Preliminary results from phase 2 of CC-92480- MM- 001: Mezigdomide plus dexamethasone in relapsed/refractory multiple myeloma (RRMM)

In phase 1 of CC-92480- MM- 001 (NCT03374085), the recommended phase 2 dose (RP2D) of mezigdomide plus dexamethasone (MEZI-d) was selected at 1 mg once daily for 21/28 days. Here we report preliminary results from the MEZI-d dose-expansion cohort in patients with heavily pretreated RRMM. Key eligibility criteria were: RRMM;>=3 prior lines of therapy;disease progression <=60 days of last myeloma therapy;refractoriness to lenalidomide/pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 monoclonal antibody. Oral mezigdomide 1 mg was given on days 1-21 of each 28-day cycle, plus weekly dexamethasone (40 mg;20 mg if >75 years of age). Primary objective was to evaluate efficacy (overall response rate [ORR]);secondary objectives included safety/tolerability and additional efficacy assessments. Pharmacodynamics was an exploratory objective. As of 16/Sep/2022, 101 patients had received MEZI-d at the RP2D. Median age was 67 (range 42-85) years, median time since initial diagnosis was 7.4 (1.1-37.0) years;39.6% of patients had plasmacytomas and 37/101 patients had high-risk cytogenetics (56/101 not evaluable). Median number of prior regimens was 6 (3-15);prior therapies included stem cell transplantation (77.2%) and anti-BCMA therapy (29.7%). All patients were refractory to last myeloma regimen and triple-class refractory. Median follow-up was 7.5 (0.5-21.9) months, with a median of 4 (1-20) cycles;10.0% of patients continued treatment;progressive disease was the main reason for discontinuation (60.4%). ORR was 40.6% for all patients. Whilst data are not mature yet, median PFS was 4.4 (95% CI 3.0-5.5) months and median duration of response was 7.6 (95% CI 5.4-9.5) months. ORR was 30.0% in patients with plasmacytomas (N = 40) and 50.0% in patients with prior anti-BCMA therapy (N = 30). Ninety-one (91.1%) patients experienced a grade 3/4 treatment-emergent adverse event (TEAE). Most frequent hematologic grade 3/4 TEAEs were neutropenia (75.2%), anaemia (35.6%), and thrombocytopenia (27.7%);34.7% of patients had grade 3/4 infections, including grade 3/4 pneumonia (15.8%) and COVID-19 (7.0%). Occurrence of other grade 3/4 non-hematologic TEAEs was generally low. Due to TEAEs, 76.2% and 29.7% of patients had mezigdomide dose interruptions and reductions, respectively;90.1% of patients discontinued mezigdomide. Mezigdomide induced substrate degradation and increases in activated and proliferating T cells in patients, including those directly refractory to pomalidomide-based therapies. MEZI-d had a manageable safety profile with encouraging efficacy in patients with triple-class refractory RRMM, including patients with prior BCMA-targeted therapies. These results strongly support the continued development of mezigdomide in MM, and especially in combination.

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)

Pomalidomide Treatment in Relapsed/Refractory Multiple Myeloma Patients-Real-World Data From Hungary.

Pomalidomide is a third generation immunomodulatory drug in the treatment of refractory and relapsed multiple myeloma patients. Our aim was to investigate the efficacy and safety of pomalidomide therapy in a real world setting. Eighty-six Hungarian patients were included, 45 of whom received pomalidomide ± an alkylating agent, while in 38 of them pomalidomide was combined with a proteasome inhibitor. 56 patients (65%) showed any response to the treatment with 18 complete or very good partial remissions and 38 partial remissions. At a median duration of follow-up of 18.6 months, the median progression-free survival (PFS) was 9.03 months, while the median overall survival (OS) was 16.53 months in the whole cohort. Patients with early stage disease (R-ISS 1 and 2) had better survival results than those with stage 3 myeloma (p = 0.002). Neither the number of prior treatment lines, nor lenalidomide refractoriness had a significant impact on PFS. PFS was found similar between the cohort of patients with impaired renal function and the cohort without kidney involvement. During the study, eight mortal infections and two fatal bleeding complications occurred, however, mild hematologic and gastrointestinal toxicities were identified as the most frequent adverse events. The results of our investigations confirm that pomalidomide is an effective treatment option for relapsed/refractory MM, besides, the safety profile is satisfactory in subjects with both normal and impaired renal function.

