Real-world use of ofatumumab to treat multiple sclerosis 9 months post-FDA approval during COVID-19 pandemic.

BACKGROUND: Relapsing multiple sclerosis (MS) is an inflammatory, demyelinating, neurodegenerative disease of the central nervous system that causes episodes of neurological dysfunction (relapse) alternating with variable intervals of stability. Disease-modifying therapies (DMTs) aim to reduce the rate of relapse and slow disease progression in people with MS, particularly in those with relapsing MS. Ofatumumab is a fully human anti-CD20 monoclonal antibody approved to treat patients with relapsing forms of MS. This study describes the demographics, clinical characteristics, and prior DMT use of patients with at least one ofatumumab prescription claim following approval by the United States (US) Food and Drug Administration (FDA). Understanding ofatumumab utilization patterns and patient characteristics can help define the journey of patients with MS and aid future clinical decision-making. METHODS: This retrospective study is based on data from IQVIA's Longitudinal Prescription Data (LRx) and Medical Claims (Dx) databases in the US, collected between August 01, 2019 and May 31, 2021. The index date was defined as the date of the first ofatumumab prescription. The pre-index period was defined as the 12 months prior to the index date. Adult patients (aged ≥18 years) with a diagnosis of MS and at least one prescription for ofatumumab between August 2020 and May 2021 in the LRx database were included. Only patients with at least one medical claim in the Dx database and a diagnosis of MS 24 months prior to the index date were included. Descriptive analyses were conducted 3, 6, and 9 months after FDA approval. RESULTS: Overall, 3,600 patients with a prescription for ofatumumab were identified in the LRx claims database, and 2,101 patients remained in the study after inclusion and exclusion criteria had been applied. At the 9-month post-approval time point, patients with ofatumumab claims were characterized as primarily female (74%) and middle-aged (median age: 48 years); two-thirds (64.7%) had a mild MS disability level. Patients were otherwise generally healthy with limited comorbid conditions. Most patients (81.7%) in the study did not experience relapse during the pre-index period. DMT-naïve patients who were prescribed ofatumumab at 3, 6, and 9 months post-approval accounted for 46.9%, 54.8%, and 58.4% of the study population, respectively. Over time, this increase in DMT-naïve ofatumumab initiators was statistically significant (p = 0.0003). Among patients who had been treated with DMTs during the previous year, most had taken them orally (50.6%), some had received them via intravenous infusion (32.2%), and some via subcutaneous/intramuscular injection (21.1%). Intravenous ocrelizumab was the most common DMT switch observed (n = 205, 23.4%) among these patients. CONCLUSION: This real-world study is the first to describe patients treated with ofatumumab since FDA approval during the COVID-19 pandemic. The majority of patients in this study were middle-aged women with mild MS symptoms. Ofatumumab was increasingly used as a first-line DMT. Additionally, a number of patients aged ≥55 years (beyond the trial population) used ofatumumab, which may suggest expanding clinician confidence in the safety and clinical utility of ofatumumab therapy. However, future long-term observational studies are needed to confirm these results.

Real-world cost of care and site of care in patients with multiple sclerosis initiating infused disease-modifying therapies.

AIM: Evaluate the real-world costs over two years and costs by site of care for ocrelizumab (OCR), natalizumab (NTZ), and alemtuzumab (ATZ) in patients with multiple sclerosis (MS). METHODS: This retrospective study used HealthCore Integrated Research Database and included continuously enrolled adults with MS initiating OCR, NTZ, and ATZ between April 2017 and July 2019 (i.e. patient identification period). Annual total cost of care (pharmacy and medical costs) was evaluated for the first- and second-year of follow-up, further stratified by site of care. Costs were measured using health plan allowed amount and adjusted to 2019 US dollars. Sensitivity analyses were conducted in patients who completed yearly dosing schedule according to Food and Drug Administration approved prescribing information. RESULTS: Overall, 1,058, 166, and 46 patients were included in OCR, NTZ, and ATZ cohorts, respectively. Mean (standard deviation [SD]) total cost of care during first- and second-year follow-up were $125,597 ($72,274) and $109,618 ($75,085) for OCR, $117,033 ($57,102) and $106,626 ($54,872) for NTZ, and $179,809 ($97,530) and $108,636 ($77,973) for ATZ. Infusible drug cost was the main driver in all three cohorts accounting for >78% of the total costs. Annual total cost of care increased substantially after patients started/switched to infusible DMTs. Across site of care, hospital outpatient infusion was common (OCR 58%, NTZ 37%, ATZ 49%) and expensive followed by physician office infusion (OCR 28%, NTZ 40%, ATZ 16%); home infusion was the least common (<10%) and least expensive. LIMITATIONS: The results were limited to commercially insured patients (specifically those with Anthem-affiliated health plans). CONCLUSIONS: Real-world costs increased after patients started/switched to infusible DMTs. Drug cost is the main driver for the total costs, which varied substantially by site of care. Controlling drug cost markups and using home setting for infusion can reduce costs in the treatment of MS patients.

