A Systematic Review of Modeling Approaches to Evaluate Treatments for Relapsed Refractory Multiple Myeloma: Critical Review and Considerations for Future Health Economic Models.

BACKGROUND AND OBJECTIVE: Multiple myeloma is a rare incurable hematological cancer in which most patients relapse or become refractory to treatment. This systematic literature review aimed to critically review the existing economic models used in economic evaluations of systemic treatments for relapsed/refractory multiple myeloma and to summarize how the models addressed differences in the line of therapy and exposure to prior treatment. METHODS: Following a pre-approved protocol, literature searches were conducted on 17 February, 2023, in relevant databases for models published since 2014. Additionally, key health technology assessment agency websites were manually searched for models published as part of submission dossiers since 2018. Reported information related to model conceptualization, structure, uncertainty, validation, and transparency were extracted into a pre-defined extraction sheet. RESULTS: In total, 49 models assessing a wide range of interventions across multiple lines of therapy were included. Only five models specific to heavily pre-treated patients and/or those who were refractory to multiple treatment classes were identified. Most models followed a conventional simple methodology, such as partitioned survival (n = 28) or Markov models (n = 9). All included models evaluated specific interventions rather than the whole treatment sequence. Where subsequent therapies were included in the model, these were generally only considered from a cost and resource use perspective. The models generally used overall and progression-free survival as model inputs, although data were often immature. Sensitivity analyses were frequently reported (n = 41) whereas validation was only considered in less than half (n = 19) of the models. CONCLUSIONS: Published economic models in relapsed/refractory multiple myeloma rarely followed an individual patient approach, mainly owing to the higher need for complex data assumptions compared with simpler modeling approaches. As many patients experience disease progression on multiple treatment lines, there is a growing need for modeling complex treatment strategies, leading to more sophisticated approaches in the future. Maintaining transparency, high reporting standards, and thorough analyses of uncertainty are crucial to support these advancements.

Ixazomib plus daratumumab and dexamethasone: Final analysis of a phase 2 study among patients with relapsed/refractory multiple myeloma.

Novel therapies have improved outcomes for multiple myeloma (MM) patients, but most ultimately relapse, making treatment decisions for relapsed/refractory MM (RRMM) patients increasingly challenging. We report the final analysis of a single-arm, phase 2 study evaluating the oral proteasome inhibitor (PI) ixazomib combined with daratumumab and dexamethasone (IDd; NCT03439293). Sixty-one RRMM patients (ixazomib/daratumumab-naïve; 1-3 prior therapies) were enrolled to receive IDd (28-day cycles) until disease progression/unacceptable toxicity. Median age was 69 years; 14.8% of patients had International Staging System stage III disease; 14.8% had received three prior therapies. Patients received a median of 16 cycles of IDd. In 59 response-evaluable patients, the overall response rate was 64.4%; the confirmed ≥very good partial response (VGPR) rate (primary endpoint) was 30.5%. Rates of ≥VGPR in patient subgroups were: high-risk cytogenetics (n = 15, 26.7%), expanded high-risk cytogenetics (n = 24, 29.2%), aged ≥75 years (n = 12, 16.7%), lenalidomide-refractory (n = 21, 28.6%), and prior PI/IMiD therapy (n = 58, 31.0%). With a median follow-up of 31.6 months, median progression-free survival was 16.8 months (95% confidence interval: 10.1-23.7). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 54.1% of patients; 44.3% had serious TEAEs; TEAEs led to dose modifications/reductions/discontinuations in 62.3%/36.1%/16.4%. There were five on-study deaths. Any-grade and grade ≥3 peripheral neuropathy occurred in 18.0% and 1.6% of patients. Quality of life was generally maintained throughout treatment. IDd showed a positive risk-benefit profile in RRMM patients and was active in clinically relevant subgroups with no new safety signals.

Impact of prior lenalidomide or proteasome inhibitor exposure on the effectiveness of ixazomib-lenalidomide-dexamethasone for relapsed/refractory multiple myeloma: A pooled analysis from the INSURE study.

