syndrome after exposure to carfilzomib (KYPROLIS)

Case Report Introduction Plasma cell leukemia is very rare and an aggressive form of leukemia with a poor prognosis. Interim analysis of a phase II trial (EMN12/HOVON 129) using carfilzomib, lenalidomide, and dexamethasone (KRd) in patients with PCL ≤65 years showed a very good partial response or greater response in 80% with 33% achieving at least a complete response. Carfilzomib (Kyprolis TM) is a proteosome inhibitor and is associated with ARDS and acute respiratory failure in 2% of the cases per FDA package insert. We present a case report of acute respiratory distress syndrome presumed to be potentiated 2/2 to carfilzomib infusion. Case A 58-year-old male with a history of hypertension, recent COVID-19 infection and new diagnosis of untreated Plasma Cell Leukemia presented to our hospital with worsening chest pain, fatigue and dyspnea. Vitals on admission were notable for BP 158/88, HR 101, Tmax 99F and sating 100% on room air. Peripheral blood exam showed WBC: 27.7 x109/L, Hb: 8 gm/dl, platelet: 121000, corrected calcium: 13.3 mg/dl, creatinine: 1.16 mg/dl, total protein:11 g/ dl, uric acid: 8.2 mg/dl, B-2 micro globulin: 5.8 mg/L, Mspike: 5.6 g/dl;IgA lambda type. CT Chest abdomen pelvis revealed diffuse lytic bone lesions. Due to inability to obtain bone marrow biopsy from limited resources after Hurricane Ida and aggressive nature of the cancer, treatment was initiated based off a previous flow cytometry from the peripheral blood which showed 55% plasma cells. Patient started on chemotherapy with Cyclophosphamide, Carfilzomib, and dexamethasone with plans to change to Revlimid from cycle 2. He was also started on fluid hydration and Zometa for hypercalcemia. Patient also received aggressive blood pressure control with metoprolol, amlodipine and IV labetalol as needed. After 2nd dose of Kyprolis, he developed acute hypoxic respiratory distress and was initiated on Bipap. Chest Xray was concerning for fluid overload and/or evolving pneumonia. He was supported with diuretics and broad-spectrum antibiotics;however, he eventually was intubated. He was also started on high dose steroids. Repeat CT chest was negative for thrombosis, but showed extensive bilateral pleural -parenchymal opacities. He had a bronchoalveolar lavage with no obvious infection. Over the next 2 days, patient showed improvement and eventually self-extubated. After his recovery, we continued chemotherapy with Kyprolis and he has tolerated it without issues. Discussion The etiology of ARDS is likely multifactorial, however Kyprolis may have played a major role in his decompensation mainly due to the timing and known side effects of the medication. Based on a study from 2018, only 5 case reports of Kyprolis-associated non-infectious progressive lung injury were found at that time. Clinicians should be mindful of Kyprolis induced lung injury and emphasize the need for tight blood pressure control and careful administration of intravenous fluids to decrease the possibility of lung injury.

The development of a home-based therapeutic platform for multiple myeloma.

BACKGROUND: Multiple Myeloma (MM) accounts for 1-2% of all malignancies but is the second most common hematological malignancy. It is characterized by a proliferation of malignant plasma cells. The treatment paradigm of MM in Australia is traditionally hospital-based, complex, and costly. While MM comprises 1-2% of cancer diagnoses, it appears in the top 10 cancer diagnoses requiring hospital admission. The cumulative time spent receiving treatment is a significant burden for patients. The ability to receive treatment at home and maximize time away from hospital-based settings is a key preference for patients receiving anticancer therapies over a prolonged period of time. METHODS: The Peter MacCallum Cancer Centre and Royal Melbourne Hospital's combined Clinical Hematology Unit has collaborated with their Hospital in the Home departments to develop several innovative programs to address this. RESULTS: We describe our current active programs and potential developments in home-based MM therapy. CONCLUSION: We have enabled large numbers of patients to receive complex therapies in their own home and the COVID-19 pandemic has increased the pace of the roll out without any compromise in safety. We anticipate that the next raft of immunotherapies will be able to transition into the @Home treatment setting in the coming years.

