Teclistamab in combination with daratumumab and lenalidomide in multiple myeloma (MajesTEC-2 study)

Introduction: Combination of daratumumab (Dara) and lenalidomide (Len) may enhance the function of teclistamab (Tec), potentially resulting in improved antimyeloma activity in a broader population. We present initial safety and efficacy data of Tec-Dara- Len combination in patients with multiple myeloma (MM) in a phase 1b study (MajesTEC-2;NCT04722146). Method(s): Eligible patients who received 1-3 prior lines of therapy (LOT), including a proteasome inhibitor and immune-modulatory drug, were given weekly doses of Tec (0.72-or- 1.5 mg/kg with step-up dosing) + Dara 1800 mg + Len 25 mg. Responses per International Myeloma Working Group criteria, adverse events (Aes) per CTCAE v5.0, and for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) per ASTCT guidelines, were assessed. Result(s): 32 patients received Tec-Dara- Len (0.72 mg/kg, n = 13;1.5 mg/kg, n = 19). At data cut-off (11 July 2022), median follow-up (range) was 5.78 months (1.0-10.4) and median treatment duration was 4.98 months (0.10-10.35). Median age was 62 years (38-75);87.5% were male. Median prior LOT was 2 (1-3), 18.8% were refractory to Dara and 28.1% refractory to Len. CRS was most frequent AE (81.3% [n = 26], all grade 1/2), 95% occurred during cycle1. Median time to onset was 2 days (1-8), median duration was 2 days (1-22). No ICANS were reported. Frequent Aes (>=25.0% across both dose levels) were neutropenia (75.0% [n = 24];grade 3/4: 68.8% [n = 22]), fatigue (43.8% [n = 14];grade 3/4: 6.3% [n = 2]), diarrhoea (37.5% [n = 12];all grade 1/2), insomnia (31.3% [n = 10];grade 3/4: 3.1% [n = 1]), cough (28.1% [n = 9];all grade 1/2), hypophosphatemia (25.0% [n = 8];all grade 1/2), and pyrexia (25% [n = 8];grade 3/4: 6.3% [n = 2]). Febrile neutropenia frequency was 12.5% (n = 4). Infections occurred in 24 patients (75.0%;grade 3/4: 28.1% [n = 9]). Most common were upper respiratory infection (21.9% [n = 7]), COVID-19 (21.9% [n = 7]), and pneumonia (21.9% [n = 7]). Three (9.4%) had COVID-19 pneumonia. One (3.1%) discontinued due to COVID-19 infection and this patient subsequently died of this infection. Overall response rate (ORR, median follow-up) was 13/13 (8.61 months) at 0.72 mg/kg and 13/16 evaluable patients (less mature at 4.17 months) at 1.5 mg/kg. 12 patients attained very good/better partial response at 0.72 mg/kg dose, and response was not mature for 1.5 mg/kg group. Median time to first response was 1.0 month (0.7-2.0). Preliminary pharmacokinetic concentrations of Tec-Dara- Len were similar as seen with Tec monotherapy. Tec-Dara- Len- treatment led to proinflammatory cytokine production and T-cell activation. Conclusion(s): The combination of Tec-Dara- Len has no new safety signals beyond those seen with Tec or Dara-Len individually. Promising ORR supports the potential for this combination to have enhanced early disease control through the addition of Tec. These data warrant further investigation.

Building Thinking Classrooms Online: From Practice to Theory and Back Again

In the COVID-19 era of adapting to pandemic lockdown protocol, teaching practices have become more negotiable and less tethered to the familiar and institutionally normative practices found in educational settings around the world. With a shift to online teaching, many practices are being adapted from face-toface settings and being imported into online settings. However, this sort of adaptation is by no means trivial, and a direct transfer of practices may not necessarily be effective or plausible. While adaptation is undeniably necessary, a theory for teaching can offer guideposts around which adaptation may occur. Over many years of empirical investigation into how to enhance the synergy and capacity of students' thinking in face-to-face mathematics classrooms through systematically bypassing institutionally normative practices, the Building Thinking Classrooms framework offers a basis for one such theory. While this framework is used in many different contexts, one of these is in the education and professional development of mathematics teachers in tertiary and professional settings. However, with COVID-19 protocols in place, the tightly woven face-to-face practices of this framework had to evolve and be adapted. In this article, we discuss and exemplify how we drew from these face-to-face practices a set of principles, which served as guideposts for designing adaptations for engaging adult learners in mathematical tasks in a fully online setting. In our analysis, we consider not only the adaptations for online teaching we made, but the process of adaptation through a theory for teaching we used in designing effective and intentional learning settings for adults experiencing mathematics. © 2022, Adults Learning Mathematics. All rights reserved.

