ADDITION OF IXAZOMIB TO POMALIDOMIDE AND DEXAMETHASONE IMPROVES PROGRESSION-FREE SURVIVAL FOR MULTIPLE MYELOMA PATIENTS PROGRESSING ON LENALIDOMIDE AS PART OF 1ST LINE THERAPY: ALLIANCE A061202

Background: Lenalidomide (LEN) maintenance and continuous LEN-based induction therapy until disease progression have become standard of care for frontline therapy of multiple myeloma (MM). As such, an increasing number of patients (pts) in need of 2nd line therapy have LEN-refractory disease. Optimal treatment in this setting has not been rigorously assessed in randomized studies. The phase I portion of Alliance A061202 demonstrated the safety of the ixazomib-pomalidomide-dexamethasone (IXA-POM-DEX) combination for the treatment of pts with LEN and proteasome inhibitor (PI)-refractory MM. Aims: In the randomized phase II portion, we evaluated the addition of IXA to POM-DEX for PI naïve / sensitive pts progressing on LEN as part of 1st line therapy. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall response rate (ORR), depth of response, survival and safety. Methods: Pts were randomized 1:1 to IXA-POM-DEX or POM-DEX and stratified by prior bortezomib exposure, International Staging System stage (1 and 2 vs 3) and the presence of high-risk cytogenetics. POM was administered at 4 mg on days 1-21;IXA 4 mg on days 1, 8 and 15;and DEX 20 mg (>75 years (yrs)) or 40 mg (≤75 yrs) on days 1, 8, 15 and 22 of a 28-day cycle. Treatment was continued until disease progression, the emergence of unacceptable side effects or withdrawal of treatment consent. Results: 38 and 39 eligible pts were assigned to IXA-POM-DEX and POM-DEX, respectively. The median age was 66 yrs (range 41-83) and 64 yrs (range 52-85). A planned first interim analysis was conducted after 43 out of 57 required events had occurred. PFS favored the IXA-POM-DEX arm (one-sided log rank test value = 4.6345, p=0.03134 [< p-value boundary of 0.058]), yielding a hazard ratio of 0.528 (upper 90% bound = 0.777). A stratified log-rank test found that PFS was superior for the triplet after adjusting for stratification factors (one-sided stratified log rank test value = 5.8371;p=0.0157), adjusted hazard ratio 0.451 (upper 90% bound = 0.694). The ORR favored IXA-POM-DEX (63.2% vs 43.6%, p=0.0853), and the ≥very good partial response was 26.3% vs 5.1%, respectively (p=0.01). The clinical benefit rate (ORR + minimal response rate) was 73.7% and 56.4%. The most common grade 3/4 adverse events included lymphopenia, neutropenia, anemia, and fatigue in 40%, 37%, 16% and 16% of IXAPOM-DEX-treated pts and 26%, 21%, 13%, and 15% of POM-DEX-treated pts. Therapy was discontinued for disease progression in 47.4% of pts on IXA-POM-DEX and 76.9% of pts on POM-DEX and for adverse events in 7.9% and 7.7% of pts, respectively. Summary/Conclusion: The addition of IXA to the POM-DEX backbone improved the depth of response and PFS for pts relapsing on LEN as part of 1st line therapy. Hematologic toxicity was increased with the addition of IXA, but side effects were manageable. The ease of administration of this all-oral combination allowed for safer, uninterrupted treatment during the COVID pandemic. Our results should be confirmed in phase III trials but lend support for this regimen as part of 2nd line therapy for this patient population.

DREAMM-9: PHASE I STUDY OF BELANTAMAB MAFODOTIN PLUS STANDARD OF CARE IN PATIENTS WITH TRANSPLANT-INELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA

Background: The bortezomib, lenalidomide, and dexamethasone (VRd) regimen is a standard of care for newly diagnosed multiple myeloma (NDMM). Belantamab mafodotin (belamaf) is a B-cell maturation antigen-binding antibody-drug conjugate that eliminates myeloma cells by a multimodal mechanism: direct cell kill and anti-myeloma tumor immune response. Belamaf has demonstrated deep and durable responses as a monotherapy in the DREAMM-2 study of patients (pts) with relapsed/refractory multiple myeloma (RRMM). Preclinical evidence of belamaf in combination with bortezomib or lenalidomide suggests enhanced anti-myeloma activity, providing rationale for this treatment combination. Aims: To evaluate the safety and tolerability of this combination in adult pts with transplant-ineligible (TI) NDMM and establish the recommended Phase III dose. Methods: DREAMM-9 (NCT04091126) is an ongoing Phase I, open-label, randomized study of belamaf + VRd. The belamaf dose cohorts currently being evaluated are Cohort 1 (1.9 mg/kg Q3/4W), Cohort 2 (1.4 mg/kg Q6/8W), Cohort 3 (1.9 mg/kg Q6/8W), Cohort 4 (1.0 mg/kg Q3/4W), and Cohort 5 (1.4 mg/kg Q3/4W). Belamaf is given with VRd Q3W until Cycle 8, and with Rd Q4W thereafter. After evaluation of safety data for Cohort 1, Cohorts 2-5 were opened in parallel and enrolled pts were randomized 1:1:1:1. Primary endpoint is safety. Secondary endpoints include efficacy, tolerability, and pharmacokinetics (PK). Results: As of data cutoff (07 Dec 2021), 64 pts were analyzed across all cohorts. Median age (range) was 73.0 (51- 88) years, 55% were male, 80% were white, 8% had extramedullary disease, 59% were International Staging System stage II or III, 20% had amp1q, and 17% had high-risk cytogenetics (≥1 of: t(4;14), t(14;16), del17p). The median duration of follow-up varied: Cohort 1 (17.4 months [mo]), Cohort 2 (5.9 mo), Cohort 3 (6.1 mo), Cohort 4 (4.7 mo), Cohort 5 (5.8 mo). Median number of belamaf cycles were: Cohort 1 (6), Cohort 2 (3), Cohort 3 (3.5), Cohort 4 (4.5), and Cohort 5 (5). Most common adverse events (AEs) across cohorts included thrombocytopenia (49%), constipation (43%), diarrhea (32%), and peripheral sensory neuropathy (30%). AEs related to study treatment were experienced by 61 (97%) pts. Belamaf-related grade 3/4 AEs occurred in 24 (38%) pts. Belamaf dose reductions occurred in 11 (18%) pts, with dose delays in 10 (16%) pts. Three pts experienced a fatal severe AE (unrelated to study treatment);2 due to COVID-19 infection, 1 due to pancreatic adenocarcinoma. Early deep responses were observed;67-92% pts achieved ≥very good partial response (VGPR) (Table), with median time to VGPR of 2.1-2.9 months across cohorts. Of pts with ≥VGPR, 17 were minimal residual disease (MRD) negative, 10 in Cohort 1. As of data cutoff, 8-75% of pts achieved best response of complete response (CR) or stringent CR (sCR). Grade 3 corneal exam findings were reported in 25-58% of pts;grade 3 visual acuity changes were reported in 21-75% of pts. No grade 4 corneal exam findings or visual acuity changes were reported in pts receiving belamaf Q6/8W, compared with 0-17% and 0-8%, respectively, in the Q3/4W cohorts. Belamaf PK profile was similar to that in pts with RRMM, accounting for baseline characteristics. Image: Summary/Conclusion: Belamaf + VRd demonstrated high response rates in pts with TI NDMM, with a high rate of MRD negativity indicating deep responses. No new safety signals were observed relative to DREAMM-2. Study is ongoing to evaluate the safety and efficacy of variable dose intensities of belamaf in combination with VRd.

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.

