Time to initiation of antiresorptive agents in multiple myeloma to reduce skeletal related events

PurposeCurrent treatment guidelines strongly support the use of antiresorptive therapy in patients with newly diagnosed multiple myeloma (NDMM) with the goal of preventing skeletal related events (SRE). Despite these concrete, data-driven recommendations, the impact of delays in antiresorptive initiation in NDMM patients is understudied. Through a multicenter retrospective study, we examined the impact of delays in antiresorptive initiation on the rates of SREs. We furthered our exploration of this topic in a separate retrospective analysis with a focus on reasons for delays in antiresorptive therapy initiation.MethodsElectronic health records from two large academic institutions were used to identify patients with NDMM between July 1, 2016, and June 30, 2019. Exclusion criteria included patients with previous antiresorptive use and patients never prescribed antiresorptives. Time to antiresorptive initiation and its subsequent impact on the rate of SREs was analyzed using hazard ratios. A follow up, single-center retrospective study was conducted using EHR data with an emphasis on the identification of barriers to antiresorptive initiation. Here, descriptive, and inferential statistics were used to identify variables that have a statistically significant impact on antiresorptive initiation.ResultsA total of 759 patients with newly diagnosed MM met inclusion criteria for our multicenter study. Our study found that a delay in initiation of anti-resorptive therapy of greater than 31 days from diagnosis resulted in an increased risk for SRE with a hazard ratio of 1.654 (95% CI: 1.054-2.598; p-value = 0.029). In our follow up study, a total of 45.6% of patients with newly diagnosed MM were prescribed antiresorptive therapy, while 59% of patients with identified lytic lesions on screening imaging received anti-resorptive therapy. Statistically insignificant differences were observed in the time to initiation of anti-resorptive therapy based on health insurance. Variables such as race and gender were not found to have a statistically significant relationship with delays in antiresorptive initiation.ConclusionsPatients with NDMM should be initiated on antiresorptive therapy without delay to minimize the rates of SREs, and clinicians should be diligent in anticipating delays in initiation such as need for dental clearance and renal disease

Retrospective Analysis of the Relationship between Time to Anti-Resorptive Therapy and Incidence of Skeletal Related Events in Patients with Multiple Myeloma

Background Multiple Myeloma (MM) is a plasma cell neoplasm causing a proliferation of monoclonal immunoglobulins that causes end organ damage in the form of hypercalcemia, renal insufficiency, anemia, and lytic bone lesions. Specifically, patients with MM are at risk for developing significant bone disease eventually leading to development of skeletal related events (SRE) (pathological fractures, spinal cord compression, and/or need for radiotherapy or surgery to bone). It is well established that the use of anti-resorptive agents (i.e. Bisphosphonates, Denosumab) lead to fewer bony lesions, less severe bone disease, and fewer SREs. However, while anti-resorptive therapy is recommended for all MM patients undergoing treatment, it is common for initiation of anti-resorptive therapy to be delayed due to the need for dental clearance, clinician preference, or relative contraindications to the medications. Current studies show that this therapy is overall underutilized, likely for similar reasons. However, the effect on SRE with regards to time to initiation of anti-resorptive agent has not been well studied. Herein, we conducted a retrospective analysis to determine if time to anti-resorptive agent has an effect on incidence of SREs. Methods: We performed a retrospective cohort study using our Electronic Health Record system to identify and analyze data of patients with newly diagnosed Multiple Myeloma from July 1st, 2016 until June 30th, 2019 to determine whether time to anti-resorptive therapy affects the incidence of SRE. Patients previously treated with bisphosphonates, and patients not treated with anti-resorptive therapy were excluded. The study's primary endpoint was probability of developing SRE based on time to anti-resorptive therapy. The relationship between incidence of SREs and time to anti-resorptive therapy, sex, age, ISS stage at diagnosis, Area Deprivation Index (ADI), and prior SRE present at diagnosis was analyzed by multivariable Cox proportional hazards model. The cutoff point of anti-resorptive therapy delay was based on the recursive partitioning of univariable Cox model. Results: Three hundred and seventy-five patients with newly diagnosed multiple myeloma patients were identified. In total, 237 patients were included in the final analysis. Demographic information is detailed in the table provided. Of these, 208 patients (88%) used bisphosphonates and 29 (12%) used a RANK ligand inhibitor as their anti-resorptive agent. The median time to therapy was 55 days (IQR 135 days). One hundred twenty four (55%) patients had an SRE present at diagnosis. Forty-one (15.2%) patients developed a new SRE after initiation of anti-resorptive therapy. The model showed that patients who had a delay to anti-resorptive therapy of 31 days or greater had a higher risk of developing SRE after diagnosis (HR 2.49, 95% CI 0.95-6.55, p=0.064). In addition, when comparing ISS II to ISS I, patients with ISS II disease had a higher risk of developing SRE (HR 2.78, 95% CI 1.02-7.57, p=0.045). Conclusions: Patients with longer delays to anti-resorptive therapy had higher risk of developing SRE after diagnosis, however the difference was not statistically significant. One explanation for this may be that starting anti-resorptive therapy at any time point may be more important than time it takes to start therapy in the setting of effective anti-myeloma treatment. However, the rate of SRE in this study was lower than initially predicted based on previous studies, and therefore, our sample size may have been too small to detect a significant outcome related to time to initiation of anti-resorptive agents. Ongoing efforts to increase the sample size through multi-institutional initiatives are underway. Disclosures Binder: Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy. </jats:sec