Vaccination immunology in SARS-CoV-2

The duration of immunity after SARS-CoV-2 infection or vaccination is uncertain, but major advances have been made in the understanding of SARS-CoV-2 B-and T-cell protection. In this review, key data from studies of reinfection as well as B-and T-cell immunity after infection and vaccination are presented. © 2021

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.

Response to COVID-19 Vaccination Post-CAR T Therapy in Patients with Non-Hodgkin Lymphoma and Multiple Myeloma

Background:COVID-19 adversely affects individuals with cancer. Several studies have found that seroconversion rates among patients with hematologic malignancies are suboptimal when compared to patients without cancer. Among patients with hematologic malignancies, seroconversion rates also appear to be influenced by recent treatment and the type of treatment they have received. Patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) are immunocompromised due to impaired humoral and cellular immunity in addition to prescribed immunosuppressive therapy. Chimeric antigen receptor T-cell (CAR T) therapy is now widely used for NHL and MM, but little is known about seroconversion rates after COVID-19 vaccination among these populations. Current national guidelines recommend COVID-19 vaccination to be offered to CAR T recipients as early as three months thereafter. We retrospectively evaluated SARS-CoV-2 spike-binding IgG antibody levels following COVID-19 vaccination among NHL and MM CAR T therapy recipients. Methods:This retrospective study was conducted at three Mayo Clinic sites on NHL and MM patients that received CAR T infusions from Sept 2016 to June 2021. Baseline characteristics were ascertained from medical records. All NHL and MM patients who had received CAR T at any point and were alive at the time that the COVID-19 vaccine first became available were eligible for inclusion for antibody response evaluation. For antibody response to vaccination, antibody spike values > 0.80 U/mL were considered positive. Results: Out of 104 CAR T infusions, 73 patients are alive at the time of this submission. We have had 7 patients with known COVID-19 pre-CAR T and all 7 are currently alive (5 have antibody titers and 2 have not been tested yet). Nineteen patients developed known COVID infection post-CAR T (13 alive and 6 deceased). The mortality of COVID post-CAR T in our sample was 31.5%. Furthermore, of the 13 patients that survived COVID-19, they received CAR T an average of 416 days prior to COVID-19 infection (median = 337, range = 54 - 1406);the 6 patients who died from COVID-19 had received CAR T an average of 250 days prior to COVID-19 infection (median = 164, range = 7 - 846). All 6 deceased patients did not receive COVID-19 vaccination pre-CAR T. Out of 17 CAR T patients tested for antibody spike titers post COVID-19 vaccination, 76.4% were able to mount an antibody response. More patients with MM had a higher titer response to the vaccine (>250 U/mL) compared to the NHL counterparts (0.80-249 U/mL). All patients that received the vaccine, regardless of antibody response, were alive at the time of this submission. Conclusions:The majority of CAR T recipients with NHL and MM are able to mount an antibody response following COVID-19 vaccination in our relatively small sample. The frequency of seroconversion among CAR T recipients seems to be similar to patients with hematologic malignancy who had received a hematopoietic cell transplant reported elsewhere. These findings are limited by our small sample size and may be influenced by the timing of vaccination relative to CAR T. Furthermore, almost half of our patients received IVIG post CAR T which could potentially cause false positive antibody results as pooled immunoglobulin preparations may contain COVID-19 antibodies from vaccinated healthy donors. To better understand the characteristics of the immunologic response against SARS-CoV-2 in patients post-CAR T, larger multicenter studies exploring both humoral and cellular immunity will be needed. JEWN, MI and JM are co-first authors and PV, HM and AR are co-senior authors. [Formula presented] Disclosures: Munoz: Physicians' Education Resource: Honoraria;Seattle Genetics: Honoraria;Bayer: Research Funding;Gilead/Kite Pharma: Research Funding;Celgene: Research Funding;Merck: Research Funding;Portola: Research Funding;Incyte: Research Funding;Genentech: Research Funding;Pharmacyclics: Research Funding;Seattle Genetics: Research Funding;Janssen: Research Funding;Millennium: Research Funding;Gilea /Kite Pharma, Kyowa, Bayer, Pharmacyclics/Janssen, Seattle Genetics, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche.: Speakers Bureau;Pharmacyclics/Abbvie, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, Beigene, Fosunkite, Innovent, Seattle Genetics, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, Beigene, Servier: Consultancy;Targeted Oncology: Honoraria;OncView: Honoraria;Kyowa: Honoraria. Bergsagel: Oncopeptides: Consultancy, Honoraria;Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse;Pfizer: Consultancy, Honoraria;Celgene: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;Genetech: Consultancy, Honoraria;GSK: Consultancy, Honoraria. Wang: Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding;LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding;Genentech: Research Funding;InnoCare: Research Funding;Novartis: Research Funding;MorphoSys: Research Funding;Eli Lilly: Membership on an entity's Board of Directors or advisory committees;TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Fonseca: Juno: Consultancy;Kite: Consultancy;Aduro: Consultancy;OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees;GSK: Consultancy;AbbVie: Consultancy;Patent: Prognosticaton of myeloma via FISH: Patents & Royalties;Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees;Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees;BMS: Consultancy;Amgen: Consultancy;Sanofi: Consultancy;Merck: Consultancy;Mayo Clinic in Arizona: Current Employment;Celgene: Consultancy;Takeda: Consultancy;Bayer: Consultancy;Janssen: Consultancy;Novartis: Consultancy;Pharmacyclics: Consultancy. Palmer: Sierra Oncology: Consultancy, Research Funding;CTI BioPharma: Consultancy, Research Funding;Protagonist: Consultancy, Research Funding;Incyte: Research Funding;PharmaEssentia: Research Funding. Dingli: Novartis: Research Funding;GSK: Consultancy;Apellis: Consultancy;Alexion: Consultancy;Sanofi: Consultancy;Janssen: Consultancy. Kapoor: Sanofi: Research Funding;AbbVie: Research Funding;Takeda: Research Funding;Karyopharm: Consultancy;Cellectar: Consultancy;BeiGene: Consultancy;Pharmacyclics: Consultancy;Sanofi: Consultancy;Amgen: Research Funding;Ichnos Sciences: Research Funding;Regeneron Pharmaceuticals: Research Funding;Glaxo SmithKline: Research Funding;Karyopharm: Research Funding. Kumar: Roche-Genentech: Consultancy, Research Funding;Oncopeptides: Consultancy;Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS: Consultancy, Research Funding;Beigene: Consultancy;Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding;Novartis: Research Funding;Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding;Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Tenebio: Research Funding;Merck: Research Funding;Carsgen: Research Funding;KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Amgen: Consultancy, Research Funding;Bluebird Bio: Consultancy;Antengene: Consultancy, Honoraria;Sanofi: Research Funding. Paludo: Karyopharm: Research Funding. Bennani: Kymera: Other: Advisory Board;Vividion: Other: Advisory Board;Kyowa Kirin: Other: Advisory Board;Daichii Sankyo Inc: Other: Advisory Board;Purdue Pharma: Other: Advisory Board;Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Kite, a Gilead Company: Consultancy, Research Funding;Merck: Research Funding;Gamida Cell: Consultancy;Takeda: Research Funding;Juno: Consultancy;Bluebird Bio: Consultancy, Research Funding;Celgene: Consultancy, Research Funding;Novartis: Consultancy;Janssen: Consultancy, Research Funding;Sorrento: Consultancy;Legend: Consultancy;Vineti: Consultancy. Murthy: CRISPR Therapeutics: Research Funding.

