ABSTRACT
Introduction Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, is particularly serious in patients with multiple myeloma (MM), with estimated mortality of over 30% in several studies. In the general population, SARS-CoV-2 vaccination has been demonstrated to be an effective approach to preventing infection. However, patients with MM were not included in vaccination trials. Recent studies suggest that patients with compromised immune systems exhibit reduced antibody response to SARS-CoV-2 vaccination, and MM patients are often immunocompromised both due to MM itself and due to MM treatment. Thus, the objective of this retrospective cohort study in the national Veterans Affairs (VA) healthcare system was to evaluate the real-world effectiveness of SARS-CoV-2 vaccination to prevent COVID-19 infection in MM patients during the 140-day period following initial vaccine availability. Methods This is a multicenter study of SARS-CoV-2 infection among vaccinated and unvaccinated patients at VA hospitals nationwide during the period from 12/15/2020 to 5/4/2021. We identified a cohort of MM patients who were alive and without prior SARS-CoV-2 infection on their date of vaccination or inclusion as a control. For added comparison with a less immunocompromised population, we also identified a cohort of cancer survivors, defined as patients with any solid or hematologic malignancy who had been treated with systemic cancerdirected therapy subsequent to 8/15/2010, but had not been treated with such therapy in the 6 months prior to vaccination or inclusion as a control, and were alive and without prior SARS-CoV-2 infection on that date. Vaccinated patients were exactly matched 1:1 to unvaccinated controls on race, VA facility, rurality of home address, cancer type, and treatment timing and modality with minimum distance matching on age. The primary exposure was receipt of a SARS-CoV-2 vaccine. The primary outcome was laboratory-confirmed SARS-CoV-2 infection. Vaccination effectiveness was defined as 1 minus the risk ratio of SARS-CoV-2 infection for vaccinated individuals compared to unvaccinated controls. Results 6,891 MM patients met eligibility criteria and 4,367 were vaccinated during the study period. Of those, 1,606 vaccinated MM patients were matched 1:1 to 1,606 unvaccinated or not yet vaccinated controls. In addition, for comparison, 2,476 vaccinated cancer survivors were matched 1:1 to 2,476 unvaccinated or not yet vaccinated controls. Median follow-up was 44 days among MM patients and 46 days among cancer survivors. Vaccine effectiveness in the matched cohort of MM patients was 22.2% (95% CI, -133 to 82.7%) starting 14 days after the second dose. In contrast, effectiveness was 82.3% (95% CI 16.4 to 100%) starting 14 days after the second dose in the matched cohort of cancer survivors. Among vaccinated MM patients in the matched cohort, 14 (8.7 per 1000 patients) were infected with SARS-CoV-2 subsequent to vaccination. Among vaccinated cancer survivors in the matched cohort, 10 (4.0 per 1000 patients) were infected subsequent to vaccination. Conclusion Vaccination is an effective strategy for preventing SARS-CoV-2. However, effectiveness may be reduced in patients with MM, likely due to a co-existing immunosuppression both due to the disease process as well as associated therapy. Future studies are needed to evaluate the relationship between MM disease states, types of therapy used and treatment timing that may impact vaccine effectiveness, and to also determine if MM patients would benefit from post-vaccination serologies or a booster vaccination.
ABSTRACT
Background Lenalidomide, bortezomib, and dexamethasone (RVD) is a standard front-line regimen for both transplant eligible and ineligible multiple myeloma (MM) patients. Based on original APEX study data, obtaining a complete blood count (CBC) before every administration of bortezomib has been recommended. Waiting for labs could add several hours to each visit. This can be inconvenient and costly for patients, payers, and institutions. There is a clear need to decease the frequency of labs drawn to promote increased cost-savings, improved patient safety, and decreased clinic wait times. Methods The primary objective of this study was to implement and evaluate a process change to decrease the frequency of labs for eligible patients on RVD for MM. First, an institutional review board-approved descriptive, retrospective study that included patients aged ≥ 18 years with MM receiving treatment with RVD was performed to assess trends in lab values. The objective of the retrospective review was to identify patients who can safely receive RVD without repeat labs prior to each bortezomib injection. Results from this retrospective review was presented to Dana-Farber Cancer institute (DFCI) and Massachusetts General Hospital myeloma clinicians, as well as the DFCI Pharmacy and Therapeutics committee. After approval was granted to implement institutional changes, we evaluated the impact of the process change. Results Retrospective study results Eighty-nine patients were included in the study. All patients had a platelet (PLT) count ≥ 75,000 cells/µL on day 1 of cycle 2 and beyond. Grade ≥ 3 thrombocytopenia developed in less than 3% of patients. Greater than 93% patients had an absolute neutrophil count (ANC) ≥ 1,000 cells/µL on day 1 of cycle 2 and beyond. Grade 3 and 4 neutropenia developed in 6.7% and 1.1% of patients, respectively. This study demonstrated that beyond the first cycle, patients with PLTs ≥ 75,000 cells/µL and an ANC ≥ 1,000 cells/µL on the first day of a cycle do not need labs prior to each administration of bortezomib in the cycle. These results provided the rationale for implementation of a new routine workflow. Workflow Implementation Implementation of a new workflow started on July 1, 2021 and included 71 adult patients receiving RVD for MM. First, a communication order was added to all RVD treatment plan templates in the electronic medical record specifying, “if on Day 1: ANC is ≥ 1,000 and PLTs are ≥ 75,000, no labs are required for remainder of that cycle.” Following that, a flowchart was developed by nursing that instructed infusion nurses to request a cancelation of future labs within the current treatment cycle (if the patient met criteria). Workflow Evaluation The Centers for Medicare & Medicaid Services reimbursement rates for a comprehensive metabolic panel and CBC with differential is $18.33. Following the implementation of this workflow, we saved over $3,904 in unnecessary healthcare related costs per month (figure 2). The average time it takes for our patients on RVD to check into their lab appointment and have labs resulted is 55 minutes. It takes an average of 47 minutes for patients to have bortezomib administered after labs are reviewed and orders are released for preparation (figure 1). Ultimately, patients spend more than 50% of their time in clinic waiting for labs compared to the time it takes to have bortezomib prepared, delivered, and administered. The implementation of this new workflow resulted in saving 195 hours of clinic chair time per month (figure 2). This time saved results in improved quality of life for patients who already have multiple visits at various healthcare facilities. Spending less time in clinic and reducing the frequency of venipunctures could potentially reduce the risk of bleeding, bruising, and discomfort amongst a patient population that is typically older and more at risk for complications. Conclusion This study demonstrates that it is economical, resourceful, and safe to implement a workflow process aimed at decreasing the frequenc of lab draws in patients receiving RVD for multiple myeloma. It allowed our institution to maximize chair time that could be used for other patients and generate additional value-added revenue. This is particularly very important with the Covid-19 pandemic, where reducing several hours of wait time will keep our patients and staff safer. [Formula presented] Disclosures: Munshi: Legend: Consultancy;Janssen: Consultancy;Abbvie: Consultancy;Adaptive Biotechnology: Consultancy;Karyopharm: Consultancy;Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties;Takeda: Consultancy;Amgen: Consultancy;Novartis: Consultancy;Celgene: Consultancy;Pfizer: Consultancy;Bristol-Myers Squibb: Consultancy.
ABSTRACT
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.