Ocrelizumab (OCR), natalizumab (NTZ), and alemtuzumab (ATZ) are infusible drugs to treat patients with multiple sclerosis (MS). We did a study to understand the costs of these infusible MS drugs in real-world settings by analyzing a patients' pharmacy and medical claims database. A total of 1,058 patients were included. We found that the annual total costs increased substantially after patients started to use these infusible MS drugs. Specifically, the average first- and second-year total costs for patients were $125,597 and $109,618 for OCR, $117,033 and $106,626 for NTZ, and $179,809 and $108,636 for ATZ, respectively. We also found that the cost of the drug itself is the main driver for the overall healthcare spending, accounting for >78% of the total costs. Additionally, we found that the cost varies depending on where patients receive these infusible MS drugs, and generally speaking, infusions received from hospital outpatient settings would be more expensive than received from home settings. In summary, this study showed that the real-world costs of these infusible MS drugs are very high. Shifting patients away from more costly hospital outpatient departments or using MS drugs that do not require infusion resources (e.g. oral/self-injectable) may help reduce the overall healthcare spending on MS.

Systematic literature review of immunoglobulin trends for anti-CD20 monoclonal antibodies in multiple sclerosis.

OBJECTIVE: To exp lore changes in immunoglobulin (Ig) levels for people with relapsing-multiple sclerosis (RMS) treated with ocrelizumab or ofatumumab and the relationship between Ig levels and infections. METHODS: A systematic literature review (SLR) was conducted to identify clinical trials and real-world evidence (RWE) studies on Ig levels over time and studies on associations with infections for ocrelizumab and ofatumumab for people with RMS through 10 September 2021. Searches were conducted in Embase, MEDLINE, Cochrane Library, trial registries, and recent conference abstracts. RESULTS: Of 1,580 articles identified, 30 reporting on 11 trials and 5 RWE studies were included. Ocrelizumab trials (n = 4) had 24-336 weeks of follow-up and reported decreasing Ig G (IgG) levels, while RWE (n = 5) had 52-78 weeks of follow-up and reported IgG to be stable or decrease only slightly. IgG levels were stable in ofatumumab trials (n = 5; 104-168 weeks of follow-up), but no RWE or longer-term studies were identified. No apparent association between decreased Ig levels and infections was observed during ofatumumab treatment (ASCLEPIOS I/II), while for ocrelizumab, the only data on apparent associations between decreased IgG levels and serious infection rates were for a pooled population of people with RMS or primary progressive MS. CONCLUSION: Decreasing IgG levels have been correlated with increased infection risk over time. IgG levels appeared to decrease over time in ocrelizumab trials but remained relatively stable over time in ofatumumab trials. Additional research is needed to understand differences between ocrelizumab and ofatumumab and identify people at risk of decreasing IgG levels and infection.

Longitudinal adaptive immune responses following sequential SARS-CoV-2 vaccinations in MS patients on anti-CD20 therapies and sphingosine-1-phosphate receptor modulators.

BACKGROUND: Adequate response to the SARS-CoV-2 vaccine represents an important treatment goal in caring for patients with multiple sclerosis (MS) during the ongoing COVID-19 pandemic. Previous data so far have demonstrated lower spike-specific IgG responses following two SARS-CoV-2 vaccinations in MS patients treated with sphingosine-1-phosphate (S1P) receptor modulators and anti-CD20 monoclonal antibodies (mAb) compared to other disease modifying therapies (DMTs). It is unknown whether subsequent vaccinations can augment antibody responses in these patients. OBJECTIVES: The goal of this observational study was to determine the effects of a third SARS-CoV-2 vaccination on antibody and T cell responses in MS patients treated with anti-CD20 mAb or S1P receptor modulators. METHODS: Vaccine responses in patients treated with anti-CD20 antibodies (ocrelizumab and ofatumumab) or S1P receptor modulators (fingolimod and siponimod) were evaluated before and after third SARS-CoV-2 vaccination as part of an ongoing longitudinal study. Total spike protein and spike receptor binding domain (RBD)-specific IgG responses were measured by Luminex bead-based assay. Spike-specific CD4+ and CD8+ T cell responses were measured by activation-induced marker expression. RESULTS: MS patients and healthy controls were enrolled before and following SARS-CoV-2 vaccination. A total of 31 MS patients (n = 10 ofatumumab, n = 13 ocrelizumab, n = 8 S1P) and 10 healthy controls were evaluated through three SARS-CoV-2 vaccinations. Compared to healthy controls, total spike IgG was significantly lower in anti-CD20 mAb-treated patients and spike RBD IgG was significantly lower in anti-CD20 mAb and S1P-treated patients following a third vaccination. While seropositivity was 100% in healthy controls after a third vaccination, total spike IgG and spike RBD IgG seropositivity were lower in ofatumumab (60% and 60%, respectively), ocrelizumab (85% and 46%, respectively), and S1P-treated patients (100% and 75%, respectively). Longer treatment duration, including prior treatment history, appeared to negatively impact antibody responses. Spike-specific CD4+ and CD8+ T cell responses were well maintained across all groups following a third vaccination. Finally, immune responses were also compared in patients who were vaccinated prior to or following ofatumumab treatment. Antibody responses were significantly higher in those patients who received their primary SARS-CoV-2 vaccination prior to initiating ofatumumab treatment. CONCLUSIONS: This study adds to the evolving understanding of SARS-CoV-2 vaccine responses in people with MS treated with disease-modifying therapies (DMTs) known to suppress humoral immunity. Our findings provide important information for optimizing vaccine immunity in at-risk MS patient populations.