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.

UPDATE AND FOLLOW-UP OF NEWLY DIAGNOSED MULTIPLE MYELOMA (NDMM) WITH HIGH-RISK CYTOGENETIC (HRC)

Background: Despite therapeutic strategies improvement, there is still a subgroup of NDMM patients (pts) that pose a clinical challenge, whose represents a <20%, we refer to HRC. HRC Pts are associated with a poor prognosis and aggressive course, although, recent studies propose different clinical evolution according to the cytogenetic alteration (CA). IMWG identified a 4-year progression free survival (PFS) of 12% and OS of 35%. Aims: Describe our clinical experience and therapeutic management, also the clinical-biochemical alterations at diagnosis in a heterogeneous NDMM HRC's cohort. Evaluate survival curves according to HRC. Methods: Descriptive and retrospective analysis, using clinical and analytical NDMM HRC patient's data from 2009 to 2022 at Guadalajara University Hospital. 61/201 pts were selected in the MM treatment (tto) protocols. FISH results were not found in <30% NDMM, due to lack of metaphases or no request. Pts with t(4;14), t(14;16), gain 1q, t(14;20), plasmablastic leukemia and/or del(17p13) were classified as HRC. Survival data and Pearson (P) correlation were used. P value <0.05 was considered significant. Results: Total HRC NDMM 61 pts were analyzed. 21 of 61 pts (35%) were diagnosed with stage monoclonal gammopathy of undetermined significance (MGUS) prior to HRC NDMM, with a mean 4 years (y) (IR 2-10 y), greater % representation of MGUS were del17p (38), gain 1q (48), t (14;16) (4,5) and del17p + gain1q (9,5). Clinical characteristics data at diagnosis according to HRC are shown in Table 1. Pts receiving 1st line were 100% (61), 90,2% of the pts received bortezomib (V) - based induction, of them 29% (n=16) were treated with alkylating agents, 49,1% (n=27) received IMIDs and 18,2% (n=10) V with dexamethasone (d), plus two of these pts received regimens composed of 3xVCd + 3xVPd and the other dara-VRd. 25 pts (40,98%) were transplant eligible (TPH). 2nd line, 32 pts (52,5%), (n=3) VTD-PACE, (n=6) daratumumab (n=1 alone, 3 R, 1 V, 1 K), (n=1) Kdexa, (n=1) Pocydex and (n=9) V plus 3 IMIDs, 2 alkylating, 2 P or 2 alone and (n=12) IMIDs and alkylatings in combination. 5 pts (8,2) were TPH (1 alogenic). 3rd line, 16 pts (26,2), just 3 pts were TPH. 4th line, 7 pts (11,4), 1 pts were TPH. 5th line, 4 pts (6,5). 6th line, 2pts (3,3). In the last lines, the use of triplets with pomalidomide, karfilzomib or intensive chemotherapy prevail. After a median follow-up of 3 y (IR 1,6-6,2) from diagnosis, pts had relapsed at least one time (60,6%) and more than 3 times (11,5%), and 25 had died (40,9%), 16 of them due to infections (14 bacteremia, 2 COVID), 5 cardiorespiratory arrest and 3 due to progression. (Image 1) represents PFS y OS for only 5 CA, as data were no representative in other CA. Correlation between ISS and ISS-R data were only able to execute in HRC gain1q, due to lack of sample in other CA. We found a P coefficient of 0.568399 or 56.83% (p- <0.00578, CI 95%). Summary/Conclusion: Our case series continues with a longer survival curve compared to those commented in other studies. As cytogenetic abnormalities (t(4;14), t(14;16), t(14;20) and gain1q), similar % of representation are described as Kumar. Nat Rev Clin Oncol. 2018, except for del(17p), 23% vs 10%. From the second line, the probability of receiving a new line, the duration of tto and the interval without tto decreased with each line of tto. As treatment lines progress, therapeutic combinations are more heterogeneous and less concordant. A further longer follow-up and higher HRC NDMM pts's recruitment will be necessary to clarify the response to tto regimens based on individual cytogenetic groups.

