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AIMS: The goal of this study was to review the economic evaluations of health technologies in multiple myeloma (MM) and provide guidance and recommendations for future health economic analyses. MATERIALS AND METHODS: A systemic literature review (SLR) was conducted on original economic assessment studies and structured review papers focusing on the studies in MM. The search was limited to English language papers published from 1 January 2000 onwards. Publications not applying any type of modelling methodology to describe disease progression and patient pathways over a specific time horizon were excluded. RESULTS: A total of 2,643 publications were initially identified, of which 148 were eligible to be included in the full-text review phase. From these, 49 publications were included in the final analysis. Most published health economic analyses supported by models came from high-income countries. Evaluations from middle-income countries were rarely published. Diagnostic technologies were rarely modelled and integrated care had not been modelled. Very few models investigated MM treatments from a societal perspective and there was a relative lack of evaluations regarding minimal residual disease (MRD). LIMITATIONS: Limitations of the publications included differences between trial populations and modelled populations, justification of methods, lack of confounder analyses, and small trial populations. Limitations of our study included the infeasibility of comparing MM economic evaluations due to the significant variance in modelled therapeutic lines and indications, and the relative scarcity of published economic evaluations from non-high-income countries. CONCLUSIONS: As published economic models lacked many of the elements of the complex and heterogeneous patient pathways in MM and they focused on single decision problems, a thorough, open-source economic whole disease modelling framework is needed to assess the economic value of a wide range of technologies across countries with various income levels with a more detailed view on MM, by including patient-centric and societal aspects.

AIM: The goal of this research was to quantify and qualify all the costs associated with multiple myeloma (MM) from a healthcare and societal perspective and to highlight certain costs that are often underestimated. MATERIALS AND METHODS: The study used a mixed methods approach that consisted of three phases: a systemic literature review (SLR), a virtual roundtable discussion based on the results of the SLR, and an online survey. RESULTS: In total, 4321 records were identified by literature and snowball searches. After applying the eligibility criteria, 49 articles were included in the narrative summary. As combination treatments have become the mainstay of MM treatment, drug costs have become the most important component of the total healthcare costs. Collected evidence suggests that optimizing treatment pathways, besides prolonging patient survival and maintaining quality of life, has the potential to generate cost savings for all stakeholders (payers and patients). Improved patient access to new therapies that can improve outcomes may reduce the "financial toxicity" of MM by decreasing patients' and caregivers' productivity loss due to better prognosis and it also has the potential of reducing patients' direct health care payments. LIMITATIONS: Heterogeneity of research objectives of included studies, costing methods, and applied measurement units limited the comparability of cost data between studies. Data for more than half of the world's population, including China, Russia, the Middle East, and Africa were not investigated. CONCLUSION: While treatment costs are burdensome for healthcare systems, it is only one of several items that make up the True Cost of MM. Understanding these burdens is one way to argue for optimized treatment pathways and improve patient outcomes by tearing down access barriers.

Background: Multiple myeloma (MM), an incurable plasma cell malignancy, has a relative 5-year overall survival (OS) of 48.5% for newly diagnosed patients. Prospective real-world data reveals that 23% of transplant eligible MM patients relapse within 12 months of starting first-line bortezomib based therapy with a median OS of only 16.8 months (high-risk - HR). Genomic studies for these HR patients could inform rational secondary therapeutic options and prolong survival. Bone marrow (BM) genomic analysis in MM has methodological and conceptual shortcomings owing to the spatially and genomically heterogeneous nature of MM that can be largely overcome with circulating tumour DNA (ctDNA) analysis. Objective: To determine whether ctDNA analysis can define the mutational spectrum of patients with HR MM. Design: Phase II, multicentre single arm study of carfilzomib-thalidomide-dexamethasone (KTd) in 50 transplant-eligible newly diagnosed MM patients from September 2016 to April 2018 (Australasian Leukaemia and Lymphoma Group (ALLG) - MM17 trial) who were refractory (REF) to or demonstrated a suboptimal response (SOR) to bortezomib-based induction therapy. A total of 186 peripheral blood plasma and BM samples were obtained at baseline, at Cycle 3 day 1 (C3D1), end of the study (EOS) and/or at relapse. Somatic variants were identified with an ultra-sensitive targeted amplicon sequencing (TAS) assay incorporating 22-genes known to be mutated in MM. The mutational spectrum was correlated with progression-free survival (PFS) and OS. Results: TAS of 31 BM samples and 48 ctDNA samples revealed that in BM, KRAS mutations were detected in 42% of patients followed by ATR in 29% while in ctDNA, ATR mutations were prominent (36%), followed by FGFR3 and ATM (27% and 26.8%). We compared the ctDNA mutational spectrum at baseline between non-relapse and relapse patients on KTd and identified a significant difference in the proportion of patients with specific mutations - RAS/RAF: 3% vs 25%; ATM/ATR/TP53: 17% vs 41%, respectively (p Conclusions: Our results demonstrate that RAS/RAF and ATM/ATR/TP53 mutations in ctDNA are prognostic biomarkers of outcome to secondary salvage therapy in HR patients thus enabling design of targeted therapeutic approaches to improve survival. Citation Format: Sridurga Mithraprabhu, John Reynolds, Anna Kalff, Krystal Bergin, Rose Turner, Hang Quach, Noemia Horvath, Ian Kerridge, Flora Yuen, Kawa Choi, Malarmathy Ramachandran, Ashley George, Tiffany Khong, Brian Durie, Andrew Spencer. Circulating tumour DNA mutations correlate with relapse in a phase II trial of bortezomib-primary refractory multiple myeloma patients receiving salvage therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3373.