RISK AND PATTERN OF INFECTIONS IN NEWLY DIAGNOSED PATIENTS OF MULTIPLE MYELOMA VACCINATED UPFRONT AGAINST PNEUMOCOCCUS & INFLUENZA

Background: Infections contribute to an early mortality risk of 15 percent in newly diagnosed multiple myeloma(NDMM) cases. There is a limited literature on the type of infections in fully vaccinated NDMM patients. Aims: To study epidemiology, clinical profile and predictors of infection in NDMM who are immunised against pneumococci and influenza. Methods: NDMM patients were prospectively studied for 6 months for the pattern of infections . All patients were vaccinated with pneumococcal and Influenza vaccine at diagnosis. PJP prophylaxis and fluconazole prophylaxis was given for patients receiving high dose steroids while acyclovir was given to all. Infections were classified as microbiologically defined, clinically defined and fever of unknown focus according to definitions published by the International Immunocompromised Host Society. Severity of infections were graded according to the NCI CTCAE Ver5. Results: Forty-eight NDMM patients with a median age 55 years comprising of 26 males and 22 females were enrolled. Renal involvement was noted in 42% of enrolled patients and two third of them required renal replacement therapy. ISSIII and R-ISS III were 70.8 % and 62.5 % respectively. 85% had poor performance status(ECOG ≥2) at baseline. RVD was the most common regimen (37%)used. 6 patients received daratumumab based regimen. Treatment response of atleast VGPR was seen in 97 % of NDMM patients. A total of 19 episodes of infections were observed during 6 months. All episodes of infections were reported in the first 45 of myeloma diagnosis(Median 6 days;Range 0-45). Ten of these episodes of infection were diagnosed during the initial evaluation for myeloma defining events. Microbiological diagnosis was possible in 63 %. Commonest infectious agent was COVID 19(n=8) followed by Gram negative bacteria (n=5) viz E.coli and Klebsiella pneumoniae . None of the eight patients who developed COVID 19 infection had received COVID vaccine as they antedated the operationalisation of national guidelines for immunisation. Respiratory and the urinary tract were the most common focus of infection. All critically ill COVID patients succumbed to progressive respiratory failure and all patients with mild and moderate COVID illness recovered uneventfully. Early mortality in our cohort of forty eight patients was twenty percent(n=10). Three fourths of infections in our cohort were Grade≥3 severity. A total of seven deaths were attributable to infectious diseases in this cohort of NDMM patients. Imune paresis was seen in eighty four percent of patients at diagnosis. On follow up at 6 months;immune paresis had persisted in only thirty seven percent. Regression analysis of variables with odds of infection is shown in Table 1 Baseline BMI<18.5 kg/m2;albumin<3g/dl and ISS or R-ISS stage ≥ 2 was found to be have statistically significant odds of predicting infection risk in the cohort of patients. The choice of myeloma regimen, presence of high risk cytogenetics and response to therapy did not correlate with increased odds of infection in our cohort. Summary/Conclusion: Conclusion In this prospective study of NDMM patients vaccinated against pneumococci and influenza at baseline;infection attributable early mortality was 14.5 %. Advanced stage of presentation, hypoalbuminemia and baseline BMI < 18.5 kg/m2 correlated with increased odds of infection. COVID vaccination and COVID appropriate behavioural practices may mitigate COVID related outcomes including deaths in myeloma patients.

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.

Real-world outcomes of myeloma patients who fulfil the SLiM part only of the SLiM-CRAB criteria and who underwent monitoring during the COVID -19 pandemic: a single centre analysis

International Myeloma Working group (IMWG) diagnostic criteria for myeloma (MM) requires the presence of ≥10% clonal plasma cells alongside a MM defining event-traditionally a CRAB feature (hypercalcaemia, renal impairment, anaemia, bone disease). In 2014, three biomarkers were added (≥60% plasma cells in the marrow, light chain ratio ≥100 and ≥2 focal lesions on MRI), each associated with around an 80% probability of developing CRAB features within 2 years. These biomarkers are the SLiM criteria and the recommendation is that such patients are treated. In March 2020 UK Myeloma Forum issued guidance for MM therapy during the Covid-19 pandemic, recommending patients who fulfil the SLiM part only of the SLiM/CRAB (SLiM positive) or who only have anaemia should be monitored. There is a lack of real-world data available to validate the recommendation to treat based on SLiM criteria. The impact of not treating these patients during the Covid-19 pandemic remains unknown. We conducted a retrospective analysis of the outcomes of SLiM positive patients at Nottingham University Hospitals (NUH) NHS Trust who underwent observation rather than treatment during the Covid-19 pandemic. SLiM positive patients were detected via the MM MDT min from 1st April 2020-30 Nov 2021. Time to progression (TTP) was defined as the time from diagnosis of SLiM positive MM until the time systemic therapy was initiated (day 1 cycle 1). Decision to treat was based on development of CRAB features, worsening of SLiM criteria and patient choice. 22 SLiM positive patients were identified. Patient characteristics and outcomes for the entire cohort and for those who did and did not progress are shown in Table 1. No patients were R-ISS stage III and 1q gain was the only high-risk cytogenetic abnormality detected. This may suggest higher risk patients are more likely to present with CRAB features and less likely to be SLiM positive. The median follow-up was 12 months. Forty-one percent of patients progressed to require therapy in keeping with the IMWG data suggesting 80% of SLiM positive patients will progress over a 2-year period. The median TTP was not reached. For those patients who did progress, the median TTP was 3.8 months. Reasons for progression are shown in Table 1. Overall survival (OS) was 100% hence no suggestion thus far that observation of SLiM positive patients during the Covid-19 pandemic increased MM-related mortality. The majority who remained under observation were SLiM positive on WBMRI alone. In contrast, the majority who did progress had been SLiM positive on SFLC ratio, marrow infiltrate or a combination of features. We acknowledge the small numbers and relatively short follow-up of this study. Results thus far are in keeping with the IMWG finding that SLiM positive patients have around an 80% chance of progression at 2 years. There is a suggestion that patients who present with SLiM criteria only may have genomically lower risk disease. OS has not been affected thus far by monitoring SLiM patients. Our results also suggest that patients SLiM positive due to SFLC ratio or BM infiltration are more likely to require early intervention than those positive on WBMRI. We recommend a future multicentre UK wide analysis of the outcome of SLiM positive patients during Covid-19. Results would help counsel UK MM patients regarding when to offer treatment and potentially help develop a UK-based biomarker model to predict risk of progression..

Cybord-Dara in Newly Diagnosed Transplant-Eligible Multiple Myeloma: Follow up Results from the 16-Bcni-001/Ctrial-IE 16-02 Study Show High Rates of MRD Negativity at End of Treatment