Cryptococcosis in a patient with multiple myeloma receiving pomalidomide: a case report and literature review.

While overall survival with multiple myeloma (MM) has improved, patients suffer from overwhelming tumor burden, MM-associated comorbidities, and frequent relapses requiring administration of salvage therapies. As a result, this vicious cycle is often characterized by cumulative immunodeficiency stemming from a combination of disease- and treatment-related factors leading to neutropenia, T-cell deficiency, and hypogammaglobulinemia. Infectious etiologies differ based on the duration of MM and treatment-related factors, such as number of previous treatments and cumulative dose of corticosteroids. Herein, we present the case of a patient who was receiving pomalidomide without concomitant corticosteroids for MM and was later found to have cryptococcosis, as well as findings from a literature review. Most cases of cryptococcosis are reported in patients with late-stage MM, as well as those receiving novel anti-myeloma agents, such as pomalidomide, in combination with corticosteroids or following transplantation. However, it is likely cryptococcosis may be underdiagnosed in this population. Due to the cumulative immunodeficiency present in patients with MM, clinicians must be suspicious of cryptococcosis at any stage of MM.

Repurposing Thalidomide, Its Analogue And Apremilast For Possible Antiviral In Situation Of Severe Covid Cytokine Syndrome.

BACKGROUND: COVID-19, caused by SARS-corona virus-2, is a global wide expanded public health risk at a bizarre level. In this current situation, COVID-19 became a serious emerging pandemic. Choosing drug reusing is a crucial step in identifying the new uses of old established drugs. To achieve a significant and healthy way of treatment in COVID patients within a short duration, drug repurposing is a novel method. OBJECTIVE: The present study concentrated on the molecular docking of thalidomide and its analogues and Apremilast against Coronavirus infectious symptoms, evaluated on virus proteins (Spike Protein, 3cl Protease, Nucleocapsids). METHODS: The present study explores the possibility of repurposing thalidomide for the treatment of SARS-COV-2 infection by assessing and confirming with docking affinity scores of thalidomide & its analogues and Apremilast, with spike protein, 3cl protease, and nucleocapsids. RESULTS: From the study results, thalidomide, pomalidomide, lenalidomide, and Apremilast exhibited better binding affinity to N Protein (4KXJ), Protease (4WY3) and Spike Protein (5WRG). In comparison of targets, N Protein - 4KXJ is the best for the four ligands. It is finalized that all four ligands (Thalidomide - -8.6, Pomalidomide - -8.8, Lenalidomide,and - -8.2,and Apremilast - -8.1) have good docking scores with the target N Protein. CONCLUSION: The present study shows confirmation that thalidomide and its analogues and apremilast as a better fit for treating high risk patients of COVID -19 viral infection which are supposed to promote beneficial effects for both respiratory illnesses like COVID-19 symptoms as well as improve the pathological state of condition.

Bendamustine in combination with pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: A phase II trial.