Utilizing HealthTree ® Cure Hub's Real-World Data to Assess Treatment Management of Patients with Multiple Myeloma during the COVID-19 Pandemic

Background: Patients with multiple myeloma (MM) are uniquely susceptible to viral and bacterial illnesses, including COVID-19, due to their immunocompromised state, age, treatments, and comorbidities. With the advent of COVID-19, changes to treatment were recommended whenever possible, in order to reduce visits to the clinic. The total effect of these changes on cancer patients with multiple myeloma remains unclear. The aim of this project was to assess treatment management by changes to treatment of patients with MM during the COVID-19 pandemic. Methods: We utilized HealthTree ® Cure Hub for Multiple Myeloma (healthree.org) and invited patients with active MM cancer or precursor conditions to participate in an online survey. We analyzed patient responses to questions regarding their myeloma treatments during the COVID-19 pandemic. Results: 978 MM patients participated in the survey between February to June 2021. Since March 2020, 151 patients (15%) either delayed, postponed, or stopped a myeloma treatment because of COVID-19. The four most common treatments were daratumumab (20%), lenalidomide (15%), stem cell transplant (13%) and zoledronic acid (11%). There were 110 patients that canceled a planned myeloma treatment. Of these patients, 55 (50%) canceled a planned chemotherapy, 15 (14%) canceled a stem cell transplant, 1 (1%) canceled radiation and 39 (35%) indicated other. Eight patients replaced an intravenous or subcutaneous treatment with an oral treatment because of COVID-19. There were 9 patients that started a new myeloma treatment because of COVID-19, the most common being daratumumab (44%), ixazomib (22%), lenalidomide (22%) and carfilzomib (11%). Finally, 15 patients had their lenalidomide (50%), steroid (42%) and carfilzomib (8%) dose changed. Conclusions: Our results show that decision-making regarding treatment changes were made on an individual basis and that patients who required a change in treatment were the minority. Aggregating real-world data can provide evidence that despite the changes, patients with MM still received and efficacious treatment and avoided putting these patients at risk or mortality. Disclosures: Ahlstrom: Bristol Myers Squibb: Other: Patient Advisory;Janssen: Other: Patient Advisory;Pfizer: Other: Patient Advisory;Takeda: Other: Patient Advisory.

Hospital in the Home Delivery of Supportive Care for Autologous Stem Cell Transplantation: A Novel Single Centre Patient Focused Approach