Real-world treatment patterns and outcomes of triple-class treated patients with multiple myeloma in the United States.

OBJECTIVES: Although multiple myeloma (MM) survival has improved following the introduction of proteosome inhibitors, immunomodulatory drugs, and anti-CD38 therapies, patients become refractory to these agents. Real-world outcomes of triple-class exposed patients are limited and were investigated in this study. METHODS: The Integra Connect Database was used to assess the treatment patterns of triple-class exposed patients with relapsed/refractory MM (RRMM) (January 2016-December 2019). RESULTS: During this period, patients (N = 501) reached triple exposure in a median of three lines of therapy (LOTs) over 995 days. A new LOT was started in a median of 18 (1-691) days after triple exposure; 71% of the patients started a new LOT within 30 days. Throughout the follow-up period, 8% of the patients had a therapy gap greater than 90 days. Following triple exposure, 103/501 patients (21%) received only triple-class agents in subsequent LOTs, while 24 (4.8%) patients received only non-triple-class agents. The median apparent survival from initiation of first therapy after triple exposure was 308 days. CONCLUSION: These results indicate that recycling of triple-class agents after previous exposure is widespread and prognosis in the RRMM population remains poor, highlighting the continuing unmet need for new agents with novel mechanisms to improve patient outcomes.

Real-world utilization and outcomes of systemic therapy among patients with advanced or recurrent endometrial cancer in the United States.

OBJECTIVE: Evaluate systemic therapy utilization patterns and outcomes by line of therapy among patients with advanced/recurrent endometrial cancer (EC) treated in the United States. METHODS: This retrospective observational study used the Optum Clinformatics Extended Data Mart Date of Death database (1 January 2004-31 December 2019) and included de-identified data from adult patients with advanced/recurrent EC who were treated with first-line (1L) platinum-based chemotherapy and initiated second-line (2L) anti-neoplastic therapy. The index date was the date of 1L therapy initiation. The number and sequence of treatments received and the proportion of patients who received each type of treatment for each line of therapy were evaluated. To account for new drug approvals, patients first treated in 2018 or 2019 were also assessed separately. RESULTS: Among the 1317 patients who met all eligibility criteria, 520 (39.5%) and 235 (17.8%) patients received 3 or 4+ lines of treatment, respectively, during a median total follow-up time of 25.2 months (range, 2.5-173.3 months) following the index date. Chemotherapy, including platinum- and non-platinum-based regimens, was the most common treatment across all lines of therapy: 2L, 80.0%; 3L, 66.2%; 4L+, 80.4%. Overall, 2.5%, 2.3%, and 8.9% of 2L, 3L, and 4L + patients, respectively, received anti-program death 1 (anti-PD-1) immunotherapies. In patients first treated in 2018 and 2019 (n = 163), 9.8% of patients received anti-PD-1 immunotherapy in the 2L. In the overall population, median time to next treatment (TTNT) was 19.3, 10.5, and 8.1 months for patients undergoing 2L, 3L, and 4L treatment, respectively. CONCLUSIONS: Among patients with advanced/recurrent EC treated with 1L platinum-based therapy in clinical practice, chemotherapy was the most common treatment choice across all lines of therapy. Immunotherapy use was low overall but increased in patients who started treatment in 2018 or 2019. Overall, median TTNT decreased as lines of therapy increased.

An Epidemiology Model for Estimating the Numbers of US Patients With Multiple Myeloma by Line of Therapy and Treatment Exposure.

OBJECTIVES: Estimates on the distribution of patients with multiple myeloma (MM) by line of therapy (LOT) are scarce and get outdated quickly as new treatments become available. The objective of this study was to estimate the number of patients with MM by LOT and the number of patients who have received at least 4 previous LOTs including proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies (mAbs). METHODS: A compartmental model was developed to calculate the number of patients by LOT. Two pathways were considered based on stem cell transplant eligibility, and at each pathway, treatments were stratified in 2 types: anti-CD38 mAbs or other. The model population was stratified into 4 subgroups based on age and cytogenetic risk. Model inputs were informed from real-world evidence. RESULTS: The model estimated that, in 2020, 126 869 patients were living with MM in the United States. Of these, 105 701 received treatment in any LOT, with 56 959, 27 252, 11 258, and 5217 in lines 1 to 4, respectively, and 5015 in line 5 or beyond. The model estimated that 3497 patients received at least 4 previous LOTs including proteasome inhibitors, immunomodulatory agents, and anti-CD38 mAbs. The model overall prevalence predictions aligned well with publicly available estimates. CONCLUSIONS: This study proposes a novel framework to estimate MM prevalence. It can assist clinicians to understand future trends in MM epidemiology, healthcare systems to plan for future resource use allocation, and payers to quantify the budget impact of new treatments.