The anti-CD38 monoclonal antibody Daratumumab has shown impressive activity in combination with other agents for the treatment of multiple myeloma (MM), improving progression free survival and overall survival in several phase 3 studies. We conducted a phase 1b study of intravenous Daratumumab (16 mg/kg) with weekly subcutaneous bortezomib (1.3-1.5 mg/m 2 ), cyclophosphamide (150-300 mg/m 2), and dexamethasone (40 mg) (CyBorD-DARA) as induction before autologous stem cell transplantation (ASCT), followed by CyBorD-DARA consolidation (2 cycles) and monthly DARA +/- bortezomib (in high-risk disease) maintenance for 24 months. We hypothesized that the addition of cyclophosphamide could lead to enhanced antibody dependent cellular phagocytosis (ADCP). This trial was registered at www.clinicaltrials.gov as NCT02955810. We previously reported the initial results of this study. 1. In addition to a favourable safety profile we observed promising anti-MM activity with 10 of 13 patients (77%) in whom assessment was possible achieving measurable residual disease (MRD) negativity at a sensitivity of 10 -5 by next generation sequencing (NGS) after ASCT. We now report the results at EOT, with a focus on MRD. Eligible patients were ≤70 years of age with untreated transplant-eligible MM. 18 patients were enrolled. Median age was 56.5 years (range, 32-66 years), 61% were male and 94% of patients had Eastern Cooperative Oncology Group performance status ≤1. The International Staging System stages were I, II, and III in 78%, 17%, and 6% of patients, respectively. 29% of patients had high-risk genetic features by fluorescent in situ hybridisation (FISH) or gene expression profiling, including 17p deletion in 12% and t(4;14) and t(14;16) in 6% each. On an ITT basis, the rates of very good partial remission or better (≥VGPR) after ASCT, consolidation and at end of treatment (EOT) (after completion of 24 months of DARA) were 94%, 94% and 81% respectively, and rates of complete response or better (≥CR) were 50%, 63% and 63% respectively. Measurable residual disease (MRD) assessment was possible in 13 patients after induction, ASCT and consolidation, and 10 at EOT. Sustained MRD negativity (ie. MRD negativity after ASCT, consolidation and at EOT) to a level of 10 -5 by NGS was achieved in 33% (ITT). Of 13 patients who remained on study at EOT in VGPR or better, 54% were MRD negative (MRD was unavailable in 23%). 7 patients were MRD negative after both ASCT and consolidation. Of these patients, all evaluable at EOT(6/7) remained MRD negative, with 1 patient unable to undergo MRD assessment due to the COVID-19 pandemic, but remaining in CR. Nausea and diarrhoea occurred in 89% of patients, but were mostly grade 1-2 (Grade ≥3 nausea 17%;diarrhoea 6%). Neutropenia occurred in 44% (Grade ≥3 17%), anaemia in 39% (Grade ≥3 22%), and thrombocytopenia in 33% (Grade ≥3 22%). The rate of neutropenic sepsis was 11%. Infusion-related reactions occurred in 50% (Grade ≥3 6%) and peripheral neuropathy occurred in 33% (Grade ≥3 0%) The most commonly reported serious adverse event (SAE) was sepsis in 22%. One patient developed abnormal liver function tests leading to discontinuation from the trial. CyBorD-DARA induction, consolidation and DARA-maintenance is an effective and well-tolerated IMiD free regimen in transplant-eligible patients with MM. MRD negativity at a level of > 10 -5 after ASCT and consolidation may be predictive of sustained MRD negativity at EOT. References: 1. Naicker SD, et al. Cyclophosphamide alters the tumor cell secretome to potentiate the anti-myeloma activity of daratumumab through augmentation of macrophage-mediated antibody dependent cellular phagocytosis. Oncoimmunology. 2021 Jan 25;10(1):1859263. doi: 10.1080/2162402X.2020.1859263. PMID: 33552684;PMCID: PMC7849715. 2. O'Dwyer M, et al. CyBorD-DARA is potent initial induction for MM and enhances ADCP: initial results of the 16-BCNI-001/CTRIAL-IE 16-02 study. Blood Adv. 2019 Jun 25;3(12):1815-1825. doi: 10.1182/bloodadvances.2019000010. PMID: 31201169;PMCI : PMC6595251. Disclosures: O'Dwyer: ONK Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy;Bristol Myers Squibb: Research Funding. Quinn: Takeda: Honoraria. Szegezdi: ONK Therapeutics: Research Funding.

Fitness, a UK Myeloma Research Alliance (UK-MRA) Frailty-Adjusted Therapy Study, Supports the Feasibility of Recruiting Frail Newly Diagnosed Myeloma Patients to Large Clinical Trials

Background Although the median age of patients with newly diagnosed multiple myeloma (MM) is 70-74 years, recruitment of frail older patients to clinical trials is poor. The International Myeloma Working Group (IMWG) frailty score predicts survival, adverse events and treatment tolerability using age, the Katz Activity of Daily Living, the Lawton Instrumental Activity of Daily Living, and the Charlson Comorbidity Index, rather than age alone. Despite IMWG score prognostic biomarker capability, to date no evidence exists of its predictive biomarker potential. The UK-MRA Myeloma Risk Profile (MRP) has also been shown in both clinical trial and real-world populations to be a prognostic biomarker in transplant ineligible patients but prospective comparisons of the two scores have not been previously conducted. Study Design/Methods The FiTNEss trial (Myeloma XIV, NCT03720041, Figure 1A) is a UK-MRA phase III, multi-centre, randomised controlled trial for newly diagnosed MM patients not suitable for stem cell transplant. The primary objectives are 1) to compare early treatment cessation (<60 days from randomisation) between patients randomised to standard (reactive) and frailty-adjusted (adaptive, based on IMWG score) induction therapy delivery with the triplet ixazomib, lenalidomide and dexamethasone (IRd) 2) to compare progression free survival for maintenance lenalidomide plus placebo (R) and lenalidomide plus ixazomib (IR). The FiTNEss trial is designed as an all-comers study with few exclusion criteria other than necessary for safety including some haematological and biochemical parameters, but there is no exclusion based on renal function. Patients with grade 2 or greater baseline peripheral neuropathy, current systemic infection or recent surgery or other cancer are excluded. Here we report the demographics for the first patients recruited, including IMWG frailty assessments and MRP to demonstrate the feasibility of recruiting frail patients to randomised phase III clinical trials. Results The FiTNEss trial opened on 04/08/2020 during the second wave of the COVID-19 pandemic in the UK. At the time of data cut off (14/07/2021) recruitment is active at 84 sites, with 180 patients randomised. Baseline characteristics for the randomised patients are shown in Figure 1B. The median age of patients is 77 years (range 64, 93) with 36.1% aged 76-80 and 26.1% over 80. In keeping with the older patient population 26.6% have an ECOG performance status of 2 or 3 and 31.7% ISS stage III. The IMWG frailty classification at baseline is FIT 43/180 (23.9%), UNFIT 53/180 (29.4%) and FRAIL 84/180 (46.7%). The effect of using age groups on the definition of patient frailty was explored. The IMWG frailty score defines all patients over 80 as FRAIL whilst an age of 76-80 contributes one point to the score. An analysis of patients' frailty was repeated with the contribution of age removed. For those aged over 80 years (n=47, 100% FRAIL) we found that 20 (42.6%) would have been re-classified as FIT and 18 (38.3%) as UNFIT, with only 9 (19.2%) retaining the FRAIL category. For those aged 76-80 (n=65, 53.8% UNFIT, 46.2% FRAIL) all 35 patients previously classified as UNFIT became FIT (53.8%) whilst 19 (29.2%) classed as FRAIL became UNFIT with 11 (16.9%) remaining FRAIL. The MRP classification, using age as a continuous variable, was Low-risk 45/180 (25.0%), Medium-risk 46/180 (25.6%), High-risk 75/180 (41.7%) and not available for 14/180 (7.8%) patients. Concordance between the IMWG frailty score and the MRP occurred in 48.9% of patients (88/180). 37.2% of FIT patients were classified as MRP Low-risk, 32.1% of UNFIT patients as MRP Medium-risk and 65.5% of FRAIL patients as MRP High-risk. Discussion The FiTNEss trial demonstrates the feasibility of recruiting older, less fit patients to clinical trials. Recruitment of patients classified as FRAIL was very high despite the COVID pandemic, likely due to the all-oral nature of the regimen under investigation enabling patients to avoid attendance at hospital day units for treatment and associa ed exposure risk. In the population recruited to date we found age to be a key contributor to the FRAIL category of the IMWG frailty score. Concordance between IMWG frailty score and MRP was highest in FRAIL/High-risk patients. The first interim analysis of the primary objectives is planned when 50% of required participants for R1 have reached 60 days post R1, which is anticipated in Q2 of 2022. [Formula presented] Disclosures: Cook: Amgen: Consultancy, Honoraria, Research Funding;BMS: Consultancy, Honoraria, Research Funding;Sanofi: Consultancy, Honoraria;Karyopharm: Consultancy, Honoraria;Roche: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria;Oncopeptides: Consultancy, Honoraria;Takeda: Consultancy, Honoraria, Research Funding;Janssen: Consultancy, Honoraria, Research Funding. Pawlyn: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene / BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Honoraria. Royle: BMS: Research Funding;Merck Sharpe and Dohme: Research Funding;Amgen: Research Funding;Takeda: Research Funding. Coulson: BMS / Celgene: Honoraria;Merck Sharpe and Dohme: Research Funding;Amgen: Research Funding;Takeda: Research Funding. Jenner: BMS/Celgene: Consultancy, Honoraria, Speakers Bureau;Janssen: Consultancy, Honoraria, Speakers Bureau;Pfizer: Consultancy;Takeda: Consultancy. Kishore: Sanofi: Other: Attending fees;Celgene: Other: Attending fees;Takeda: Other: Attending fees;Jannsen: Other: Attending fees. Rabin: BMS / Celgene: Consultancy, Honoraria, Other: Travel support for meetings;Takeda: Consultancy, Honoraria, Other: Travel support for meetings;Janssen: Consultancy, Honoraria, Other: Travel support for meetings. Best: BMS/Celgene: Research Funding;Merck Sharpe and Dohme: Research Funding;Amgen: Research Funding;Takeda: Research Funding. Gillson: BMS / Celgene: Research Funding;Meck Sharpe and Dohme: Research Funding;Amgen: Research Funding;Takeda: Research Funding. Henderson: Takeda: Research Funding;Amgen: Research Funding;Merck Sharpe and Dohme: Research Funding;BMS / Celgene: Research Funding. Olivier: Merck Sharpe and Dohme: Research Funding;Takeda: Research Funding;Amgen: Research Funding;Celgene / BMS: Research Funding. Kaiser: AbbVie: Consultancy;GSK: Consultancy;Karyopharm: Consultancy, Research Funding;Pfizer: Consultancy;Amgen: Honoraria;Seattle Genetics: Consultancy;Takeda: Consultancy, Other: Educational support;Janssen: Consultancy, Other: Educational support, Research Funding;BMS/Celgene: Consultancy, Other: Travel support, Research Funding. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jones: Janssen: Honoraria;BMS/Celgene: Other: Conference fees. Cairns: Merck Sharpe and Dohme: Research Funding;Amgen: Research Funding;Takeda: Research Funding;Celgene / BMS: Other: travel support, Research Funding. Jackson: celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau;amgen: Consultancy, Honoraria, Speakers Bureau;takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau;GSK: Consultancy, Honoraria, Speakers Bureau;J and J: Consultancy, Honoraria, Speakers Bureau;oncopeptides: Consultancy;Sanofi: Honoraria, Speakers Bureau. OffLabel Disclosure: Frailty-score adapted dosing strategies