OBJECTIVES: To characterize the impact of prior exposure and refractoriness to lenalidomide or proteasome inhibitors (PIs) on the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma (RRMM). METHODS: INSURE is a pooled analysis of adult RRMM patients who had received IRd in ≥2 line of therapy from three studies: INSIGHT MM, UVEA-IXA, and REMIX. RESULTS: Overall, 391/100/68 were lenalidomide-naïve/-exposed/-refractory and 37/411/110 were PI-naïve/-exposed/-refractory. Median duration of therapy (DOT) was 15.3/15.6/4.7 months and median progression-free survival (PFS) was 21.6/25.8/5.6 months in lenalidomide-naïve/exposed/refractory patients. Median DOT and PFS in PI-naïve/exposed/refractory patients were 20.4/15.2/6.9 months and not reached/19.8/11.4 months, respectively. The proportion of lenalidomide-naïve/exposed/refractory patients in INSIGHT and UVEA-IXA who discontinued a study drug due to adverse events (AEs) was ixazomib, 31.6/28.2/28.0% and 18.6/6.7/10.5%; lenalidomide, 21.9/28.2/16.0% and 16.1/6.7/10.5%; dexamethasone, 18.4/20.5/16.0% and 10.6/0/10.5%, respectively. The proportion of PI-naïve/exposed/refractory patients in INSIGHT and UVEA-IXA who discontinued a study drug due to AEs was: ixazomib, 44.4/28.8/27.8% and 22.2/16.7/15.7%; lenalidomide, 33.3/22.0/19.4% and 16.7/15.9/11.8%; dexamethasone, 33.3/17.4/16.7% and 16.7/9.5/7.8%, respectively. REMIX AE discontinuation rates were unavailable. CONCLUSION: IRd appeared to be effective in RRMM patients in routine clinical practice regardless of prior lenalidomide or PI exposure, with better outcomes seen in lenalidomide- and/or PI-nonrefractory versus refractory patients.

Comparative effectiveness of lenalidomide/dexamethasone-based triplet regimens for treatment of relapsed and/or refractory multiple myeloma in the United States: An analysis of real-world electronic health records data.

BACKGROUND: This retrospective longitudinal study compared the effectiveness of dexamethasone+lenalidomide (Rd)-based triplet regimens containing proteasome inhibitors (PIs) ixazomib (IRd), carfilzomib (KRd), and bortezomib (VRd) or monoclonal antibodies (MABs) elotuzumab (ERd) and daratumumab (DRd) in patients with relapsed/refractory multiple myeloma (RRMM)-including those with high cytogenetic risk-primarily treated at community oncology clinics in the United States. METHODS: Electronic health records of adult RRMM patients in a deidentified real-world database (01/01/2014-09/30/2020) who initiated IRd, KRd, VRd, ERd, or DRd in the second or later line of therapy (LOT) were analyzed. The index date was the date of initiation of each LOT and baseline was the 6-month pre-index period. Duration of therapy (DOT), time to next therapy (TTNT), progression-free survival (PFS), and overall survival (OS) were compared across regimens with multivariable Cox proportional hazards models. RESULTS: Of the 1,185 patients contributing 1,332 LOTs, 985 had standard cytogenetic risk (median age, 71 years) and 180 had high risk (median age, 69 years). Compared with other regimens, DRd was associated with longer DOT overall (adjusted hazard ratio [95 % confidence interval]: 1.84 [1.42, 2.38] vs. KRd, 1.65 [1.20, 2.28] vs. ERd, 1.58 [1.23, 2.04] vs. IRd, and 1.54 [1.18, 2.00] vs. VRd), and longer TTNT and PFS. KRd was associated with shorter OS compared with DRd (1.45 [1.01, 2.08]) and VRd (1.32 [1.01, 1.73]). High-risk patients had similar outcomes with all triplet regimens. CONCLUSION: Although DRd improved clinical outcomes overall, Rd-based triplet regimens containing a PI or MAB are similarly effective in high-risk RRMM.

INSURE: a pooled analysis of ixazomib-lenalidomide-dexamethasone for relapsed/refractory myeloma in routine practice.

Aim: We pooled data from three observational studies (INSIGHT MM, UVEA-IXA and REMIX) to investigate the real-world effectiveness of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory myeloma. Materials & methods: INSIGHT MM was a prospective study conducted in countries across Europe, Asia and North/Latin America while UVEA-IXA and REMIX were multicenter, retrospective/prospective studies conducted in Europe. Patients who had received IRd as ≥2nd line of therapy were analyzed. Primary outcomes were time-to-next treatment (TTNT) and progression-free survival (PFS). Results: Overall, 564 patients were included (median follow-up: 18.5 months). Median TTNT and PFS were 18.4 and 19.9 months; both outcomes were numerically longer for earlier versus later lines. Median treatment duration was 14.0 months. Overall response rate was 64.6%. No new safety concerns were noted. Conclusion: The effectiveness of IRd in routine practice appears similar to the efficacy observed in TOURMALINE-MM1. IRd benefit in earlier versus later lines was consistent with previous reports.

Development and validation of algorithms for identifying lines of therapy in multiple myeloma using real-world data.