Introduction: High dose therapy with Autologous Stem Cell Transplantation (ASCT) has traditionally been performed as an inpatient procedure. However, with improvements in care and patient selection it is possible to safely deliver conditioning chemotherapy and supportive care in an Daytherapy setting (Kodad SG et al., 2019). While deemed an “outpatient procedure” this method is often delivered on large day units which requires the patient to attend daily, often only spending overnight at home. To reduce these daily visits the Clinical Haematology Department of Peter MacCallum and Royal Melbourne Hospital (CHD) in collaboration with the Hospital in the Home department (HIHD) at Royal Melbourne Hospital developed an innovative program to safely deliver supportive care for Myeloma Patients undergoing ASCT at home (HIH-ASCT). The HIHD is an acute inpatient unit that exists as a “virtual” inpatient ward. Patients are reviewed daily by a HIHD Doctor with twice daily visits by a HIHD Nurse for administration of supportive care measures (e.g. intravenous electrolyte and fluid replacement) in the comfort of their home. Here we report on the safety outcomes of our HIH-ASCT program, specifically patient complications and outcomes. Methods: A retrospective case note audit identified 54 consecutive HIH-ASCT patients who received HIH-ASCT for Myeloma between 2018 and 2021 under HIHD. Patients were eligible for our HIH-ASCT program if they had Myeloma requiring ASCT;an ECOG ≤1;had not been admitted to ICU previously;lived within 30 minutes drive of the hospital;had a safe home environment (for both the patient and visiting staff) and a carer who could stay with them throughout their HIH-ASCT. While undertaking HIH-ASCT patients did not receive prophylactic antibiotics and they were not routinely given GCSF to minimise the risk of engraftment fevers. Results: Of those treated as HIH-ASCT patients the median age was 60 years (range 33-72). 39% patients were female (n=21) and 61% male (n=33). Underlying disease groups included IgA (n=8;15%), IgG (n=35;64%), IgM (n=1;2%), Light Chain (n=9;17%) and Oligosecretory (n=1;2%). 43% had High-risk Cytogenetics. ASCT-1 (n=48;88%), ASCT-2 (n=5;9%) and one patient underwent a ASCT-Tandem (both under HIHD). Conditioning regimes included Melphalan200 (n=37;68%), Velcade-Melphan200 (n=13;23%) and Carfilzomib-Melphalan200 (n=5;9%). The average stem dose was 3.80 x10 6/kg (range 2.14-8.4). Median time to Neutrophil engraftment was 12 days (range = 10-21) and Platelet engraftment 12 days (range = 8-18). The total number of bed days saved through the HIH-ASCT program was 466, with a median length of stay (LOS) under the HIHD team of 9 days (Range = 3-14). In addition, 3 patients were not readmitted to the hospital (6%) and were discharged directly from the HIHD team. The most common reason for readmission was fever (n=43;80%), of which only 11 were culture positive, and diarrhoea (n=44;81%). Only 1 patient required intensive care support. There were no deaths. The median LOS as an inpatient once readmitted was 6 days (range = 2-27). In regards to cost savings, an acute inpatient bed under the CHD is approximately $1300 USD versus $900 USD per day for a HIHD bed. This equated to a potential cost saving for the CHD of approximately $186000 USD. Conclusion: The delivery of supportive care for patients undergoing HIH-ASCT in is both safe and effective with comparable outcomes for what would be expected for an inpatient cohort. It resulted in a median of 9 bed days saved per patient (total number of bed days saved = 466). This is important as it allowed our department to increase bed capacity across the unit without the associated costs of building a new ward. In addition, during our COVID-19 outbreaks the HIH-ASCT program has allowed us to continue to deliver optimal patient care, while minimising the infection risk for our patients. More recently we have introduced remote monitoring (e.g. temperature, heart rate, blood pressure and oxygen saturations) with video reviews with the aim of increasing the capacity of our HIHD and further improving the HIH-ASCT experience for our patients. Disclosures: Routledge: Amgen: Honoraria, Speakers Bureau;Sandoz: Consultancy, Honoraria, Speakers Bureau;BMS: Honoraria. Harrison: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Eusa: Consultancy, Honoraria, Speakers Bureau;Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Terumo BCT: Consultancy, Honoraria;Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ritchie: CRISPR Therapeutics: Research Funding;Amgen Inc: Honoraria, Research Funding;Novartis: Honoraria;CSL: Honoraria;BMS: Research Funding;Takeda: Research Funding.

BNT162b2 mRNA COVID-19 Vaccination (BNTCV) in Patients (Pts) Having Hematological Malignancies (HM): Early tolerance with telemedicine application connecting and antibody anti-Spike IgG response (AcAS)