Physician treatment preferences for relapsed/refractory multiple myeloma: a discrete choice experiment.

Aim: This study aimed to assess physician preferences for later lines (third to fifth) of therapy in patients with relapsed/refractory multiple myeloma (RRMM) in the USA. Materials & methods: Factors relevant to physicians' treatment preferences for RRMM were identified from a literature search and refined in a qualitative phase. Preferences were quantitatively assessed using a discrete choice experiment. Physicians (n = 227) made choices regarding treatment scenarios for RRMM. Results: Efficacy had the highest mean relative importance, with overall survival valued as most important when making treatment decisions for patients with RRMM. Reduced incidences of keratopathy and thrombocytopenia had similar relative importance in later-line treatment. Conclusion: Greater understanding of physicians' criteria for clinical decision-making may help inform wider adoption of new treatments.

When deciding which treatment patients with relapsed or refractory multiple myeloma should receive, physicians have to weigh the benefits of each treatment against the risk of side effects. This study required physicians to complete a survey on aspects involved in their treatment decisions and identified those of highest importance. Physicians chose patient survival as the most important factor and minimization of side effects as less important considerations. Reducing patients' risk of developing corneal conditions or low platelet (a type of blood cell) count were of equal importance to doctors. Understanding physicians' treatment preferences and the reasons behind them will help identify gaps in education about new therapies as they become available.

Incidence of corneal adverse events in patients with multiple myeloma and their clinical and economic impact: A real-world retrospective cohort study.

AIMS: Ocular toxicities are common adverse events (AEs) associated with anticancer agents. There is a paucity of data documenting their impact on patient care. This study assessed the clinical and economic burden of corneal AEs and related symptoms (collectively termed corneal AEs) in patients receiving multiple myeloma (MM) treatment. MATERIALS AND METHODS: Adults with a newly diagnosed MM (MM cohort) were identified from PharMetrics Plus, a US insurance claims database. Incidence, outpatient (OP) care, emergency department (ED) visits, hospitalizations, and costs were assessed for corneal AEs of interest: keratopathy/keratitis, blurred vision/decreased acuity, dry eye, eye pain, and photophobia. Incidence of new corneal AEs, healthcare resource utilization (HCRU), corneal AE-related HCRU, and costs were assessed and benchmarked against a hematology cohort of patients. RESULTS: The MM cohort included 2,120 patients with a median follow-up of 734.5 days. Overall, 11.7% of patients in the MM cohort and 7.4% in the hematology cohort had ≥1 corneal AE of interest. In the MM cohort, dry eye (6.1%), blurred vision/decreased acuity (3.4%), and keratopathy/keratitis (2.5%) were the most frequent. The overall median corneal AE-related per-patient-per-month (PPPM) cost was $27, predominantly contributed by OP care (median $19 PPPM). During follow-up, 4.8% of patients visited the ED, 3.6% were hospitalized, and 42.5% of patients visited an ophthalmologist/optometrist (∼1.69 visits/year). Costs of these visits were negligible (median PPPM $19) compared to total all-cause costs (median PPPM $17,286). LIMITATIONS: The results can only be generalized to commercially insured and Medicare Advantage patients. Claims-based diagnosis of corneal AEs may underestimate true incidences. CONCLUSIONS: Corneal AEs were observed in ∼12% of patients in the MM cohort, the most common were keratopathy/keratitis, dry eye, and blurred vision. Most of them required only OP care. The clinical and economic burden for treating corneal AEs was low when compared with total all-cause or MM-related PPPM costs.

Budget impact analysis of niraparib for first-line maintenance therapy in advanced ovarian cancer from a US payer perspective.