Aim: To validate algorithms based on electronic health data to identify composition of lines of therapy (LOT) in multiple myeloma (MM). Materials & methods: This study used available electronic health data for selected adults within Henry Ford Health (Michigan, USA) newly diagnosed with MM in 2006-2017. Algorithm performance in this population was verified via chart review. As with prior oncology studies, good performance was defined as positive predictive value (PPV) ≥75%. Results: Accuracy for identifying LOT1 (N = 133) was 85.0%. For the most frequent regimens, accuracy was 92.5-97.7%, PPV 80.6-93.8%, sensitivity 88.2-89.3% and specificity 94.3-99.1%. Algorithm performance decreased in subsequent LOTs, with decreasing sample sizes. Only 19.5% of patients received maintenance therapy during LOT1. Accuracy for identifying maintenance therapy was 85.7%; PPV for the most common maintenance therapy was 73.3%. Conclusion: Algorithms performed well in identifying LOT1 - especially more commonly used regimens - and slightly less well in identifying maintenance therapy therein.

Electronic health data helps us understand treatment in the 'real world'. The data has great value in cancer if we can identify the drugs patients get. Yet this is hard in multiple myeloma (MM), where treatment is complex. Algorithms (set of decision rules) to identify drugs can help here. We tested an existing algorithm for identifying 'lines of therapy' (LOT) given to patients with MM. Each LOT included one or more drugs for MM. We also developed and tested a new algorithm for 'maintenance therapy'. This is a treatment given to help maintain the response to the main MM treatment. We tested how well the algorithms identified MM treatments in electronic health data. This data came from Henry Ford Health, a healthcare system in Michigan, USA. Treatments were confirmed by cancer specialists who reviewed medical charts. The LOT algorithm was good at finding the first LOT patients. The maintenance algorithm did a fair job of identifying the most used therapy. Our algorithms could help researchers study the real-world treatment of MM.

In-class transition from bortezomib-based therapy to IRd is an effective approach in newly diagnosed multiple myeloma.

Aim: To compare the effectiveness of in-class transition to all-oral ixazomib-lenalidomide-dexamethasone (IRd) following parenteral bortezomib (V)-based induction versus continued V-based therapy in US oncology clinics. Patients & methods: Non-transplant eligible patients with newly diagnosed multiple myeloma (MM) receiving in-class transition to IRd (N = 100; US MM-6), or V-based therapy (N = 111; INSIGHT MM). Results: Following inverse probability of treatment weighting, overall response rate was 73.2% with IRd versus 57.5% with V-based therapy (p < 0.0001). Median duration of treatment was 10.8 versus 5.3 months (p < 0.0001). Overall, 18/24% of patients discontinued IRd/V-based therapy due to adverse events. Conclusion: IRd after V-based induction was associated with significantly improved overall response rate and duration of treatment than continued V-based combination therapy. Clinical Trial Registration: US MM-6: NCT03173092; INSIGHT MM: NCT02761187 (ClinicalTrials.gov).

In-class transition (iCT) of proteasome inhibitor-based therapy: a community approach to multiple myeloma management.

Long-term proteasome inhibitor (PI) treatment can improve multiple myeloma (MM) outcomes, but this can be difficult to achieve in clinical practice due to toxicity, comorbidities, and the burden of repeated parenteral administration. US MM-6 (NCT03173092) enrolled transplant-ineligible patients with newly diagnosed MM to receive all-oral ixazomib-lenalidomide-dexamethasone (IRd; ≤39 cycles or until progression or toxicity) following three cycles of bortezomib-based induction. Primary endpoint: 2-year progression-free survival (PFS). Key secondary/exploratory endpoints included overall response rate (ORR), overall survival (OS), safety, quality of life (QoL), treatment satisfaction, and actigraphy. At datacut, in the fully accrued cohort of 140 patients, median age was 73 years with 42% aged ≥75 and 61% deemed frail; 10% of patients were ongoing on treatment. After a median follow-up of 27 months, the 2-year PFS rate was 71% (95% confidence interval: 61-78). ORR increased from 62% at the end of induction to 80% following in-class transition (iCT) to IRd for a median of 11 months. The 2-year OS rate was 86%. The overall safety profile/actigraphy levels were consistent with previous reports; QoL/treatment satisfaction scores were stable with ongoing therapy. iCT to IRd may allow prolonged PI-based therapy with promising efficacy and a tolerable safety profile, while maintaining QoL.

Comparison of health care costs and resource utilization for commonly used proteasome inhibitor-immunomodulatory drug-based triplet regimens for the management of patients with relapsed/refractory multiple myeloma in the United States.