A Phase I/II Study of Twice Weekly Ixazomib Plus Pomalidomide and Dexamethasone in Relapsed and Refractory Multiple Myeloma

Introduction: Ixazomib is an oral proteasome inhibitor (PI) that is currently approved to be administered once weekly in combination with lenalidomide (LEN) and dexamethasone in RRMM (Moreau et al N Eng J Med 2016;374:1621-1634). As most patients are LEN refractory at the time of first relapse, pomalidomide-based regimens are commonly utilized due to their proven efficacy in this population. We hypothesized that twice weekly dosing of ixazomib may be more efficacious as this has been previously studied as monotherapy (Richardson et al, Blood 2014 Aug 14;124(7):1038-46) and in combination with LEN demonstrating promising activity and safety (Richardson et al, Br J Haematol. 2018 Jul;182(2):231-244). We present results of our phase I/II trial of twice weekly ixazomib in combination with pomalidomide and dexamethasone in RRMM, including the recommended phase II dose and first report of efficacy of this combination. Methods: This is a phase I/II multicenter, single-arm, open label study evaluating the combination of twice weekly ixazomib with pomalidomide and dexamethasone in RRMM. The primary objective for phase I portion is to determine safety and the maximum tolerated dose (MTD) of this combination using a standard 3+3 dose escalation design and primary objective of the phase II portion is overall response rate (ORR) with secondary outcomes including progression-free survival (PFS) and clinical benefit rate (CBR) Ixazomib is studied at doses of 3mg or 4mg on days 1, 4, 8, 11, pomalidomide at a dose of 2mg, 3mg and 4mg on days 1-14 and dexamethasone is administered at a dose of 12mg on days 1, 2, 4, 5, 8, 9, 11, 12 (8mg for patients > 75 years old) on a 21 day cycle (Table 1). Patients were included if they received 2 prior lines of therapy, but 1 prior line was allowed if first line treatment included a PI and an immunomodulatory agent and disease relapse occurred within 60 days of last therapy. Patients who were ixazomib exposed or pomalidomide refractory were excluded. Results: At the time of data cutoff, 22 patients have been enrolled across all cohorts. There were two dose-limiting toxicities (DLT) noted during the dose escalation phase (upper respiratory infection and neutropenia, respectively) establishing the RP2D of 4mg ixazomib and 4mg pomalidomide. Median age at the time of enrollment was 68 years old with ISS stage at diagnosis of I (14%), II (32%), and III (23%). High-risk FISH abnormalities were seen in 43% of patients as follows: del 17p (9%), gain 1q (36%), t(4;14) (5%), t(14;16) (9%). Median prior lines of therapy was 2 (range 1-4) with 100% of patients having prior treatment with lenalidomide and 95% with prior bortezomib. Fifty-nine percent of patients had a prior autologous stem cell transplant. Ten patients have been enrolled at the RP2D at the time of data cut off. The most common treatment-related toxicities were mainly low grade (Grade 1-2) and included neutropenia (45%), lower extremity edema (41%), insomnia (36%), dyspnea (32%) and weight gain (32%). Grade 3 or greater toxicities were noted in 36% of patients and included neutropenia (18%), thrombocytopenia (5%), anemia (5%), atrial fibrillation (5%), dehydration (5%), diarrhea (5%), fall (5%), lung infection (5%), and pneumonitis (5%). Dose reductions occurred in 13 patients and predominantly involved dexamethasone due to weight gain, insomnia, atrial fibrillation and fatigue. There have been no discontinuations due to toxicity and no treatment related mortality at the time of data cutoff. The ORR in all cohorts was 45%, with 9% achieving sCR, 9% VGPR and 86% achieving stable disease or better. At the RP2D, the ORR was 50% with 30% of patients achieving VGPR or better. At the median follow up of 10 months, median PFS was 13 months (95% CI: 11-NR) and median overall survival was not reached. Conclusions: Twice weekly ixazomib in combination with pomalidomide and dexamethasone is a generally well-tolerated regimen with promising activity. The recommended phase II dose has been established at 4mg of ixazomib and 4mg of pomalidomide demonstrat ng efficacy in a high-risk cohort of RRMM patients. The all-oral nature of this regimen has allowed for robust accrual during the COVID 19 pandemic. [Formula presented] Disclosures: Nadeem: BMS: Membership on an entity's Board of Directors or advisory committees;Karyopharm: Membership on an entity's Board of Directors or advisory committees;GSK: Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees;Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Mo: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria;GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees;Epizyme: Consultancy;Eli Lilly: Consultancy;BMS: Membership on an entity's Board of Directors or advisory committees;Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees;AbbVIE: Consultancy. Bianchi: Jacob D. Fuchsberg Law Firm: Consultancy;MJH: Honoraria;Karyopharm: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria. Sanchorawala: Celgene: Research Funding;Pfizer: Honoraria;Sorrento: Research Funding;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda: Research Funding;Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding;Abbvie: Membership on an entity's Board of Directors or advisory committees;Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding;Regeneron: Membership on an entity's Board of Directors or advisory committees;Proclara: Membership on an entity's Board of Directors or advisory committees;Oncopeptide: Research Funding;Karyopharm: Research Funding. Sperling: Adaptive: Consultancy. Munshi: Janssen: Consultancy;Takeda: Consultancy;Bristol-Myers Squibb: Consultancy;Celgene: Consultancy;Amgen: Consultancy;Karyopharm: Consultancy;Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties;Legend: Consultancy;Abbvie: Consultancy;Adaptive Biotechnology: Consultancy;Novartis: Consultancy;Pfizer: Consultancy. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy. Anderson: Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees;Pfizer: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees;Gilead: Membership on an entity's Board of Directors or advisory committees;Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees;Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Membership on an entity's Board of Directors or advisory committees;Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company;Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Richardson: AbbVie: Consultancy;Karyopharm: Consultancy, Research Funding;Janssen: Consultancy;Protocol Intelligence: Consultancy;Takeda: Consultancy, Research Funding;GlaxoSmithKline: Consultancy;Regeneron: Consultancy;Secura Bio: Consultancy;Sanofi: Consultancy;AstraZeneca: Consultancy;Celgene/BMS: Consultancy, Research Funding;Oncopeptides: Consultancy, Research Funding;Jazz Pharmaceuticals: Consultancy, Research Funding.