[SARS-CoV-2 vaccines]

Control of the ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will require one or more vaccines. Currently, numerous SARS-CoV-2 vaccines are in either pre-clinical or clinical development. Twenty are in fase III development. In this review we summarise available safety and efficacy data of two RNA based vaccines, two non-replication competent vector-based vaccine, one inactivated whole-virus vaccine, and one subunit. All being either approved or nearing approval.

Investing in innovative and productive capabilities for resilient economies in a post-COVID-19 world

The COVID-19 pandemic continues to batter the world, with millions of positive cases, leading to more than 600,000 casualties by the end of July 2020. With the persistent threat of contagion, this sanitary emergency is turning a rapidly deteriorating economic situation into one of the deepest economic and social crises the world has ever experienced. Debates on the best approaches to reopen economic activities, on policies to foster a speedy and sustainable recovery, and on strategies to create the conditions necessary to address similar events in the future are pervasive. Based on pertinent lessons from history, in this paper, we advocate coordination, cooperation and investment in science, technology, productive and innovative capabilities, as strategic ingredients for addressing grand challenges and for building resilience. In responding to the COVID-19 pandemic, governments - particularly of developing countries - should retain these lessons and enact active strategies for implementing comprehensive and coordinated policies. Copyright © 2020 Inderscience Enterprises Ltd.