BACKGROUND: Economic differences among currently available proteasome inhibitors (PI)-based lenalidomide-dexamethasone (Rd)-backbone triplet regimens-ixazomib (I), bortezomib (V), and carfilzomib (K) plus Rd-remain poorly understood. OBJECTIVE: To assess health care resource utilization (HCRU) and health care costs of patients with relapsed/refractory multiple myeloma (RRMM) in the United States treated with IRd, VRd, and KRd. METHODS: This retrospective longitudinal cohort study using IQVIA PharMetrics Plus adjudicated claims US data (January 1, 2015, to September 30, 2020) included adult patients with all available data who initiated IRd, VRd, or KRd in second line of therapy or later (LOT2+) on or after September 1, 2015. The index date was the treatment initiation date for each LOT (multiple LOTs per patient were included) and the baseline was 6 months pre-index. MM-related and all-cause HCRU/costs were assessed during follow-up and reported per patient per month (PPPM; 2020 US Dollars). For MM-related costs only, treatment administration costs were excluded from outpatient (OP) costs and instead summed with pharmacy costs. HCRU/costs were compared between treatment groups using generalized linear models (GLMs). Cost variables were compared using 2-part models and GLM with log transformation and γ distribution. Inverse probability of treatment weighting (IPTW) adjusted for imbalance of baseline confounders across treatment groups. RESULTS: The study included 511 patients contributing 542 LOTs (IRd: n = 153; VRd: n = 262; KRd: n = 127). Before IPTW, mean observed time spent on therapy was 8.5, 9.3, and 7.3 months for the IRd, VRd, and KRd cohorts, respectively. During follow-up and after IPTW, IRd and VRd were associated with significantly fewer OP visits vs KRd. Post-IPTW comparisons of MM-related costs for IRd vs KRd yielded lower OP costs for IRd (mean diff. PPPM: -$3,428; P < 0.001), contributing to lower total medical costs (-$3,813; P < 0.001) and total health care cost savings with IRd vs KRd (-$5,813; P = 0.001). MM-related OP costs were lower for VRd (mean diff. PPPM: -$3,543; P < 0.001) than KRd, reducing its total MM-related medical costs (-$3,997; P = 0.002), leading to total MM-related health care cost savings with VRd vs KRd (-$12,357; P < 0.001). All-cause cost comparisons yielded similar results (total health care cost savings for IRd and VRd vs KRd: -$6,371 and -$13,629, respectively; all P < 0.001). CONCLUSIONS: From the US insurance-payer perspective, patients treated with IRd and VRd had significant medical cost savings vs KRd due to lower OP costs when excluding treatment administration costs. The differential economic impacts of PI-Rd regimens in this study may help to inform treatment decisions for patients with MM. DISCLOSURES: This study and article were supported by Takeda Development Center Americas, Inc. Dr Sanchez has no conflicts to declare. Dr Chari has the following relationships: Research Support/Principal Investigator: Amgen, Array Biopharma, Celgene, Glaxo Smith Klein, Janssen, Millenium/Takeda, Novartis Pharmaceuticals, Oncoceutics, Pharmacyclics, Seattle Genetics; Consultant: Amgen, Bristol-Myers Squibb, Celgene, Millenium/Takeda, Janssen, Karyopharm; Scientific Advisory Board: Amgen, Celgene, Millenium/Takeda, Janssen, Karyopharm, Sanofi, Seattle Genetics. Drs Cherepanov, Huang, Dabora, and Noga are current employees of Takeda, while Drs Stull and Young are ex-employees of Takeda; Drs Cherepanov and Huang also own stocks in Takeda. Dr DerSarkissian, Ms Cheng, Ms Zhang, Mr Banatwala, and Dr Duh are employees of Analysis Group, Inc. (AG), a consulting firm that received funding from Takeda to conduct this study. Ms Pi was an employee of AG at the time of the study. Dr Ailawadhi has the following relationships to declare: Research Support and Consulting for BMS, GSK, and Janssen; Research Support from AbbVie, Arch Oncology, Cellectar, Medimmune, Pharmacyclics, and Xencor; Consulting for Beigene, Oncopeptides, Regeneron, Sanofi, and Takeda.

Ixazomib Versus Placebo as Postinduction Maintenance Therapy in Newly Diagnosed Multiple Myeloma Patients: An Analysis by Age and Frailty Status of the TOURMALINE-MM4 Study.

BACKGROUND: The TOURMALINE-MM4 trial demonstrated a significant and clinically meaningful progression-free survival (PFS) benefit with ixazomib versus placebo as postinduction maintenance in nontransplant, newly-diagnosed multiple myeloma patients, with a manageable and well-tolerated toxicity profile. MATERIALS AND METHODS: In this subgroup analysis, efficacy and safety were assessed by age (< 65, 65-74, and ≥ 75 years) and frailty status (fit, intermediate-fit, and frail). RESULTS: In this analysis, PFS benefit with ixazomib versus placebo was seen across age subgroups, including patients aged < 65 years (hazard ratio [HR], 0.576; 95% confidence interval [CI], 0.299-1.108; P = .095), 65-74 years (HR, 0.615; 95% CI, 0.467-0.810; P < .001), and ≥ 75 years (HR, 0.740; 95% CI, 0.537-1.019; P = .064). PFS benefit was also seen across frailty subgroups, including fit (HR, 0.530; 95% CI, 0.387-0.727; P < .001), intermediate-fit (HR, 0.746; 95% CI, 0.526-1.058; P = .098), and frail (HR, 0.733; 95% CI, 0.481-1.117; P = .147) patients. With ixazomib versus placebo, rates of grade ≥ 3 treatment-emergent adverse events (TEAEs; 28-44% vs. 10-36%), serious TEAEs (15-29% vs. 3-29%), and discontinuation due to TEAEs (7-19% vs. 5-11%) were higher or similar across age and frailty subgroups, and generally somewhat higher in older age groups and intermediate-fit/frail patients in both arms. Treatment with ixazomib versus placebo did not adversely affect patient-reported quality-of-life scores across age and frailty status subgroups. CONCLUSION: Ixazomib is a feasible and effective maintenance option for prolonging PFS across this heterogeneous patient population.