Treatment of patients with resistant/refractory multiple myeloma (MM) is an unmet need. In this phase II study, we evaluated the role of bendamustine, pomalidomide and dexamethasone combination in this setting. Between February 2020 and December 2021, 28 patients were recruited. Patients received bendamustine 120 mg/m2 day 1, pomalidomide 3 mg days 1-21, and dexamethasone 40 mg days 1, 8, 11, 22, regimen given for a maximum of six cycles. The median (range) age of the patients was 54 (30-76) years and 15 (53.6%) were males. Patients had received a median (range) of three (two-six) prior lines and 85.7% were refractory to both lenalidomide and bortezomib. The primary end-point was the overall response rate (ORR) defined as ≥partial response after at least three cycles. Secondary objectives were toxicity, progression-free survival (PFS), time to progression and overall survival (OS). An intent-to-treat analysis was done. An ORR of 57.6% was achieved. Patients with extramedullary myeloma had a better response rate. At a median follow-up of 8.6 months, the median PFS and OS were 6.2 and 9.7 months respectively. Toxicity was manageable; mainly haematological (neutropenia, 46.4%; anaemia, 42.8%; and thrombocytopenia, 7.1%). Bendamustine, pomalidomide and dexamethasone could be a novel combination for the heavily pretreated, lenalidomide-refractory myeloma population.

Chronic Eosinophilic Pneumonia - A Challenging Case with Multiple Triggers

Introduction Eosinophilic pneumonia is a class of lung diseases characterized by accumulation of eosinophils in the lung. Chronic eosinophilic pneumonia (CEP) is diagnosed through radiographic imaging and bronchoalveolar lavage (BAL) with elevated eosinophil count (>25%) in the setting of pulmonary symptoms for more than 2 weeks. While CEP is often an idiopathic disease, it may also be caused by medications, illicit substances, or infections. Identifying the trigger is imperative for successful treatment. A 71-year-old man presented with fever and chronic shortness of breath that started after COVID-19 infection (6 months prior to presentation). Medical history was also significant for multiple myeloma, asthma, hypertension, type 2 diabetes, coronary artery disease, chronic kidney disease, and Alzheimer's dementia. Current medications included bortezomib, pomalidomide, aspirin, clopidogrel , donepezil, tramadol and insulin. Lenalidomide was discontinued 3 months prior due to generalized skin rash and high peripheral eosinophilia (19%). On presentation, physical exam revealed mild respiratory distress, bibasilar crackles, and bilateral pedal edema. Long COVID Syndrome was suspected. He was started on antibiotics and diuretics with no improvement. Labs revealed mild peripheral eosinophilia. Chest X-ray showed diffuse bilateral reticular nodular opacities predominantly on the right. CT chest revealed reticulonodular infiltrates in both lungs predominantly in the right upper lobe with small pleural effusion. Bronchoscopy with BAL was negative for infection but revealed 28% eosinophils. Pomalidomide was discontinued and oral prednisone started. Discussion: CEP is part of a group of eosinophilic lung diseases characterized by abnormal accumulation of eosinophils in the lung tissue. Symptoms include dyspnea and cough in the majority of cases, but may also include fever, sinusitis, rhinitis, fatigue and weight loss. The radiographic hallmarks are bilateral alveolar infiltrates peripherally predominantly in the upper lobes and may be ground glass or consolidation. The presence of an elevated eosinophil count (>25%) in a BAL confirms the diagnosis. Though often idiopathic, identification of possible causes is important for proper management. In our case, the patient has multiple risk factors including possible Long COVID Syndrome and malignancy. Medications such as bortezomib, lenalinomide and pomalidomide have been known to cause diffuse lung injury. To the best of our knowledge there is one case report illustrating Lenalinomide related CEP. History of asthma is present in most cases of idiopathic CEP. Our patient had multiple potential triggers for CEP. We suspect that CEP was medication-related in this case. (Figure Presented).

Infections in relapsed myeloma patients treated with isatuximab plus pomalidomide and dexamethasone during the COVID-19 pandemic: Initial results of a UK-wide real-world study.