BACKGROUND: Ovarian cancer (OC) is the fifth leading cause of cancer death in women and has the highest mortality rate of gynecological cancers. Niraparib was recently approved by the FDA for the maintenance treatment of adult patients with advanced epithelial OC in complete or partial response to first-line platinum-based chemotherapy (PBC) regardless of biomarker status. OBJECTIVE: To estimate the direct economic impact on US payers of adding niraparib as a first-line maintenance therapy for patients with advanced OC. METHODS: The model considered 2 scenarios: a current scenario in which niraparib does not have regulatory approval for first-line maintenance therapy and a future scenario in which niraparib has regulatory approval for first-line maintenance therapy. The budget impact was calculated as the difference in cost between the 2 scenarios. The budget impact model (BIM) considered 2 different US health care payer perspectives: a commercial health plan and a Medicare plan. Both payer perspectives were assumed to have a hypothetical 1 million affiliates that were covered. Epidemiological data was used to estimate the eligible incident population of patients with OC. Active surveillance, bevacizumab (as a monotherapy), and olaparib (as a monotherapy restricted to patients with the breast cancer gene [BRCA] mutation) were included in the model as alternative maintenance treatment options (maintenance treatment options required 1% market share for inclusion). Cost categories considered in the BIM included diagnostic testing, treatment acquisition and administration, treatment-emergent adverse events, and subsequent therapy. Results were presented as an incremental budget impact to payers over 3 years. RESULTS: For a commercial health plan of 1 million affiliates, the estimated impact of adding niraparib as a first-line maintenance treatment option for advanced epithelial OC was calculated as $87,906, $93,106, and $87,037 for years 1, 2, and 3, respectively. The average budget impact per member per month was $0.007. For a Medicare health plan of 1 million affiliates, the estimated impact was calculated as $206,785, $219,017, and $204,739 for years 1, 2, and 3, respectively. The average budget impact per member per month was $0.018. One-way sensitivity analyses suggested that budget impact was most sensitive to the treatment duration and market share of niraparib, the non-treatment-specific data on overall survival rates, and the treatment duration of bevacizumab. Treatment of drug-specific adverse events had little impact on the budget model. CONCLUSIONS: The model estimated a minimal budget impact to both a commercial or Medicare health plan following the introduction of niraparib as a first-line maintenance therapy for patients with advanced epithelial OC who are in complete or partial response to first-line PBC regardless of biomarker status. DISCLOSURES: This study was financially supported by GlaxoSmithKline. Liu, Hawkes, Maiese, and Hurteau are employees of GlaxoSmithKline. Travers was employed by GlaxoSmithKline at the time of this study. Spalding and Walder are employees of FIECON Ltd., which was contracted by GlaxoSmithKline to develop the budget impact model used in this study.

Budget Impact of Belantamab Mafodotin (Belamaf) Adoption in the Treatment of Patients with Relapsed or Refractory Multiple Myeloma in the United States.

PURPOSE: Estimate the budget impact of belantamab mafodotin (belamaf) for patients with relapsed/refractory multiple myeloma (RRMM) who have received ≥4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. METHODS: A budget impact analysis (BIA) was developed to estimate the cost difference between current (no belamaf) and projected (with belamaf) market scenarios over 3 years. Comparators were identified from a systematic literature review and included selinexor + dexamethasone or best supportive care. The number of treatment-eligible patients were estimated using an epidemiology model. Base-case analyses were conducted from a US commercial payer perspective (cost year: 2019). Model inputs included market share estimates, treatment duration, and costs of drug acquisition/administration, concomitant medications, adverse event (AE) management, treatment monitoring, and subsequent treatments based on published literature/cost databases. Budget impact, calculated as the difference in costs between current and projected scenarios over 3 years, was reported as cost per member per month (PMPM) and per member per year (PMPY). One-way sensitivity analysis assessed which key parameters most affected model outcomes. Alternative scenarios were tested (1- or 5-year time horizon; Medicare perspective; negligible cost of mental status change AE). RESULTS: In a hypothetical commercial payer health plan with 1 million members, 33 patients were identified as treatment-eligible over 3 years. Introducing belamaf for patients with RRMM resulted in an estimated budget-neutral PMPM cost of -$0.0003 and PMPY of -$0.004, based on n=9/33 patients receiving treatment. Sensitivity analyses showed that budget impact in the base case was most sensitive to changes in treatment duration and drug acquisition costs. Base-case results were consistent across all scenarios assessed. CONCLUSION: BIA indicates that adoption of belamaf in this patient population would be budget neutral for a US health plan.

Real-World Utilization and Safety of Daratumumab IV Rapid Infusions Administered in a Community Setting: A Retrospective Observational Study.

BACKGROUND: Some institutions have implemented a daratumumab intravenous rapid-infusion protocol in which patients with multiple myeloma (MM) receive their third and subsequent infusions within ~ 90 min instead of ≥ 3 h. OBJECTIVE: This study sought to understand the utilization, effectiveness, and infusion reactions (IRs) observed in patients with MM who received daratumumab rapid infusions. METHODS: Electronic medical records from Florida Cancer Specialists & Research Institute were used. Adult patients with MM who received one or more rapid daratumumab infusion (full dose in ≤ 110 min) at their third or later infusion of the first daratumumab-containing regimen (index date: 16 November 2015 to 15 March 2019) were included. IRs included events that (1) occurred ≤ 24 h post-daratumumab infusion or (2) were stated as an IR in the patient charts. Non-IR adverse events (AEs) were events attributed to daratumumab in patient charts that did not meet the IR definition. RESULTS: In total, 147 patients received one or more rapid infusion in their first daratumumab-containing regimen. Median time from initial MM diagnosis to index date was 2.5 years. Non-IR AEs occurred in 10.2% of patients during treatment, and 36.7% experienced one or more IR after receiving a daratumumab infusion. No IRs occurred after a rapid infusion. The overall response rate was 91.1% (after rapid infusions only: 71.3%). CONCLUSIONS: This study provides real-world evidence on the practice patterns of daratumumab rapid infusions in a large community-based oncology clinic system. These results suggest that treatment regimens including daratumumab rapid infusions at the third infusion or later were well-tolerated, and their effectiveness was comparable to that observed in clinical trials.