Network meta-analysis of efficacy of ixazomib, lenalidomide, and dexamethasone in relapsed/refractory multiple myeloma.

OBJECTIVES: In the absence of head-to-head comparisons across relapsed/refractory multiple myeloma (RRMM) treatments following the approval of the oral proteasome inhibitor ixazomib, in combination with lenalidomide and dexamethasone (IRd), we conducted an indirect comparison of the efficacy of IRd relative to several RRMM therapies using Bayesian fixed-effects network meta-analysis (NMA) models. METHODS: Data for the NMA were obtained through a systematic literature review (conducted in June 2020), which identified randomized controlled trials (base case) and observational studies (extended network analysis) reporting overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). RESULTS: In the base case, IRd was associated with a significantly longer PFS than lenalidomide and dexamethasone (Rd), bortezomib monotherapy (V), dexamethasone (Dex), and pomalidomide and dexamethasone (Pom-dex), a significantly shorter PFS than daratumumab, lenalidomide, and dexamethasone (DRd), and a PFS comparable to elotuzumab, lenalidomide, and dexamethasone (ERd) and carfilzomib, lenalidomide, and dexamethasone (KRd). IRd was associated with a significantly longer OS than V, Dex, and Pom-dex, and an OS comparable to Rd, ERd, KRd, and DRd. The ORR of IRd was significantly higher than Rd, V, and Dex, significantly lower than KRd and DRd, and comparable to Pom-dex and ERd. The extended network analyses and sensitivity analyses were consistent with the base case. DISCUSSION: This NMA shows that IRd is relatively efficacious among RRMM treatments. Being an oral regimen, IRd is also convenient to manage. CONCLUSION: IRd could be a preferable treatment option for many patients with RRMM, particularly those seeking an efficacious and convenient therapeutic option.

Quality of life and symptoms among patients with relapsed/refractory AL amyloidosis treated with ixazomib-dexamethasone versus physician's choice.

Patient-reported outcomes in AL amyloidosis have not been well-studied. We analyzed health-related quality of life (HRQOL) and AL amyloidosis symptoms data from the phase 3 TOURMALINE-AL1 trial (NCT01659658) (ixazomib-dexamethasone, n = 85; physician's choice of chemotherapy [PC], n = 83). HRQOL and symptom burden were measured with the SF-36v2, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity subscale (FACT/GOG-Ntx), and an amyloidosis symptom questionnaire (ASQ). Score changes during treatment were analyzed descriptively and using repeated-measures linear mixed models; analyses were not adjusted for multiplicity. Least-squares (LS) mean changes from baseline were significantly higher (better HRQOL) for ixazomib-dexamethasone at several cycles for SF-36v2 Role Physical and Vitality subscales (p < .05); no subscales demonstrated significant differences favoring PC. For FACT/GOG-Ntx, small but significant differences in LS mean changes favored ixazomib-dexamethasone over PC at multiple cycles for seven items and both summary scores; significant differences favored PC for one item (trouble hearing) at multiple cycles. ASQ total score trended downward (lower burden) in both arms; significant LS mean differences favored ixazomib-dexamethasone over PC at some cycles (p < .05). Patients with relapsed/refractory AL amyloidosis treated with ixazomib-dexamethasone experienced HRQOL and symptoms that were similar to or trended better than patients treated with PC despite longer duration of therapy.

Duration of frontline therapy and impact on clinical outcomes in newly diagnosed multiple myeloma patients not receiving frontline stem cell transplant.