OBJECTIVES: There are no real-world data describing infection morbidity in relapsed/refractory myeloma (RRMM) patients treated with anti-CD38 isatuximab in combination with pomalidomide and dexamethasone (IsaPomDex). In this UK-wide retrospective study, we set out to evaluate infections experienced by routine care patients who received this novel therapy across 24 cancer centres during the COVID-19 pandemic. METHODS: The primary endpoint was infection morbidity (incidence, grading, hospitalization) as well as infection-related deaths. Secondary outcomes were clinical predictors of increased incidence of any grade (G2-5) and high grade (≥G3) infections. RESULTS: In a total cohort of 107 patients who received a median (IQR) of 4 cycles (2-8), 23.4% of patients experienced ≥1 any grade (G2-5) infections (total of 31 episodes) and 18.7% of patients experienced ≥1 high grade (≥G3) infections (total of 22 episodes). Median time (IQR) from start of therapy to first episode was 29 days (16-75). Six patients experienced COVID-19 infection, of whom 5 were not vaccinated and 1 was fully vaccinated. The cumulative duration of infection-related hospitalizations was 159 days. The multivariate (MVA) Poisson Regression analysis demonstrated that a higher co-morbidity burden with Charlson Co-morbidity Index (CCI) score ≥4 (incidence rate ratio (IRR) = 3, p = 0.012) and sub-optimal myeloma response less than a partial response (

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).

Lack of Induction of RBD-Specific Neutralizing Antibodies despite Repeated Heterologous SARS-CoV-2 Vaccination Leading to Seroconversion and Establishment of T Cell-Specific Memory in a Patient in Remission of Multiple Myeloma.

BACKGROUND: Prophylactic vaccination against infectious diseases may induce a state of long-term protection in the otherwise healthy host. However, the situation is less predictable in immunocompromised patients and may require adjustment of vaccination schedules and/or basic therapy. METHODS: A patient in full remission of multiple myeloma since the last three years and on long-term maintenance therapy with pomalidomide, a drug inhibiting angiogenesis and myeloma cell growth, was vaccinated twice with Comirnaty followed by two vaccinations with Vaxzevria. Seroconversion and SARS-CoV-2-specific cellular responses were monitored. RESULTS: No signs of seroconversion or T cellular memory were observed after the first "full immunization" with Comirnaty. Consequently, long-term-maintenance therapy with Pomalidomide was stopped and two additional shots of Vaxzevria were administered after which the patient seroconverted with Spike(S)-protein specific antibody levels reaching 49 BAU/mL, mild S-peptide pool-specific T cell proliferation, effector cytokine production (IL-2, IL-13), and T cellular activation with increased numbers of CD3+CD4+CD25+ T cells as compared to vaccinated and non-vaccinated control subjects. However, despite suspension of immunosuppression and administration of in total four consecutive heterologous SARS-CoV-2 vaccine shots, the patient did not develop neutralizing RBD-specific antibodies. CONCLUSIONS: Despite immunomonitoring-based adjustment of vaccination and/or therapy schedules vaccination success, with clear correlates of protection, the development of RBD-specific antibodies could not be achieved in the immunocompromised patient with current SARS-CoV-2 vaccines. Thus, our report emphasizes the need for improved active and passive immunization strategies for SARS-CoV-2 infections.

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.

Iberdomide (IBER) in Combination with Dexamethasone (DEX) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Results from the Dose-Expansion Phase of the CC-220-MM-001 Trial