Background: A phase II trial evaluating the response rate with sequential administration of Bortezomib, cyclophosphamide, and dexamethasone (3 cycles) followed by Bortezomib, Thalidomide, and dexamethasone (3 cycles). The primary endpoints are overall response, achievement of ≥ very good partial response (VGPR), as well as assessment of safety and tolerability. This report provides results for 25 of 43 planned eligible pts. Methods: Pts with newly diagnosed, untreated symptomatic myeloma were eligible. Treatment consisted of three 21-day cycles of Bortezomib 1.3mg/m2 days 1, 4, 8, and 11, Cyclophosphamide 300mg/m2 IV days 1 and 8 and dexamethasone 40mg po or IV days 1, 2, 4, 5, 8, 9, 11, 12; followed by three 21-day cycles of Bortezomib 1.0 mg/m2 days 1, 4, 8, and 11; Thalidomide 100 mg po daily and dexamethasone as before. Pts received thrombosis prophylaxis with ASA cycles 4–6. Upon completion of the 6 courses, pts proceeded to stem cell harvest and/or maintenance therapy. Responses were assessed by International Response Criteria. Results: As of August 2007, 25 pts have been enrolled: median age 60 years; 65% male; 75% Stage III (D/S); IgG 66%, IgA 16%; 17% light chain only. All pts fully evaluable for response thus far (13/13 [100%]) have achieved at least PR. Of these, 7/13 (54%) have achieved ≥VGPR (with nCR/CR in 31%). The median time to PR was 2 cycles or 42 days. Maximum response occurred by cycle 4 for 12/13 (92%)pts. Overall, both components of the sequential regimen were very well tolerated. One pt had a ruptured colonic diverticulum related to dexamethasone, but recovered well and achieved nCR on trial. There have been 24 therapy attributed toxicity events ≥Grade 2 of which 11 have required drug/schedule adjustments: 3 each for cyclophosphamide (neutropenia), dexamethasone (hyperglycemia, pneumonia, perforated viscus) and Thalidomide (neuro related) plus 2 for Bortezomib (neuropathy). No deep vein thromboses (DVT) have occurred in the study. 3 pts have already proceeded to successful stem cell harvest with transplant planned. Conclusion: The addition of cyclophosphamide and Thalidomide to Bortezomib/dexamethasone combination has improved the depth of response with ≥VGPR (54%) and CR/nCR (31%) compared to our previous 2-drug experience which produced ≥VGPR (38%). This very well tolerated new regimen is potentially an important step forward with further results and confirmation available by December 2007.

In contrast to the upfront setting in which the role of high-dose therapy with autologous hematopoietic cell transplantation (HCT) as consolidation of a first remission in patients with multiple myeloma (MM) is well established, the role of high-dose therapy with autologous or allogeneic HCT has not been extensively studied in MM patients relapsing after primary therapy. The International Myeloma Working Group together with the Blood and Marrow Transplant Clinical Trials Network, the American Society of Blood and Marrow Transplantation, and the European Society of Blood and Marrow Transplantation convened a meeting of MM experts to: (1) summarize current knowledge regarding the role of autologous or allogeneic HCT in MM patients progressing after primary therapy, (2) propose guidelines for the use of salvage HCT in MM, (3) identify knowledge gaps, (4) propose a research agenda, and (5) develop a collaborative initiative to move the research agenda forward. After reviewing the available data, the expert committee came to the following consensus statement for salvage autologous HCT: (1) In transplantation-eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high-dose therapy with HCT as part of salvage therapy should be considered standard; (2) High-dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of more than 18 months; (3) High-dose therapy and autologous HCT can be used as a bridging strategy to allogeneic HCT; (4) The role of postsalvage HCT maintenance needs to be explored in the context of well-designed prospective trials that should include new agents, such as monoclonal antibodies, immune-modulating agents, and oral proteasome inhibitors; (5) Autologous Ha consolidation should be explored as a strategy to develop novel conditioning regimens or post-HCT strategies in patients with short (less than 18 months remissions) after primary therapy; and (6) Prospective randomized trials need to be performed to define the role of salvage autologous HCT in patients with MM relapsing after primary therapy comparing it to "best non-HCT therapy. The expert committee also underscored the importance of collecting enough hematopoietic stem cells to perform 2 transplantations early in the course of the disease. Regarding allogeneic Ha, the expert committee agreed on the following consensus statements: (1) Allogeneic HCT should be considered appropriate therapy for any eligible patient with early relapse (less than 24 months) after primary therapy that included an autologous HCT and/or high-risk features (ie, cytogenetics, extramedullary disease, plasma cell leukemia, or high lactate dehydrogenase); (2) Allogeneic HCT should be performed in the context of a clinical trial if possible; (3) The role of postallogeneic Ha maintenance therapy needs to be explored in the context of well-designed prospective trials; and (4) Prospective randomized trials need to be performed to define the role salvage allogeneic HCT in patients with MM relapsing after primary therapy. (c) 2015 American Society for Blood and Marrow Transplantation.