BACKGROUND: Extended first-line therapy (1LT) has improved clinical outcomes in newly diagnosed multiple myeloma (NDMM). This retrospective study of NDMM patients evaluated the relationship between dose-attenuation of 1LT and duration of therapy (DOT) and DOT on outcomes. METHODS: Adults with NDMM not undergoing stem cell transplant (SCT) from January 1, 2012 toMarch 31, 2018 from the Integrated Oncology Network were included; 300 were randomly selected for chart review. 1LT DOT, time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis. Marginal structural models evaluated relationships between DOT and TTNT, PFS, and OS at 2 years accounting for confounders and survival bias from the time-dependent nature of DOT. RESULTS: Of 300 chart-reviewed patients, 93 were excluded for incomplete data or meeting exclusion criteria. Among 207 NDMM patients, median age was 74 years; 146 (70.5%) did not receive dose-attenuation during 1LT. Patients with short DOT were older, frailer, with a higher comorbidity burden, and a significantly lower proportion had an Eastern Cooperative Oncology Group PS = 0. As DOT increased, more patients underwent dose-attenuation (p < 0.0001). The median 1LT DOT was 20.9 (95% confidence interval [CI]: 13.9, 26.4) versus 4.2 months (95% CI: 3.2, 4.9) for patients receiving versus not receiving dose-attenuation, respectively (p < 0.0001). After accounting for survival bias, confounder-adjusted TTNT was prolonged with each additional month of 1LT (odds ratio [OR]: 0.76 [95% CI: 0.75, 0.78]); likelihoods of risks of disease progression (OR: 0.87 [95% CI: 0.86, 0.88]) and death at 2 years (OR: 0.72 [95% CI: 0.70, 0.74]) were reduced with each month of 1LT (p < 0.0001 for all outcomes). CONCLUSIONS: Dose-attenuated 1LT was associated with longer DOT among patients with non-SCT NDMM. Each additional month of 1LT was associated with a reduced adjusted likelihood of disease progression and death at 2 years. Dose-attenuation of 1LT can extend DOT; longer DOT may improve clinical outcomes.

Global epidemiology of amyloid light-chain amyloidosis.

BACKGROUND: Amyloid light-chain (AL) amyloidosis is an ultra-rare disease associated with significant morbidity and mortality. Few studies have examined the global epidemiology of this condition. METHODS: This study estimated the diagnosed incidence and 1-year, 5-year, 10-year, and 20-year period prevalence of AL amyloidosis in 2018 for countries in and near Europe, and in the United States (US), Canada, Brazil, Japan, South Korea, Taiwan, and Russia. A systematic literature review (SLR) was conducted to identify country-specific, age- and gender-specific diagnosed incidence of AL amyloidosis and observed survival data-point inputs for an incidence-to-prevalence model. Extrapolations were used to estimate incidence and prevalence for countries without registry or published epidemiological data. RESULTS: Of 171 publications identified in the SLR, 10 records met the criteria for data extraction, and two records were included in the final incidence-to-prevalence model. In 2018, an estimated 74,000 AL amyloidosis cases worldwide were diagnosed during the preceding 20 years. The estimated incidence and 20-year prevalence rates were 10 and 51 cases per million population, respectively. CONCLUSIONS: Orphan medicinal product designation criteria of the European Medicines Agency or Electronic Code of Federal Regulations indicate that a disease must not affect > 5 in 10,000 people across the European Union or affect < 200,000 people in the US. This study provides up-to-date epidemiological patterns of AL amyloidosis, which is vital for understanding the burden of the disease, increasing awareness, and to further research and treatment options.

Patient perspectives on symptoms, health-related quality of life, and treatment experience associated with relapsed/refractory multiple myeloma.

PURPOSE: This study aimed to better understand the patient perspective and treatment experience of relapsed and/or refractory multiple myeloma (RRMM). METHODS: This qualitative study enrolled adult RRMM patients from 6 US clinics who had ≥ 3 months of life expectancy, ≤ 6 prior lines of therapy, and ≥ 1 treatment regimen with a proteasome inhibitor and immunomodulator, or a CD38 monoclonal antibody or an alkylating agent, and a steroid. In-person semi-structured qualitative interviews were conducted to capture concepts that were relevant and important to patients. Topics included RRMM symptoms and impacts and the mode of administration, frequency, duration, convenience, side effects, and overall experience with RRMM treatment. RESULTS: A total of 22 patients completed interviews. At enrollment, 59.1% of participants were using regimens containing dexamethasone, 36.4% daratumumab, 27.3% carfilzomib, and 18.2% lenalidomide. More participants had experience using intravenous or injectable therapy alone (40.9%) than oral therapy alone (18.2%). Back pain and fatigue were the most frequently reported symptoms (40.9% each); 27.3% reported no symptoms. Most participants reported physical function limitations (86.4%), emotional impacts (77.3%), MM-related activity limitations (72.7%), and sleep disturbances (63.6%). Most participants perceived treatment effectiveness based on physician-explained clinical signs (68.2%) and symptom relief (40.9%). Participants experienced gastrointestinal adverse events (59.1%), fatigue (59.1%), sleep disturbances (31.8%), and allergic reactions (31.8%) with treatment. Key elements of treatment burden included the duration of a typical treatment day (68.2%), treatment interfering with daily activities (54.5%), and infusion duration (50.0%). CONCLUSIONS: These results provide treatment experience-related data to further understand RRMM treatment burden and better inform treatment decision-making.