Introduction: Despite recent advances, MM remains incurable and new therapeutic options are needed, particularly for pts with RRMM. IBER is a novel, potent oral cereblon E3 ligase modulator (CELMoD ®) compound with enhanced tumoricidal and immune-stimulatory effects compared with immunomodulatory (IMiD ®) agents. Preclinically, IBER demonstrated marked synergy with DEX and with other standard myeloma treatments. CC-220-MM-001 (NCT02773030) is an ongoing phase 1/2 study evaluating IBER with different treatment combinations in independent cohorts of pts with RRMM;in phase 1, the recommended phase 2 dose of IBER, when given in combination with DEX, was determined at 1.6 mg (Lonial S, et al. Blood 2019;134[suppl 1]:3119). Here we report results from the dose expansion of IBER + DEX in pts with heavily pretreated, triple-class exposed (including ≥ 1 IMiD agent, ≥ 1 proteasome inhibitor [PI], and ≥ 1 anti-CD38 monoclonal antibody [mAb]) RRMM. Methods: Eligible pts had RRMM;had received ≥ 3 prior lines of therapy, including lenalidomide (LEN), pomalidomide (POM), a PI, a glucocorticoid, and an anti-CD38 mAb;had experienced disease progression within 60 days of last myeloma therapy;and were refractory to an IMiD agent, a PI, a glucocorticoid, and an anti-CD38 mAb. Pts with central nervous system involvement were not eligible. Pts who had received prior anti-BCMA therapy were excluded, but included in a supportive cohort for safety and preliminary efficacy assessment. IBER (1.6 mg) was given orally on days (D) 1-21, in combination with DEX (40 mg;20 mg if > 75 years of age) on D1, 8, 15, and 22 of each 28-day cycle. Thrombo-embolism prophylaxis was mandatory for all pts. Primary objective was to determine efficacy expressed as overall response rate (ORR). Secondary endpoints included additional efficacy and safety assessments. Exploratory endpoints included evaluation of health-related quality of life (HRQoL). Results: As of June 2, 2021, 107 pts had received IBER + DEX. Median age was 64 (44-83) years;median time since initial diagnosis was 6.9 (1.6-24.5) years. Extramedullary plasmacytomas were present in 25.2% of pts;29.9% of pts had high-risk cytogenetics. Median number of prior regimens was 6 (3-23). All pts were triple-class exposed;prior therapies included autologous stem cell transplantation (78.5%), PIs (100%), IMiD agents (LEN [100%] and POM [100%]), and anti-CD38 mAbs (100%);99.1% of pts were refractory to last myeloma regimen and 97.2% of pts were triple-class refractory. Median follow-up was 7.69 (0.5-17.5) months, with a median number of 4 (1-17) cycles received and 13 (12.1%) pts continuing treatment. Main reason for discontinuation was progressive disease (69.2%). ORR was 26.2%, with 1 (0.9%) stringent complete response, 8 (7.5%) very good partial responses, and 19 (17.8%) partial responses (Table);the clinical benefit rate (≥ minimal response) was 36.4% and disease control rate (≥ stable disease) was 79.4%. Median duration of response was 7.0 (4.5-11.3) months (Table), median progression-free survival was 3.0 (2.8-3.7) months, and median overall survival was 11.2 (9.0-not reached) months. Similar response rates were observed among a cohort of pts also exposed to BCMA therapies (N = 24, Table). Grade (Gr) 3-4 treatment-emergent adverse events (TEAEs) were reported in 88 (82.2%) pts. Most frequent (≥ 20% pts) hematologic Gr 3-4 TEAEs were neutropenia (44.9%;and 4.7% febrile neutropenia), anemia (28.0%), thrombocytopenia (21.5%), and leukopenia (20.6%). Gr 3-4 infections were reported in 27.1% of pts;Gr 3-4 pneumonia and COVID-19 occurred in 10.3% and 4.7% of pts, respectively. Occurrence of other Gr 3-4 