Daratumumab, Bortezomib and Dexamethasone (DVd) at First Relapse for Patients with Relapsed/ Refractory Multiple Myeloma (RRMM): A UK Myeloma Research Alliance (UK-MRA) Real-World Multicentre Analysis

Introduction: Daratumumab in combination with bortezomib and dexamethasone (DVd) demonstrated a superior overall response rates (ORR) and progression free survival (PFS) compared to Vd in the CASTOR phase 3 trial for patients with RRMM. On this basis, DVd was recommended in March 2019 for UK patients with RRMM that had 1 prior line (PL). Discrepancies in outcomes between patients treated in clinical trials compared to routine practice is well recognised due to a combination of patient, disease and treatment-related factors. In addition, bortezomib is often administered once-weekly in routine practice to minimise neuropathy, while CASTOR used bi-weekly bortezomib dosing. As a result, the real-world outcomes of patients treated with DVd are yet to be determined. The primary aims of this analysis was to assess the ORR and PFS for patients with RRMM with 1PL treated with DVd in routine practice. Secondary aims were to assess OS, time to next treatment (TTNT), and efficacy in different sub-groups (high risk cytogenetics, previous proteasome inhibitor (PI) exposure, refractoriness of prior therapies, bi-weekly vs weekly bortezomib schedule, and previous treatment free interval (TFI)). Methods: This was a retrospective analysis from 14 centres (academic and community hospitals;7 within the West Midlands Research Consortium (WMRC)) treated with DVd between March 2019 and June 2021. Patients received daratumumab (IV and then SC from June 2020) weekly in cycles 1-3, on day 1 of a 3-week cycle during cycles 4-8, and then monthly from cycle 9 to progression. SC Bortezomib was predominantly given weekly for cycles 1-8 although 5 centres used bi-weekly dosing for selected patients with aggressive disease. Adverse events were graded as per CTCAE criteria. Results: 288 patients were included, with a median age of 69 years (range 20-88) (Table 1). Patients received a median of 1 PL (range 1-2) with 93% (269) 1PL, 7% (18) 2 PL (due to COVID-19 measures). The majority had an ECOG performance status of 0-2 (98%) and most received weekly bortezomib (n=201). This population differed from those with 1PL treated on CASTOR in being older, more were ISS 3 (31% vs 19%, p=0.0145), and more had prior bortezomib exposure (71% vs 51%, p=0.0003), 4% were PI refractory, 9% had a GFR of <30ml/min (<20ml/min was an exclusion from CASTOR), and 2% had an ECOG performance status of ≥3. The ORR was 76%, with >VGPR in 54% (Table 2), with no significant difference in response between patients receiving biweekly vs weekly bortezomib (85% vs 83%;p=0.71). The median time to response was 1.6m. With a median follow up of 15m, the median PFS was 14m (95% CI 11.6-16). High cytogenetic risk patients had inferior outcomes: median PFS 10m (95% CI 6-14) for high risk vs not reached for standard risk (p=0.043);as did those with advanced ISS: median PFS was not reached, 15 and 12m for stage I, II and III respectively (p=0.05). For 15 patients with extramedullary disease (EMD), the median PFS was 3m (95% CI 1-5). Median PFS for patients who were PI refractory was shorter (10m vs 15m for PI sensitive patients (p=0.006)). There was no difference in median PFS for patients with prior PI exposure vs no prior PI (15 vs 13m;p=0.75), or according to weekly or bi-weekly bortezomib schedule (11 vs 15m;p=0.14). The median TTNT was 21m (95% CI 17-25). Overall, the median duration of treatment was 8m and 25 patients (9%) stopped treatment to receive a second autologous stem cell transplant. Those that had a prior TFI of >12m had a longer median PFS of 21m vs 10m (p=0.0004). The median OS has not been reached, with an estimated 2-year OS of 74%. For patients with high risk cytogenetics the median OS was 16m (95% CI 9-23;vs not reached for standard risk;p=0.0006), with estimated 2-year OS in the high risk group of 36%. There was no difference in OS for patients treated with biweekly vs weekly bortezomib (not reached for either;p=0.38). DVd was generally well tolerated with 6% stopping due to adverse events (CASTOR 9.5%). Grade 3 or 4 toxicity occurred in 62 (22%) most comm nly neutropenia and thrombocytopenia, with any grade infusion reactions reported in 27 (9%). Conclusions: These real-world data of DVd at 1 st relapse demonstrated good tolerability and high response rates with a weekly bortezomib schedule despite a more heterogenous population. However, high risk patients by cytogenetics, ISS or EMD had inferior outcomes as did those treated within 12 months from first line treatment. [Formula presented] Disclosures: Cook: Karyopharm: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria;Sanofi: Consultancy, Honoraria;Takeda: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Honoraria, Research Funding;BMS: Consultancy, Honoraria, Research Funding;Oncopeptides: Consultancy, Honoraria;Roche: Consultancy, Honoraria;Janssen: Consultancy, Honoraria, Research Funding. Pratt: Binding Site: Consultancy;BMS/Celgene: Consultancy;Gilead: Consultancy;Janssen: Consultancy;Takeda: Consultancy;Amgen: Consultancy. Kishore: Celgene: Other: Attending fees;Jannsen: Other: Attending fees;Sanofi: Other: Attending fees;Takeda: Other: Attending fees. Yong: Amgen: Honoraria;Autolus: Research Funding;BMS: Research Funding;Janssen: Honoraria, Research Funding;Sanofi: Honoraria, Research Funding;GSK: Honoraria;Takeda: Honoraria. Popat: Abbvie, Takeda, Janssen, and Celgene: Consultancy;Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES;GlaxoSmithKline: Consultancy, Honoraria, Research Funding;AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria;Janssen and BMS: Other: travel expenses.