Treatment patterns and outcomes among nontransplant newly diagnosed multiple myeloma patients in Spain.

Aim: To describe treatment patterns and outcomes in nontransplant newly diagnosed multiple myeloma (NDMM) patients in Spain. Methods: This retrospective study included two cohorts of NDMM patients diagnosed between 1 January 2012 to 31 December 2013 and 1 April 2016 to 31 March 2017. Results: Among 113 patients, proteasome inhibitor (PI) + alkylator combinations (49%) and PI-based regimens without an alkylator (30%) were the most common first-line (1L) therapies. Use of PI + immunomodulatory drug-based regimens increased between the cohorts; PI-based regimens without an alkylator/immunomodulatory drug decreased. Use of 1L oral regimens was low but increased over time; use of maintenance therapy was low across both periods. Median 1L duration of treatment was 6.9 months. Conclusion: Short 1L duration of treatment and low use of 1L oral regimens and maintenance therapy highlight unmet needs in NDMM.

Lay abstract This study describes treatment patterns and outcomes in newly diagnosed multiple myeloma (NDMM) patients in Spain who were not candidates for transplant. The study looked at two patient groups: patients diagnosed between 1 January 2012 and 31 December 2013 and those diagnosed between 1 April 2016 and 31 March 2017. Among the 113 patients considered, the most common first-line therapies were proteasome inhibitor (PI) + alkylator combinations (49%) and PI-based regimens without an alkylator (30%). We saw increased use of PI with immunomodulators (which arm the immune system to battle disease) and decreased use of PI-based regimens without an alkylator or immunomodulator. First-line use of oral regimens was low but increased over time. The median length of first-line treatment for both groups combined was 6.9 months. Finding low use of first-line oral regimens and maintenance therapy and a short duration of first-line treatment, our study highlights the unmet needs that exist in NDMM patients who are not transplant candidates in Spain.

Real-world comparative effectiveness of triplets containing bortezomib (B), carfilzomib (C), daratumumab (D), or ixazomib (I) in relapsed/refractory multiple myeloma (RRMM) in the US.

Multiple available combinations of proteasome inhibitors, immunomodulators (IMIDs), and monoclonal antibodies are shifting the relapsed/refractory multiple myeloma (RRMM) treatment landscape. Lack of head-to-head trials of triplet regimens highlights the need for real-world (RW) evidence. We conducted an RW comparative effectiveness analysis of bortezomib (V), carfilzomib (K), ixazomib (I), and daratumumab (D) combined with either lenalidomide or pomalidomide plus dexamethasone (Rd or Pd) in RRMM. A retrospective cohort of patients initiating triplet regimens in line of therapy (LOT) ≥ 2 on/after 1/1/2014 was followed between 1/2007 and 3/2018 in Optum's deidentified US electronic health records database. Time to next treatment (TTNT) was estimated using Kaplan-Meier methods; regimens were compared using covariate-adjusted Cox proportional hazard models. Seven hundred forty-one patients (820 patient LOTs) with an Rd backbone (VRd, n = 349; KRd, n = 218; DRd, n = 99; IRd, n = 154) and 348 patients (392 patient LOTs) with a Pd backbone (VPd, n = 52; KPd, n = 146; DPd, n = 149; IPd, n = 45) in LOTs ≥2 were identified. More patients ≥75 years received IRd (39.6%), IPd (37.8%), and VRd (36.7%) than other triplets. More patients receiving VRd/VPd were in LOT2 vs other triplets. Unadjusted median TTNT in LOT ≥ 2: VRd, 13.9; KRd, 8.7; IRd, 11.4; DRd, not estimable (NE); and VPd, 12.0; KPd, 6.7; IPd, 9.5 months; DPd, NE. In covariate-adjusted analysis, only KRd vs DRd was associated with a significantly higher risk of next LOT initiation/death (HR 1.72; P = 0.0142); no Pd triplet was significantly different vs DPd in LOT ≥ 2. Our data highlight important efficacy/effectiveness gaps between results observed in phase 3 clinical trials and those realized in the RW.

Feasibility of Long-term Proteasome Inhibition in Multiple Myeloma by in-class Transition From Bortezomib to Ixazomib.