Frontline treatment patterns and attrition rates by subsequent lines of therapy in patients with newly diagnosed multiple myeloma.

BACKGROUND: For patients with multiple myeloma (MM), each additional line of therapy (LOT) is associated with lower response rates, shorter treatment duration and treatment-free intervals, and increased rates of toxicities and comorbidities. Here, we examine frontline treatment patterns, and attrition rates by LOT among newly diagnosed MM (NDMM) patients in the United States who were eligible or ineligible for autologous stem cell transplant (ASCT). METHODS: Data were identified from three US patient-level databases collectively covering the period January 2000 to September 2018. Patients had an index diagnosis of MM on or after January 1, 2007, medical and prescription insurance coverage at diagnosis, a 1-year look-back period prior to the index diagnosis, no prior malignancies in the 1-year period before index diagnosis, and had received ≥1 LOT. RESULTS: Among patients who did not receive ASCT (non-transplant; n = 22,062), 12,557 (57%) received only 1 LOT and 9505 (43%) received > 1 LOT. Patients receiving only 1 LOT were significantly older, had higher mean Charlson Comorbidity Index (CCI) scores, and higher incidences of comorbidities. Among the 2763 patients receiving ASCT, 2184 received > 1 LOT, and 579 (21%) received only 1 LOT (ie, ASCT was the last treatment). 1682 (61%) patients received induction therapy as frontline treatment, of whom 187 (11%) also received consolidation therapy. The latter group was younger than those who received only induction therapy, had lower mean CCI scores, and comparable or lower incidences of selected comorbidities. The most common frontline therapy for non-transplant and transplant-eligible patients was bortezomib/dexamethasone and bortezomib/lenalidomide/dexamethasone, respectively. Attrition rates across all LOTs were high for non-transplant patients (range, 43-57%) and transplant patients (range, 21-37%). Treatment duration decreased by LOT for non-transplant patients and was consistent across LOTs for transplant patients. CONCLUSIONS: In this analysis, a substantial proportion of patients with NDMM who received frontline therapy did not appear to receive a subsequent LOT. These high attrition rates underscore the need to use the most optimal treatment regimens upfront rather than reserving them for later LOTs in which the clinical benefit may decrease.

Daratumumab-lenalidomide-dexamethasone vs standard-of-care regimens: Efficacy in transplant-ineligible untreated myeloma.

Daratumumab in combination with lenalidomide-dexamethasone (D-Rd) recently received FDA approval for the treatment of transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). The present PEGASUS study compared progression-free survival (PFS) in patients treated with D-Rd in the MAIA trial and patients treated with common standard-of-care regimens from the Flatiron Health electronic health record-derived deidentified database, which has data from patients treated primarily at community-based oncology practices in the United States. Individual-level patient data from both data sources were used to perform an anchored indirect treatment comparison (ITC) of D-Rd to bortezomib-lenalidomide-dexamethasone (VRd) and bortezomib-dexamethasone (Vd); lenalidomide-dexamethasone (Rd) was the common anchor for the ITC. Hazard ratios (HRs) reflecting direct comparisons of PFS within MAIA (D-Rd vs Rd) and Flatiron Health (VRd vs Rd; Vd vs Rd) were used to make ITCs for D-Rd vs VRd and Vd, respectively. After application of MAIA inclusion/exclusion criteria and propensity-score weighting, the Flatiron Health patients resembled the MAIA trial population on measured baseline characteristics. Based on the direct comparison within MAIA, treatment with D-Rd was associated with a significantly lower risk of progression or death compared to Rd (HR 0.54; 95% CI 0.42, 0.71). Based on the ITCs, D-Rd was associated with a significantly lower risk of progression or death compared to VRd (HR 0.68; 95% CI 0.48, 0.98) and Vd (HR 0.48; 95% CI 0.33, 0.69). In the absence of head-to-head trials comparing D-Rd to VRd or Vd, the present ITC may help inform treatment selection in transplant-ineligible patients with NDMM.

Letter--The Authors Respond.

DISCLOSURES: No additional funding was received for the writing of this letter. The published study referred to in this letter was funded by Janssen Scientific Affairs, which employs Maiese and funded Cornerstone Research Group, a health economic consulting group, to conduct the study. Grima is a founding partner of Cornerstone Research Group, which employs Hollmann, Goyert, and Moldaver.