Vaccination Response after Autologous Stem Cell Transplantation

Patients with autologous stem cell transplantation (ASCT) have a variable period of immune deficiency in the post-transplant period. Guidelines recommend revaccination of patients after ASCT as standard care. The response to vaccination may affect the outcome of the transplant patients. We aim to evaluate the vaccination response after ASCT. All myeloma and lymphoma patients with ASCT who had vaccination and measured vaccination response, were included in the study. We retrospectively evaluated 73 ASCT patients, 55 with multiple myeloma (MM) and 18 with lymphoma between 2013 and 2018. The current ASCT protocol for active immunization includes three doses of pneumococcal conjugate vaccine (PCV13) from 6-12 months after ASCT, followed by a 23-valent polysaccharide pneumococcal vaccine (PPSV23). Haemophilus Influenza B (HiB), hepatitis B, and TDAP/TD vaccines are administered within one year after initiation of vaccination. The responses to these vaccines were investigated by checking antibody titers at a minimum of two months after completion of vaccination. Both MM and lymphoma groups had similar pre-vaccination immunologic parameters, including IgG levels, absolute CD4+, and CD4+CD45RA+ cell counts (Table 1). Diphtheria and tetanus had 89% response rate to the vaccination in all patients (Table 2). Only half of the patients (47%) responded to hepatitis B vaccine. The response was higher but not statistically significant in the lymphoma group compared to the MM group (57 % versus 43.9 % P: NS). More than 80% of the patients had a response to H. Influenza vaccine. All patients had a 59% response to pneumococcal vaccination. We then analyzed the pneumococcal responses according to serotype. PCV13 includes vaccine against 13 serotypes of S. pneumonia (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F, 18C, and 23F). PPSV23 contains additional 11 serotypes (2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, 33F). 76 % of MM patients responded to PCV13 serotypes, while only 41 % responded to PPSV23 specific serotypes (p: &amp;lt;0.01). Lymphoma patients also showed a similar response pattern. In addition, repeated vaccination with PPSV23 did not improve the response of failure patients. We also evaluated the effects of maintenance treatment in the myeloma patients. We found that maintenance treatment did not interfere with the vaccine response in the patients with myeloma after ASCT. In conclusion, ASCT patients respond well to most vaccinations except for Hepatitis B and PPSV23. Further studies may need to explore pathophysiology of vaccine failure. Strategies to enhance immune reconstitution may augment the immune response and improve the outcome of the patients with ASCT. Disclosures Alpdogan: Seattle Genetics: Research Funding. Binder:Sanofi: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees. Kasner:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka Pharmaceutical: Research Funding. Martinez-Outschoorn:Otsuka Pharmaceutical: Research Funding. Palmisiano:AbbVie: Research Funding; Genentech: Research Funding. Porcu:Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Cell Medica: Research Funding; Daiichi: Consultancy, Honoraria; Galderma: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kiowa Kirin: Research Funding; Kura Oncology: Research Funding; Miragen: Research Funding; Verastem: Consultancy. Flomenberg:Tevogen: Consultancy, Honoraria. </jats:sec