BACKGROUND: The ongoing US MM-6 study is investigating in-class transition (iCT) from parenteral bortezomib-based induction to all-oral IRd (ixazomib-lenalidomide-dexamethasone) with the aim of increasing proteasome inhibitor (PI)-based treatment adherence and duration while maintaining patients' health-related quality of life (HRQoL) and improving outcomes. PATIENTS AND METHODS: US community sites are enrolling non-transplant-eligible patients with newly diagnosed multiple myeloma (MM) with no evidence of progressive disease after 3 cycles of bortezomib-based therapy to receive IRd (up to 39 cycles or until progression or toxicity). The patients use mobile or wearable digital devices to collect actigraphy (activity and sleep) data and electronically complete HRQoL, treatment satisfaction and medication adherence questionnaires. The primary endpoint is progression-free survival. The key secondary endpoints include response rates and therapy duration. RESULTS: At the data cutoff, 84 patients had been treated (median age 73 years; 44% aged ≥ 75 years; 49% men; 15% Black or African American; and 10% Hispanic or Latino). Of the 84 patients, 62% were continuing therapy. The mean duration of total PI therapy was 10.1 months and for the IRd regimen was 7.3 months. With an 8-month median follow-up, the 12-month progression-free survival rate was 86% (95% confidence interval, 73%-93%) from both the start of bortezomib-based treatment and the start of IRd. The overall response rate was 62% (complete response, 4%; very good partial response, 25%; partial response, 33%) after bortezomib-based induction and 70% (complete response, 26%; very good partial response, 29%; partial response, 15%) after iCT. The IRd safety profile was consistent with previous clinical trial data, and HRQoL and treatment satisfaction were maintained. CONCLUSION: The patients included in the US MM-6 study are representative of the real-world US MM population. The use of iCT might permit prolonged PI-based therapy with promising efficacy, without impacting patients' HRQoL or treatment satisfaction.

Guidelines for Management of Urgent Symptoms in Patients with Cholangiocarcinoma and Biliary Stents or Catheters using the Modified RAND/UCLA Delphi Process.

Background: Patients with cholangiocarcinoma often have indwelling biliary stents or catheters which are prone to obstructions and/or infections; studies show that 20-40% present with fever and/or jaundice requiring urgent treatment in the outpatient setting for which there are no uniform guidelines. The goal was to develop an expert panel consensus on this topic using the modified RAND/UCLA Delphi process to rate treatment appropriateness. Methods: Thirteen expert physicians from relevant specialties, geography, and practice settings were recruited for the panel. Patient scenarios were developed and panelists rated the therapies before and after a face-to-face discussion. The appropriateness of various therapies was rated on a scale from 1-9 and classified as appropriate, inappropriate, or uncertain. Scenarios with greater than 2 (>2) ratings of 1-3 (inappropriate) and greater than 2 (>2) ratings of 7-9 (appropriate) were considered to have disagreement and were not assigned an appropriateness rating. Results: Panelists were from all US regions and the UK (8%) and had practiced for a mean 16.5 years (4-33 years). Panelists rated 480 scenarios before the meeting and re-rated 288 of the clinical scenarios after the meeting. The panelists agreed that ongoing treatment with chemotherapy did not influence decision-making and, therefore, 192 scenarios were excluded from the final list. Disagreement decreased from 37.5% before to 10.4% after the meeting. Consensus on stent/tube manipulation and inpatient antibiotic therapy was obtained and summarized in patients as "appropriate" or "maybe appropriate" based on a patient's bilirubin level at presentation. Conclusions: The Delphi process produced consensus guidelines to fill an unmet need in the urgent management of ascending cholangitis in patients with cholangiocarcinoma.

Real-world treatment patterns and outcomes in non-transplant newly diagnosed multiple Myeloma in France, Germany, Italy, and the United Kingdom.

OBJECTIVES: The treatment paradigm in newly diagnosed multiple myeloma (NDMM) is evolving toward individualized, risk-directed, and longer duration of therapy (DOT). The objective of this study was to describe treatment patterns and outcomes in non-transplant NDMM in four European countries. METHODS: This retrospective chart review included adults with NDMM diagnosed between January 1, 2012, and December 31, 2013 (early cohort), or April 1, 2016, and March 31, 2017 (recent cohort). RESULTS: Among 836 patients, molecular testing was performed in 21% and 35% patients of early vs recent cohorts; proteasome inhibitor (PI)/alkylator combinations were the principal first-line (1 L) therapy (39% vs 43%). Use of immunomodulatory drug (IMID)/alkylator combinations declined from early to recent cohort (26% vs 13%) but IMID (7% vs 16%) use increased. Few patients (5%) received 1 L maintenance therapy. Two-thirds of patients were treated with a fixed duration intent, with a median 7-month 1 L DOT and progression-free survival (PFS) of 32.8 months in the early cohort. Both 1 L DOT and PFS were longer with oral compared to injectable regimens. CONCLUSIONS: Although frontline treatment patterns changed significantly, 1 L DOT is short. The uptake of molecular testing and 1 L maintenance is low. These results highlight areas of unmet need in NDMM.