Daratumumab Split First Versus Single Dosing Schedule Among Patients With Multiple Myeloma Treated in a US Community Oncology Setting: A Retrospective Observational Study.

PURPOSE: Daratumumab was initially approved by the US Food and Drug Administration to be given intravenously over the course of several hours during each administration. Because the duration of the first dose can exceed 7 h, the US Oncology Network developed a split first dose schedule to administer the first administration (dose) over 2 consecutive days. METHODS: This trial was a retrospective cohort study of adult multiple myeloma (MM) patients who initiated daratumumab within the US Oncology Network between November 1, 2015, and June 30, 2017. Descriptive analyses were conducted to compare split dose versus single-dose groups, and a multivariable linear regression model was developed to identify factors associated with total administration time. FINDINGS: In total, 622 patients were included in the analysis (364 split first dose patients and 258 single-dose patients). Infusion reactions to the first administration were documented for 47.8% of split first dose patients and 48.3% of single-dose patients. Among the total study population, the most common reactions were lower respiratory tract-related reactions (26.1%), upper respiratory tract-related reactions (17.2%), and gastrointestinal adverse events (12.5%), with no statistically significant differences between groups. The median infusion duration was 4.5 h for day 1 of the split first dose and 6.5 h for the single dose (P < 0.0001); the total median infusion time was 8.7 h for the split first dose. In multivariable regression, the only factor associated with infusion time was dosing schedule. IMPLICATIONS: These results provide real-world evidence regarding the safety and infusion time of the first infusion of daratumumab. Although the total administration time was longer among patients receiving a split first dose, the shorter day 1 infusion for this dosing schedule without increased infusion reactions may be an option for community oncology clinics.

A U.S. Cost Analysis of Triplet Regimens for Patients with Previously Treated Multiple Myeloma.

BACKGROUND: In recent years, the FDA has approved several 3-agent (i.e., triplet) combinations for previously treated multiple myeloma (MM), and the National Comprehensive Cancer Network (NCCN) now recommends triplet regimens over doublets. Little is known about the real-world cost of triplet combinations because of the limited time that they have been on the market since FDA approval. Furthermore, traditional cost analyses developed to support market entrance rely on utilization assumptions that are difficult to validate when numerous comparators simultaneously enter the market. OBJECTIVE: To perform a 1-year cost analysis of novel triplets used for the treatment of patients with previously treated MM controlling for differences in utilization. METHODS: FDA-approved, NCCN-recommended (preferred and category 1 for previously treated MM) treatments included in the analysis were daratumumab plus lenalidomide plus dexamethasone (DARA/LEN/DEX), daratumumab plus bortezomib plus dexamethasone (DARA/BOR/DEX), elotuzumab plus lenalidomide plus dexamethasone (ELO/LEN/DEX), carfilzomib plus lenalidomide plus dexamethasone (CAR/LEN/DEX), and ixazomib plus lenalidomide plus dexamethasone (IXA/LEN/DEX). To control for market uptake, the model was designed to estimate the cost of treating an average patient over a 1-year time horizon. Drug administration and dosing, required comedications, postprogression therapy, monitoring requirements, and adverse event (AE) rates were based on FDA prescribing information or clinical trials. AEs ≥ grade 3 that occurred in ≥ 5% of patients were included. RED BOOK wholesale acquisition costs were used for drug acquisition costs. Costs of drug administration, AE management, and patient monitoring were based on the 2018 Center for Medicare & Medicaid Services payment rates or from published literature (inflated to 2018 U.S. dollars). The treatment duration for each regimen was estimated from modeled progression-free survival data; the 12-month progression-free survival rate was assumed to be equivalent to the probability that an average patient remained on therapy for at least 1 year after treatment initiation, which was used to estimate time-depended treatment-related costs. The probability of progression within 1 year of treatment initiation was used to inform the average postprogression therapy costs for each regimen. RESULTS: The estimated cost per patient for each triplet regimen was $13,890 (DARA/BOR/DEX), $22,231 (IXA/LEN/DEX), $24,322 (ELO/LEN/DEX), $26,410 (DARA/LEN/DEX), and $27,432 (CAR/LEN/DEX). Drug acquisition costs and treatment duration were the largest drivers of cost. Scenario analyses with plausible alternative input parameters found the maximum per month cost of therapy to be $30,657 (CAR/LEN/DEX) and the minimum per month cost of therapy to be $13,784 (DARA/BOR/DEX). CONCLUSIONS: This analysis controlled for differential utilization rates for 5 FDA-approved, NCCN-recommended triplet therapies for the treatment of previously treated MM. Of the examined regimens, treatment with DARA/BOR/DEX was estimated to have the lowest average monthly cost per patient, while CAR/LEN/DEX was the most expensive. As is common with modeling, some assumptions were necessary, and results may not be generalizable. DISCLOSURES: This study was funded by Janssen Scientific Affairs, which employs Maiese and funded Cornerstone Research Group, a health economic consulting group, to complete the cost analysis, interpret data, and develop the manuscript. Janssen was involved in the design of the analysis, interpretation of results, and manuscript development and approval. Grima is a founding partner of Cornerstone Research Group, which employs Hollmann, Goyert, and Moldaver. Hollmann, Goyert, and Moldaver were responsible for creation of the economic model. This work was peer-reviewed and presented as an abstract at the Lymphoma and Myeloma 2017 International Congress; October 26-28, 2017; New York, NY.