non-hematologic TEAEs was generally low, including gastrointestinal disorders (5.6%), fatigue (2.8%), rash (1.9%). Fifty-six (52.3%) pts and 20 (18.7%) had IBER dose interruptions and reductions due to TEAEs, respectively. Five (4.7%) pts discontinued due to TEAEs. No pt discontinued IBER due to neutropenia. Overall, HRQoL was maintained in these pts. Conclusions: IBER + DEX demonst ated promising efficacy in pts with heavily pretreated, triple-class exposed and refractory RRMM, as well as in pts who had previously received anti-BCMA therapy;this combination was generally well tolerated and TEAEs were manageable with dose reductions and interruptions. These results support the further development of IBER in MM, including phase 3 trials in combination regimens. [Formula presented] Disclosures: Lonial: Abbvie: Consultancy, Honoraria;AMGEN: Consultancy, Honoraria;Takeda: Consultancy, Honoraria, Research Funding;GlaxoSmithKline: Consultancy, Honoraria, Research Funding;TG Therapeutics: Membership on an entity's Board of Directors or advisory committees;Merck: Honoraria;BMS/Celgene: Consultancy, Honoraria, Research Funding;Janssen: Consultancy, Honoraria, Research Funding. Popat: GlaxoSmithKline: Consultancy, Honoraria, Research Funding;Abbvie, Takeda, Janssen, and Celgene: Consultancy;Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES;AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria;Janssen and BMS: Other: travel expenses. Hulin: Sanofi: Honoraria;Celgene/BMS: Honoraria;Janssen: Honoraria;Takeda: Honoraria;abbvie: Honoraria. Jagannath: Legend Biotech: Consultancy;Bristol Myers Squibb: Consultancy;Karyopharm Therapeutics: Consultancy;Janssen Pharmaceuticals: Consultancy;Sanofi: Consultancy;Takeda: Consultancy. Oriol: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees;Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees;BMS/Celgene: 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. Richardson: Karyopharm: Consultancy, Research Funding;Regeneron: Consultancy;AbbVie: Consultancy;Celgene/BMS: Consultancy, Research Funding;Oncopeptides: Consultancy, Research Funding;GlaxoSmithKline: Consultancy;Protocol Intelligence: Consultancy;Janssen: Consultancy;Secura Bio: Consultancy;Takeda: Consultancy, Research Funding;Sanofi: Consultancy;AstraZeneca: Consultancy;Jazz Pharmaceuticals: Consultancy, Research Funding. Weisel: Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Honoraria;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Abbvie: Consultancy;Novartis: Honoraria;Pfizer: Honoraria. Minnema: Cilag: Consultancy;Janssen: Consultancy;Alnylam: Consultancy;Celgene: Other: Travel expenses;Kite/Gilead: Consultancy;BMS: Consultancy. Badros: J&J: Research Funding;Janssen: Research Funding;BMS: Research Funding;GlaxoSmithKline: Research Funding. Knop: BMS/Celgene: Consultancy, Honoraria, Research Funding;Amgen: Research Funding;Janssen: Consultancy;Oncopeptides: Consultancy;Pfizer: Consultancy;Sanofi: Consultanc . Stadtmauer: Janssen: Consultancy, Honoraria;Takeda: Consultancy, Honoraria;Abbvie: Consultancy, Honoraria;Amgen: Consultancy, Honoraria;Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Chen: Bristol Myers Squibb: Current Employment. Nguyen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Amin: Bristol Myers Squibb: Current Employment. Kueenburg: Celgene a BMS company: Current Employment. Peluso: Celgene, a Bristol-Myers Squibb Company: Current Employment. van de Donk: BMS/Celgene: Consultancy, Honoraria;Janssen: Consultancy, Research Funding;Amgen: Consultancy, Research Funding;Cellectis: Research Funding;Takeda: Consultancy;Roche: Consultancy;Novartis /bayer/servier: Consultancy.