Changes in Multiple Myeloma Treatment Patterns during the Early COVID-19 Pandemic Period

Background: Early during the COVID-19 pandemic patient and provider anxiety concerning in-person visits and travel restrictions may have delayed cancer diagnosis and altered treatment. We evaluated changes in clinical presentation and treatment patterns in multiple myeloma (MM) during the early COVID-19 period compared to historical pre-COVID periods. Methods: Using the nationwide Flatiron Health EHR-derived de-identified database, we compared clinical presentation and treatment patterns in the immediate post-COVID period (2020) to a comparable pre-COVID period (2018 and 2019). We focused on two separate clinical settings: 1) patients newly diagnosed with MM during February-June in the years of interest (NEWPT) with evidence of management within 90 days and follow-up for 7 months;and 2) patients diagnosed with MM during 2014-2019 receiving active treatment as of February (2018, 2019, 2020, ACTIVE) and follow-up for 11 months. Delayed clinical presentation was assessed using baseline (90 days before diagnosis/index date) measures of ISS stage, ECOG performance status, anemia, and kidney function. We examined treatment patterns (choice of regimen) of both cohorts in the two time periods. We compared clinical features of initial presentation in pre-COVID and COVID period using Pearson's χ 2 test. For NEWPT, we also utilized Kaplan-Meier curves and log-rank test to compare time to treatment initiation between the two periods. Multivariable Cox proportional hazards regression model with death as a competing risk was used to determine impact of COVID on treatment initiation by adjusting sex, age at diagnosis, race, insurance, stage, baseline ECOG, and hospital setting. All analyses were conducted in SAS (Version 9.4, SAS Institute, Cary, North Carolina) with 2 sided tests and a type I error of 5%. Results: Our study included 1319 NEWPT (964 pre-COVID and 355 COVID) and 2206 ACTIVE (1014 pre-COVID and 1192 COVID) patients. In the NEWPT cohort, we observed no differences between the pre-COVID and COVID periods in terms of baseline characteristics, including clinical features like stage, ECOG performance status, anemia or kidney function (Table A). Patients in the pre-COVID period were more likely to initiate any treatment (91.1% vs 86.2%, p<.01). Median time to treatment initiation was 30 days pre-Covid and 32 days during the Covid period (log-rank test p=0.04, Figure A). After adjusting for patient demographic, clinical features (extent of anemia, hypercalcemia, kidney dysfunction), and hospital variables (US region, practice type academic vs community), the difference between the two periods was not significant (COVID vs pre-COVID hazard ratio=0.88, 95% confidence interval 0.78-1.10, p=0.07). In NEWPT cohort, compared with their pre-COVID counterparts, patients in COVID period were more likely to receive monoclonal antibody (mAb) (14.4% vs 4.8%, p<.01, Figure B) and used IMID-based regimen as their first line of therapy (80.4% vs 74.3%, p<.01). In ACTIVE cohort, more patients in the pre-COVID period were anemic (Hemoglobin <10 g/L, 14.9% vs 9.7%, p<.01) at baseline than those in the COVID period. As in NEWPT cohort, ACTIVE patients in the COVID period used mAb-based regimen more commonly (28.9% vs 16.9%, p<.01) (Figure C). In addition, fewer ACTIVE treatment patients in the COVID period received cyclophosphamide regimens (7.9% vs 15.1% p<.01). Conclusions: During early COVID-19 pandemic we did not observe evidence of delayed diagnosis or more advanced stage, anemia or kidney disease for NEWPT with MM. MM treatment patterns were notable for higher utilization of mAb, IMID-based therapies and decreased use of cyclophosphamide regimens, without significant change in time to treatment initiation. Reassuringly, changes in treatment-patterns during COVID pandemic were modest, some likely reflecting changes in MM treatment landscape (advances in mAb regimens) rather than direct impact of COVID. Further studies are needed to understand how these changes evolve and affect clinical outcomes over time beyond 2020. [Formula presen ed] Disclosures: Neparidze: GlaxoSmithKline: Research Funding;Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees;Janssen: Research Funding. Zeidan: Jasper: Consultancy;AstraZeneca: Consultancy;Aprea: Consultancy, Research Funding;Gilead: Consultancy, Other: Clinical Trial Committees;Loxo Oncology: Consultancy, Other: Clinical Trial Committees;Astellas: Consultancy;Agios: Consultancy;Kura: Consultancy, Other: Clinical Trial Committees;Jazz: Consultancy;Pfizer: Other: Travel support, Research Funding;Genentech: Consultancy;Geron: Other: Clinical Trial Committees;BMS: Consultancy, Other: Clinical Trial Committees, Research Funding;ADC Therapeutics: Research Funding;Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding;Boehringer Ingelheim: Consultancy, Research Funding;Astex: Research Funding;BeyondSpring: Consultancy;Incyte: Consultancy, Research Funding;Daiichi Sankyo: Consultancy;Epizyme: Consultancy;BioCryst: Other: Clinical Trial Committees;Cardiff Oncology: Consultancy, Other: Travel support, Research Funding;Janssen: Consultancy;Ionis: Consultancy;Amgen: Consultancy, Research Funding;Acceleron: Consultancy, Research Funding;AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Podoltsev: Pfizer: Honoraria;PharmaEssentia: Honoraria;Blueprint Medicines: Honoraria;Incyte: Honoraria;Novartis: Honoraria;CTI BioPharma: Honoraria;Bristol-Myers Squib: Honoraria;Celgene: Honoraria. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Ma: Celgene/Bristol Myers Squibb: Consultancy, Research Funding. Davidoff: Amgen: Consultancy;AbbVie: Other: Family member consultancy. Huntington: AstraZeneca: Consultancy, Honoraria;TG Therapeutics: Research Funding;Thyme Inc: Consultancy;Flatiron Health Inc.: Consultancy;Genentech: Consultancy;SeaGen: Consultancy;Novartis: Consultancy;Pharmacyclics: Consultancy, Honoraria;Servier: Consultancy;Bayer: Honoraria;DTRM Biopharm: Research Funding;AbbVie: Consultancy;Celgene: Consultancy, Research Funding.

Safety of Daratumumab Combined with Bortezomib, Cyclophosphamide and Dexamethasone for the Treatment of Patients with Multiple Myeloma Presenting with Extramedullary Disease during the COVID-19 Pandemic