Pts with HM and particularly those under therapy or with secondary immune deficiency have been reported to have a low or delayed specific immune response. In addition, pts receiving rituximab for either HM or auto-immune disease presented a low specific antibody response. Daratumumab, an anti-CD38 moAb was demonstrated to lower normal plasma cells and to reduce polyclonal IgA, M and E in pts with multiple myeloma (MM). It is fundamental to evaluate the early post-vaccination tolerance and the level of seroconversion for such pts. Patients' population. 194 pts having HM and followed at the Institute (IC), received at least 2 doses of BNTCV (BioNTech Pfizer, Paris, France) by IM route with 3 weeks between the 2 doses. Currently, analysis was performed on 147 pts, including 63 pts with non-Hodgkin lymphoma (NHL), 18 with B-chronic lymphocytic leukemia (CLL), 34 with MM, 14 with monoclonal gammopathy of undetermined significance (MGUS) and 18 with myeloproliferative disorder (MPD). Mean age was 69 years-old (range 27-92). Follow-up of early tolerance in pts using a telemedicine application. 43 pts vaccinated at the IC received Thess®, a telemedicine system connecting the patient to the IC, developed by La Valeriane Inc. (Montpellier, France, www.thess-corp.fr) 24/24h, 7days. Local pain (<1 day) was common and transient, particularly reported after the 2nd dose. Only 4/43 patients reported significant adverse events through telemedicine and followed by a medical call, including mainly severe asthenia for 2 days or more, fever (>38°C) for at least 2 days, headache, or general pain. The satisfaction survey of monitoring system was good. In addition, adherence to vaccination was excellent with only one refusal out of the 194 pts. AcAS follow-up IgG AcAS and IgG+M AcAS were analyzed in the serum 3 to 4 weeks after the 1st dose and 4-8 weeks after the 2 nd dose and every 2 months, respectively by SARS-CoV-2 IgG II Quant ® Assay with a threshold of positivity at 50 AU/mL (Abbott, Rungis, France) and Elecsys ® Anti-SARS-CoV-2 S (Roche Diagnostics, Meylan, France) with a threshold of positivity at 0.8 U/mL. 270 samples were analyzed in duplicate with the 2 assays, by 2 independent labs. Data were reported and statistically analyzed by the clinical research team. 17 results were discordant including 12 with Abbott IgG test undetectable and Roche IgG+M detectable, and 5 with Abbott test detectable and Roche undetectable. After the first dose of BNTCV, 72/147 (49%) pts were seroconverted, including 7/18 (39%) with CLL, 27/63 (43%) with NHL, 10/14 (71%) with MGUS, 17/34 (50%) with MM and 11/18 (61%) with SMD. The median levels of the AcAS response for pts were 0 (range 0-40 000 AU/mL) for the AdviseDX test as compared to 12 normal subjects (mean 257 AU/mL, range 226-283), and 0 U/mL (range 0-2500) for the Elecsys test. 49/75 (65%) of untreated pts were seroconverted after the 1 st dose as compared to 26/72 (36%) of treated patients (p<0.001), with rituximab or ibrutinib as negative factors in addition to low gammaglobulin level (<5g/L, p=0.019), similarly to the IgG level. Analysis of CRP levels, circulating lymphocyte counts, and lymphocyte subpopulations will be performed. After the second dose of BNTCV, 50 pts have currently been tested, with only 25 additional pts seroconverted. The median levels of the AcAS response for pts were 310 AU/mL (range 62-11760) for the AdviseDX test as compared to 12 normal subjects (mean 6725 AU/mL, range 3002-9787), and 1250 U/mL (range 0.87-2500) for the Elecsys test. The 25 patients who were not seroconverted after the 2nd dose received a 3rd dose of BNTCV, including 8 with MM, 9 with NHL, 5 with CLL, 1 with MGUS (with polyneuropathy under daratumumab) and 2 with SMD. Currently, 9 pts were tested after the 3 rd dose. AcAS levels were respectively 268 AU/mL for 1 MM treated by daratumumab, 103 and 313 AU/mL for 2 MM under carfilzomib, 1622 AU/mL for 1 untreated SMD, 29100 AU/mL for 1 untreated MGUS, 537 AU/mL for 1 CLL and 2 negative NHL. In conclusion, there is a need to follow AcAS for pts aving HM including SMD after BNTCV aiming to adapt vaccine strategy including a 3 rd dose and eventual recall. As some pts are always negative after a 3 rd dose, vaccination strategy could be discussed by using different combinations of vaccine or the addition of immune adjuvant in a more personalized medicine. In addition, the usage of telemedicine connecting system may help to follow the early tolerance and to improve the pts' adherence. Disclosures: Rossi: NPO Petrovax Pharm: Consultancy;LEO Pharma: Consultancy;EUSA Pharma: Consultancy;E-SANA Inc: Other: Co-founder of E-SANA Inc.

A combination of carfilzomib, dexamethasone, and daratumumab for treatment of adult patients with relapsed/refractory multiple myeloma in two dosing regimens: once-weekly and twice-weekly.

INTRODUCTION: Despite the development of new therapeutic agents, relapsed/refractory multiple myeloma (RRMM) is associated with poor survival outcomes. Furthermore, many patients develop resistance to immunomodulatory drugs (IMiD), creating a need for IMiD-free regimens. Areas covered: This review focuses on the combination of carfilzomib, dexamethasone, and daratumumab (KdD or DKd) which has shown promising results in patients with RRMM who have tried multiple lines of therapy, and has been approved in the U.S., EU, and Japan. The KdD triplet has two recommended dosage regimens, carfilzomib once-weekly (KdD70 QW) and carfilzomib twice-weekly (KdD56 BIW), with comparable efficacy and safety profiles. Expert opinion: These options provide flexibility to patients and healthcare providers, especially in the era of COVID-19. Carfilzomib-based regimens remain a standard of care based on multiple randomized phase 3 studies. Additional studies are currently underway investigating carfilzomib-based regimens such as KdD combined with novel agents. Nevertheless, KdD is one of the most efficacious options for patients with RRMM.