Bortezomib-Pomalidomide-Dexamethasone (VPD) As Novel Induction Therapy in Newly-Diagnosed Multiple Myeloma: Early Safety Data from an Ongoing Single Arm Phase-II Investigator-Initiated Clinical Trial (PRIME Study)

Introduction: Pomalidomide is a third-generation immunomodulatory drug approved for relapsed and/or refractory Multiple Myeloma (RRMM). In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone demonstrated superior efficacy in patients with RRMM. PRIME study (CTRI/2019/10/021618) is testing this combination in Newly Diagnosed Multiple Myeloma (NDMM) Aim: To determine safety of Pomalidomide in combination with Bortezomib and dexamethasone (VPD) in NDMM Study design: A prospective, single arm, phase II study from a tertiary center. Both transplant eligible and ineligible patients with NDMM aged between 18-70 years are being recruited in the study. Patients with Plasma cell leukemia, POEMS and amyloidosis were excluded. The regimen consists of weekly Bortezomib 1.3mg/sq.m (subcutaneous), Tab. Pomalidomide 2-4mg once daily for 21days, and Tab Dexamethasone 20mg twice weekly, with the cycle repeating every 28 days, 9-12 cycles. Here we report the adverse events (AE) by NCI CTCAE v5.0, upon recruiting 26 patients, as predetermined in the study. Results: Of the proposed 45-50 patients, 26 patients were enrolled in the study between April 2020 to May 2021 and 23 (88.4%) have completed 4 cycles of VPD. The median age is 55years (18-70), and gender ratio 1:1. At disease presentation, bone lesions were the commonest (96.2%, n=25), IMWG high risk cytogenetics were seen in 42.4% (n=11), RISS-2 in 69.3% (n=18), IgG kappa paraproteinemia in 54% (n=14) patients and ECOG performance score 2-3 in 57.6%(n=15). Ten (38.5%) patients have completed 9 cycles, and 3 underwent auto-transplant (between Cycle 4 & 6). Protocol adherence was 96.1% (25/26 patients). Table-1 shows drug-induced toxicity, hematological toxicities were the commonest. Two patients withdrew consent in view of bortezomib-induced peripheral neuropathy. Serious adverse events (SAE) were reported in 9 (34.6%) patients and were considered unrelated to the regimen by the safety committee (PSVT=1, Bony pain=2, dyspnea=1, pneumonia=1, constipation=1, diarrhea=1, hypotension=1) and one death due to SARS-CoV2 pneumonia. Treatment delays of 2 weeks in 4 patients (SARS-CoV2 = 3, Syncope = 1) After 4 cycles (n=23), 6 (26%) patients were in stringent Complete Response (sCR), 17(74%) in Very Good partial response (VGPR) and 13 (56.5%) are Measurable Residual Disease (MRD) negative. Of 10 patients who completed cycle 9, 9 were MRD negative and 1 showed disease progression. Conclusion: Safety data from the PRIME study demonstrates that VPD regimen has a favorable tolerance profile in patients with NDMM. Early efficacy signals are encouraging, and recruitment continues. [Formula presented] Disclosures: Radhakrishnan: Dr Reddy's Laboratories: Honoraria, Membership on an entity's Board of Directors or advisory committees;Emcure Pharmaceuticals: Research Funding;Intas Pharmaceuticals: Research Funding;Janssen India: Honoraria;NATCO Pharmaceuticals: Research Funding;Novartis India: Membership on an entity's Board of Directors or advisory committees;Roche India: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;AstraZeneca India: Honoraria, Speakers Bureau;Bristol-Myers-Squibb India: Membership on an entity's Board of Directors or advisory committees, Research Funding;Cipla Pharmaceuticals India: Research Funding;Aurigene: Speakers Bureau. Garg: Dr Reddys Laboratories: Honoraria, Speakers Bureau. Nair: Dr Reddy's Laboratories: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Intas pharmaceuticals: Honoraria, Speakers Bureau;Mylan pharmaceuticals: Honoraria;Novartis India: Honoraria;Fresenius Kabi India: Honoraria;Cipla Pharmaceuticals: Honoraria, Speakers Bureau;Janssen India: Honoraria, Speakers Bureau. Chandy: Janssen: Honoraria;Pfizer: Honoraria;Intas Pharmaceuticals: Research Funding.