Incidence, risk factors, and consequences of residual neuromuscular block in the United States: The prospective, observational, multicenter RECITE-US study.

STUDY OBJECTIVE: To determine the incidence burden and associated risk factors of residual neuromuscular block (rNMB) during routine U.S. hospital care. DESIGN: Blinded multicenter cohort study. SETTING: Operating and recovery rooms of ten community and academic U.S. hospitals. PATIENTS: Two-hundred fifty-five adults, ASA PS 1-3, underwent elective abdominal surgery with general anesthesia and ≥1 dose of non-depolarizing neuromuscular blocking agent (NMBA) for endotracheal intubation and/or maintenance of NMB between August 2012 and April 2013. INTERVENTIONS: TOF measurements using acceleromyography were performed on patients already receiving routine anesthetic care for elective open or laparoscopic abdominal surgery. Measurements allowed assessment of the presence of residual neuromuscular block (rNMB), defined as a train-of-four (TOF) ratio <0.9 at tracheal extubation. We recorded patient and procedural characteristics and assessed TOF ratios (T4/T1) at various times throughout the procedure and at tracheal extubation. Differences in patient and clinical characteristics were compared using Fisher's exact test for categorical variables and t-test for continuous variables. Multivariate logistic regression assessed risk factors associated with rNMB at extubation. MAIN RESULTS: Most of the study population, 64.7% (n = 165) had rNMB (TOF ratio < 0.9), among them, 31.0% with TOF ratio <0.6. Among those receiving neostigmine and/or qualitative peripheral nerve stimulation per clinical decision, 65.0% had rNMB. After controlling for confounders, we observed male gender (odds ratio: 2.60, P = 0.008), higher BMI (odds ratio: 1.04/unit, P = 0.043), and surgery at a community hospital (odds ratio: 3.15, P = 0.006) to be independently associated with increased odds of rNMB. CONCLUSIONS: Assessing TOF ratios blinded to the care team, we found that the majority of patients (64.7%) in this study had rNMB at tracheal extubation, despite neostigmine administration and qualitative peripheral nerve stimulation used for routine clinical care. Qualitative neuromuscular monitoring and clinical judgement often fails to detect rNMB after neostigmine reversal with potential severe consequences to the patient. Our data suggests that clinical care could be improved by considering quantitative neuromuscular monitoring for routine care.

Temporal Trends in Survival and Healthcare Costs in Patients with Multiple Myeloma in the United States.

BACKGROUND: In recent years, the development of new therapies for multiple myeloma has improved the survival of patients, but newer treatments may also affect healthcare costs. To date, no real-world study has examined the concurrent changes in survival and total healthcare costs over time in patients with multiple myeloma. OBJECTIVE: To examine the temporal changes in survival and healthcare costs among patients with multiple myeloma in the United States. METHOD: This retrospective claims-based cohort study is based on death files in the Truven Health MarketScan Research Commercial and Medicare Supplemental databases. The study included adults who had at least 1 inpatient or 2 outpatient claims with a diagnosis of multiple myeloma between January 1, 2006, and December 31, 2014; continuous insurance enrollment for at least 12 months before and at least 30 days after the first diagnosis (ie, index date); and no previous malignancy. Patients were followed from the index date through the earliest among (1) the date of death recorded in the death files, (2) the end of enrollment in the MarketScan database, or (3) end of the study (September 30, 2015). The mortality rates and the total all-cause and multiple myeloma-specific healthcare costs per patient per month were compared between patients diagnosed in 2006-2010 and those diagnosed in 2011-2014. RESULTS: A total of 5199 patients were included in the study (2597 diagnosed between 2006 and 2010 and 2602 diagnosed between 2011 and 2014). We found a 35% decrease in the risk for death (hazard ratio, 0.65; 95% confidence interval, 0.57-0.74) among patients diagnosed in 2011-2014 compared with those diagnosed in 2006-2010. In addition, 18% and 26% increases were found in all-cause and multiple myeloma-specific healthcare costs, respectively, over the same time period (adjusted mean all-cause costs, $13,960 vs $16,449, respectively; adjusted mean multiple myeloma-specific costs, $7476 vs $9422, respectively). CONCLUSION: The percent decrease in mortality in patients with multiple myeloma has been greater than the percent increase in healthcare costs in recent years, which may be attributable to improved treatments for multiple myeloma and changes in disease management. With the mortality rate having decreased more than the increase in healthcare costs over the same time period, the results of this study suggest that although healthcare spending has increased over time, there is a survival benefit.