Introduction: Extramedullary disease (EMD) in patients (pts) with multiple myeloma (MM) is a poor prognostic feature which is not curable with currently approved treatments. Consequently, there is a significant unmet need for effective therapies with good safety profiles. Daratumumab with cyclophosphamide, bortezomib and dexamethasone (daraVCD) is a novel treatment combination with a good efficacy profile in pts with EMD based on preclinical synergistic data. Methods: EMN19 is a phase 2, open-label, multicenter study which aims to enroll 40 MM pts presenting with EMD either at diagnosis or following one line of treatment but not refractory to bortezomib-based regimens, from 8 sites in Turkey, Greece and Italy. Pts with bortezomib or daratumumab hypersensitivity, who received previous autologous stem cell transplant (ASCT) ≤12 weeks before Day 1 of treatment Cycle 1, or with previous allogenic stem cell transplant were excluded. Daratumumab was initially administered intravenously at 16 mg/mL, and since July 2020 has been administered subcutaneously at a fixed dose of 1800 mg, weekly during Cycles 1-2, every 2 weeks for Cycles 3-6, and every 4 weeks thereafter. Intravenous bortezomib 1.5 mg/m 2 and oral/intravenous cyclophosphamide 300 mg/m 2 is administered weekly, and oral/intravenous dexamethasone 20 mg is administered on Days 1, 2, 8, 9, 15, 16, 22 and 23. DaraVCD will be administered until progression or unacceptable toxicity unless refractory disease is detected by the end of Cycle 3 (progressive disease [PD] or failure to achieve a confirmed partial response [PR] or better). The present analysis includes pts who initiated study treatment ≥3 months prior to the cut-off date (01 June 2021). Results: In total, 34 patients were screened, 27 patients were enrolled, 2 relapsing patients died during the screening phase due to severe COVID-19 infection, 22 pts were analyzed (59% female;median age 56 years, range 44-77);14 pts (64%) were still on treatment and 8 (36%) discontinued;due to inadequate response after 3 cycles of treatment (n=3, 38%), PD (n=4, 50%), death (n=1, 13%). Fourteen pts (64%) were newly diagnosed and 8 (36%) first relapsed. International Staging System stage at baseline was I, II and III for 8 (36%), 9 (41%) and 5 (23%) pts, respectively. Eastern Cooperative Oncology Group performance status was 0, 1 and 2 for 14 (64%), 7 (32%), and 1 patient (5%), respectively. On average, 3.0 (range 1-20) extramedullary plasmacytomas were observed per patient;most commonly reported sites were thorax (6 pts, 27%), brain, head and lower extremities (4 pts, 18% each). Twenty (91%) pts had ≥1 serious or non-serious treatment-emergent adverse event (TEAE);8 pts (36.4%) experienced ≥1 sTEAEs;COVID-19 infection (n=3, 14%) urinary tract infection (n=2, 9%), infectious myocarditis, hip arthroplasty, pneumonia, cytomegaloviral pneumonia and thrombocytopenia (n=1 each, 4.5%). Thirteen (59%) pts ≥1 Grade 3/4 TEAE;neutropenia observed in 8 pts (36%), followed by thrombocytopenia (n=4, 18%) and COVID-19 infection (n=3, 14%). Overall, 16 (73%) pts missed ≥1 dose of any of the study drugs;2 (9%) pts missed ≥1 dose due to COVID-19 infection (7 doses), 8 (36%) due to COVID-19 vaccination (37 doses), 2 (9%) due to other COVID-19-related issues (65 doses), 10 (46%) due to other safety events (104 doses) and 9 (41%) due to other reasons (25 doses). Overall, 20 cycle delays were observed in 13 (59%) pts, with median (range) delay of 12.0 (4-133) days. Two pts (9%) had a cycle delay due to COVID-19 infection (2 cycles), 1 (5%) due to COVID-19 vaccination (1 cycle), 5 (23%) due to adverse events (8 cycles), 2 (9%) due to ASCT (2 cycles) and 7 (32%) due to other reasons (7 cycles). Total number of missed doses (missed doses due to COVID-19-related issues) were 17 (3) for daratumumab, 53 (11) for bortezomib, 45 (9) for cyclophosphamide and 123 (86) for dexamethasone;238 doses missed in total. No fatalities occurred due to any infection. Conclusions: DaraVCD was associated with a good safety profile in this high ri k MM with EMD patient population. The COVID-19 impact on missed doses was greater for dexamethasone (>60% of missed doses) than other components (~20%), however overall, the pandemic did not significantly affect the patients' safety and data integrity of the study. The enrollment in the study is ongoing, and more safety and efficacy data will become available with the inclusion of additional pts in an updated analysis. Disclosures: Beksac: Amgen,Celgene,Janssen,Takeda,Oncopeptides,Sanofi: Consultancy, Speakers Bureau. Tuglular: GSK: Honoraria, Research Funding;Amgen: Honoraria, Research Funding;Karyopharm: Honoraria, Research Funding;Abbvie: Honoraria, Research Funding;Janssen-Cilag: Honoraria, Research Funding;Genesis Pharma: Honoraria, Research Funding;Sanofi: Honoraria, Research Funding. Cavo: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Honoraria;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau;Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;GlaxoSmithKline: Consultancy, Honoraria;AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Adaptive Biotechnologies: Consultancy, Honoraria. Gay: GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees;AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Membership on an entity's Board of Directors or advisory committees;Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Oncopeptides: Membership on an entity's Board of Directors or advisory committees;Bluebird bio: Membership on an entity's Board of Directors or advisory committees. Katodritou: GSK, Amgen, Karyopharm, Abbvie, Janssen-Cilag, Genesis Pharma, Sanofi: Honoraria, Research Funding. Merante: EMN Italy Medical Monitor: Research Funding. Manousou: Health Data Specialists: Current Employment. Sonneveld: Karyopharm: Consultancy, Honoraria, Research Funding;Janssen: Consultancy, Honoraria, Research Funding;Celgene/BMS: Consultancy, Honoraria, Research Funding;SkylineDx: Honoraria, Research Funding;Takeda: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Honoraria, Research Funding. Terpos: GSK: Honoraria, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;Genesis: Consultancy, Honoraria, Research Funding;Novartis: Honoraria;Janssen-Cilag: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Honoraria, Research Funding;BMS: Honoraria;Takeda: Consultancy, Honoraria, Research Funding;Sanofi: Consultancy, Honoraria, Research Funding.

DREAMM-9: Phase I Study of Belantamab Mafodotin Plus Standard of Care in Patients with Transplant-Ineligible Newly Diagnosed Multiple Myeloma

Introduction: The bortezomib, lenalidomide, and dexamethasone (VRd) regimen is an acceptable standard of care (SoC) for both transplant-eligible and transplant-ineligible newly diagnosed multiple myeloma (TI NDMM). Ongoing development of novel therapies and combinations strive to improve survival outcomes beyond what is expected from SoC. Belantamab mafodotin (belamaf) is a B-cell maturation antigen-binding antibody-drug conjugate that eliminates myeloma cells by a multimodal mechanism and has demonstrated durable responses in patients with relapsed/refractory multiple myeloma (RRMM). Preclinical evidence of belamaf in combination with bortezomib or lenalidomide suggests enhanced anti-myeloma activity, providing rationale for this treatment combination. We report the preliminary findings of belamaf + VRd for TI NDMM patients. Methods: DREAMM-9 (NCT04091126) is an ongoing Phase I, open-label, randomized, dose and schedule evaluation study of belamaf + VRd in patients with TI NDMM. Eligible patients include those ≥18 years old with ECOG status 0-2 and adequate organ system functions. The study evaluates safety and tolerability of belamaf + VRd in up to 8 cohorts, up to 144 patients, to establish the recommended phase 3 dose (RP3D). VRd is administered Q3W until cycle 8, followed by lenalidomide + dexamethasone (Rd) Q4W. Belamaf + VRd is administered until cycle 8, and then in combination with Rd thereafter. The belamaf dose cohorts currently being evaluated are: cohort 1 (1.9 mg/kg Q3/4W), cohort 2 (1.4 mg/kg Q6/8W), cohort 3 (1.9 mg/kg Q6/8W), cohort 4 (1.0 mg/kg Q3/4W), and cohort 5 (1.4 mg/kg Q3/4W). After evaluation of safety data for cohort 1, cohorts 2-5 were opened in parallel and enrolled patients were randomized 1:1:1:1. Safety data, clinical activity, and drug concentrations will be assessed, and used to determine the belamaf RP3D. This analysis reports the preliminary results from cohort 1. Primary endpoints include number of patients with adverse events (AEs). Secondary endpoints include establishing relative dose intensity of lenalidomide and bortezomib in combination with belamaf, cumulative dose of belamaf, pharmacokinetics (PK) profile of belamaf when combined with VRd, overall response rate (ORR), complete response (CR), stringent complete response (sCR), complete response rate ([CRR];% of patients with a confirmed CR or better), and rate of very good partial response or better (≥VGPR). Exploratory endpoints include assessing minimal residual disease (MRD) in patients who achieve ≥VGPR, and safety and efficacy exposure-response relationships. Results: Twelve patients in cohort 1 were included in this preliminary analysis. Eight patients (67%) were male;median age (range) was 72.5 years (63-77). Ten patients (83%) were white and 2 (17%) were Asian. Nine patients (75%), were ISS stage II or III, and 4 (33%) patients had high-risk cytogenetics (consisting of one or more of the following: t(4;14), t(14;16), del17p, 17p13del). AEs related to study treatment were experienced by all 12 patients. Dose reductions occurred in 12 (100%) patients, all of whom also experienced a dose delay. Most common AEs leading to dose modification were thrombocytopenia, neutropenia, and corneal events. Grade 3 or 4 AEs related to belamaf occurred in 9 (75%) patients. During the trial, one patient experienced a fatal severe AE due to COVID-19 infection (unrelated to study treatment;Table). All patients, 100% (n=12;95% CI: 73.5-100) achieved ≥VGPR. Early deep responses were observed;2 (17%) patients achieved VGPR as early as 4 weeks. As of data cut-off, 5 (42%) remain in CR and 3 (25%) in sCR. Based on real-time data captured in the clinical database, 7 out of 9 patients achieved MRD-negative status at the first test after VGPR. Belamaf PK profile was similar to that observed in patients with RRMM taking into consideration baseline patients characteristics. Conclusion: Preliminary data suggest addition of belamaf to VRd did not reveal new safety signals and demonstrates high response rates, albeit with short follow up. The study is ongoing to confirm safety and evaluate the efficacy of belamaf + VRd. Updated data for cohort 1 will be reported at the congress. Funding: GSK (Study 209664);belamaf drug linker technology licensed from Seagen;belamaf monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. [Formula presented] Disclosures: Usmani: Pharmacyclics: Consultancy, Research Funding;Seattle Genetics: Consultancy, Research Funding;Takeda: Consultancy, Research Funding, Speakers Bureau;Merck: Consultancy, Research Funding;SkylineDX: Consultancy, Research Funding;Sanofi: Consultancy, Research Funding, Speakers Bureau;Janssen: Consultancy, Research Funding, Speakers Bureau;Janssen Oncology: Consultancy, Research Funding;Bristol-Myers Squibb: Research Funding;EdoPharma: Consultancy;GSK: Consultancy, Research Funding;Celgene/BMS: Consultancy, Research Funding, Speakers Bureau;Array BioPharma: Consultancy, Research Funding;Abbvie: Consultancy;Amgen: Consultancy, Research Funding, Speakers Bureau. Quach: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees;CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees. Koh: Pfizer: Consultancy;Jassen: Honoraria;AstraZeneca: Honoraria;Novartis: Honoraria;GSK: Honoraria;Roche: Honoraria;Takeda: Honoraria. Guenther: Novartis: Consultancy;Celgene: Consultancy, Honoraria;Roche: Consultancy;Takeda: Consultancy, Honoraria;Amgen: Consultancy, Honoraria;AbbVie: Consultancy;Jazz Pharmaceuticals: Honoraria;Janssen Pharmaceuticals: Consultancy, Honoraria. Zhou: GlaxoSmithKline: Current Employment. Kaisermann: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Mis: GlaxoSmithKline: Current Employment. Williams: GlaxoSmithKline: Current Employment. Yeakey: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Ferron-Brady: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Figueroa: GlaxoSmithKline: Current Employment. Kremer: GlaxoSmithKline: Current Employment. Gupta: Novartis: Current equity holder in publicly-traded company;GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Janowski: Celgene: Consultancy;AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees;Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees;BMS: Membership on an entity's Board of Directors or advisory committees.

COVID-19 in Multiple Myeloma Patients: Frequencies and Risk Factors for Hospitalization, Ventilatory Support, Intensive Care Admission and Mortality -Cooperative Registry from Grupo Brasileiro De Mieloma Multiplo (GBRAM)

Patients with multiple myeloma (MM) have an increased risk for severe infections due to both the disease and anti-myeloma therapies. During the COVID-19 pandemic, case series of MM patients have demonstrated a poor outcome in those who required hospitalization due to COVID-19, and there are few data regarding those managed out of hospitals or risk factors for hospitalization. In Brazil, where the scenario is of restricted resources to treat MM patients and large numbers of COVID-19 cases and related death, the outcome can be even worse. Objective: To assess risk factors and outcomes of COVID-19 in Brazilian patients with MM. This retrospective case series investigated 81 MM patients with documented COVID-19, managed in and out-hospital, from 8 states, representing 4 of 5 regions in Brazil. This study has been conducted by “Grupo Brasileiro de Mieloma” (GBRAM), and the present analyses included cases from April 2020 to July 2021. Clinical features and risk factors were analyzed with the severity of COVID-19 and outcomes (hospital admissions, intensive care unit (ICU) admission, ventilatory support, and death). The frequency of MM treatment modification due to COVID-19 was also accessed. There were 81 MM patients (male 50%;median age 63 years;and ISS III at diagnosis 25%) diagnosed with COVID-19. At least one comorbidity was present in 47 (58%) patients: most frequently hypertension and diabetes (56% and 27%). Twenty-eight (35%) patients had more than one comorbidity. At COVID episode, 21 (26%) patients had an active disease or progression disease, and 40% received at least two prior lines of treatment. COVID-19 management required hospitalization in 49 (61%), ventilatory support in 30 (40%) and ICU in 28 (35%). Hospitalization was associated with age (p=0.008), presence of comorbidity (p=0.02), hypertension (p=0.02), presence of fever (p=0.005) and low respiratory symptoms (p=0.003). Ventilatory support was more frequent in patients with cardiac disease (p=0.05), receiving immunomodulatory (p=0.03), or monoclonal drugs (p=0.006). Patients receiving corticosteroids (p=0.02), immunomodulatory (p=0.06), or monoclonal drugs (p=0.06) in MM treatment had a higher frequency of ICU admission. By adjusted multivariate analysis, age, the clinical presentation with fever and low respiratory symptoms (p<0.001, p=0.05 and p=0.001, respectively) were independent associated with hospitalization;low respiratory symptoms and MM therapy including monoclonal drugs (p=0.07 and p=0.02) were associated with ventilatory support;therapy with corticosteroids and immunomodulatory drugs (p=0.019 and p=0.05) were associated with ICU admission. Overall mortality was 29%. Mortality rates were 47%, 68%, and 77% in hospitalized, ventilatory support, and ICU patients, respectively. By univariate analysis, age, ECOG performance status, and MM therapy including corticosteroids, were associated with increased mortality. By multivariate model, only ECOG performance status remained as an independent risk factor for death. ISS, prior lines of therapy, prior stem cell transplantation, and disease status at COVID-19 were not associated with any analyzed outcomes. MM patients who recovered from COVID had the current MM treatment delayed in 61% of cases. In this series, COVID-19 MM patients had a very high frequency of hospitalization, ventilatory support requirement, ICU admission, and deaths due to COVID-19. Although not associated with increased mortality, prior therapy drug classes were associated with severity of manifestation in our series. We also observed a high frequency of MM treatment delay in recovered patients, and the post-COVID clinical impact should be more explored. The high mortality observed reinforces the importance of preventing COVID-19, such as social distancing, wearing masks, and vaccination. Disclosures: De Queiroz Crusoe: Janssen: Research Funding. Hungria: Takeda: Honoraria;Amgen, BMS, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings/tr vel;Abbvie: Honoraria;Sanofi: Honoraria, Other: Support for attending meetings/travel.