Over the last decade, numerous drug therapies have emerged for the treatment of multiple myeloma including immunomodulating agents namely thalidomide, lenalidomide, and pomalidomide and proteasome inhibitors namely bortezomib and carfilzomib. These agents have transformed the treatment of multiple myeloma and the role of high-dose chemotherapy followed by stem cell transplantation in the treatment of the disease. There are now studies that evaluate the use of drug therapy as maintenance following autologous stem cell transplantation; these studies have shown improvements in surrogate endpoints such as progression-free survival. Studies that have evaluated thalidomide or lenalidomide maintenance therapy have demonstrated an overall survival (OS) benefit in individuals with multiple myeloma who received high-dose chemotherapy followed by stem cell transplantation. A meta-analysis of thalidomide maintenance therapy did show a possible late survival benefit. The use of dexamethasone, thalidomide, lenalidomide, or combination bortezomib with thalidomide in patients who did not undergo transplantation demonstrated progression-free survival benefit; although there was no OS advantage for these agents in this population. There are a number of important considerations when selecting a drug therapy strategy for maintenance therapy which includes practical considerations such as route of administration and frequency of administration. Additionally, patient-specific elements such as potential toxicities, end-organ function, quality of life, cytogenetics, and previous treatment should be considered. Additional studies are needed to elicit the timing for initiation and duration of maintenance therapy, determine the role of cytogenetics, further characterize possible resistance patterns, and determine the combinations necessary to achieve an optimal increase in OS. Until more data are available, the risks and benefits should be evaluated on a patient-specific basis when deciding to initiate maintenance therapy or observation.

DISEASE OVERVIEW:

Multiple myeloma is malignant plasma-cell disorder that accounts for ∼10% of all hematologic malignancies.

DIAGNOSIS:

The diagnosis requires (1) 10% or more clonal plasma cells on bone marrow examination or a biopsy-proven plasmacytoma plus (2) evidence of end-organ damage felt to be related to the underlying plasma cell disorder.

RISK STRATIFICATION:

Patients with 17p deletion, t(4;14), t(14;16), t(14;20), and karyotypic deletion 13 or hypodiploidy are considered to have high-risk myeloma. All others are considered to have standard-risk disease.

RISK-ADAPTED THERAPY:

Standard-risk patients are treated with nonalkylator-based therapy such as lenalidomide plus low-dose dexamethasone (Rd) followed by autologous stem-cell transplantation (ASCT). If patients are tolerating the induction regimen treatment well, an alternative strategy is to continue initial therapy after stem-cell collection, reserving ASCT for first relapse. High-risk patients are treated with a bortezomib-based induction followed by ASCT and then bortezomib-based maintenance. Patients not eligible for ASCT can be treated with Rd for standard risk disease or a bortezomib-based regimen if high-risk features are present. To reduce toxicity, when using bortezomib, the once-weekly dose is preferred; similarly, when using dexamethasone, the low-dose approach (40 mg once a week) is preferred, unless there is a need for rapid disease control.

MANAGEMENT OF REFRACTORY DISEASE:

Patients with indolent relapse can be treated first with lenalidomide, bortezomib, or alkylators plus low-dose corticosteroids. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. The most promising new agents in development are pomalidomide and carfilizomib.

The impact of high dose dexamethasone containing regimens with or without the novel agents thalidomide and bortezomib on the reversal of renal failure (RF) was evaluated in 41 consecutive newly diagnosed patients with multiple myeloma (MM) treated in a single institution. RF was reversed in 73% of all patients within a median of 1.9 months. In patients treated with dexamethasone and novel agents (thalidomide and/or bortezomib) the reversibility rate was 80% within a median of 0.8 months. Severe RF and significant Bence Jones proteinuria were associated with a lower probability of RF reversal. Patients who responded to treatment achieved RF reversal more often than in those who did not (85% versus 56%, p=0.046). In conclusion, RF is reversible in the majority of newly diagnosed MM patients treated with high-dose dexamethasone containing regimens. The addition of novel agents induces a more rapid RF reversal.

In the 2005-01 trial, we have demonstrated that bortezomib-dexamethasone as induction therapy before autologous stem cell transplantation was superior to vincristine-adriamycin-dexamethasone. We conducted a post-hoc analysis to assess the prognostic impact of initial characteristics as well as response to therapy in patients enrolled in this study. Multivariate analysis showed that ISS stages 2 and 3 and achievement of response less than very good partial response (VGPR) both after induction therapy and after autologous stem cell transplantation were adverse prognostic factors for progression-free survival, the most important one being achievement of response less than VGPR after induction. Progression-free survival was significantly improved with bortezomib-dexamethasone induction therapy in patients with poor-risk cytogenetics and ISS stages 2 and 3 compared with vincristine-adriamycin-dexamethasone. In these 2 groups of patients, achievement of at least VGPR after induction was of major importance. This study is registered with EudraCT (https://eudract.ema.europa.eu; EUDRACT 2005-000537-38) and http://clinicaltrials.gov (NCT00200681).

On August 5, 2013, a marketing authorization valid throughout the European Union (EU) was issued for pomalidomide in combination with dexamethasone for the treatment of adult patients with relapsed and refractory multiple myeloma (MM) who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy. Pomalidomide is an immunomodulating agent. The recommended starting dose of pomalidomide is 4 mg once daily taken on days 1-21 of repeated 28-day cycles. The main evidence of efficacy for pomalidomide in MM was based on a phase III multicenter, randomized, open-label study (CC-4047-MM-003) in which pomalidomide plus low-dose dexamethasone therapy (POM+LoDEX) was compared with high-dose dexamethasone alone (HiDEX) in previously treated adult patients with relapsed and refractory multiple myeloma who had received at least two prior treatment regimens, including both lenalidomide and bortezomib, and had demonstrated disease progression on the last therapy. For the intent-to-treat population, median progression-free survival based on International Myeloma Working Group criteria was 15.7 weeks (95% confidence interval [CI]: 13.0-20.1) in the POM+LoDEX group versus 8.0 weeks (95% CI.: 7.0-9.0) in the HiDEX group (log-rank p value <.001). Overall survival (secondary endpoint) was also different in the two treatment groups (hazard ratio 0.53 [95% CI.: 0.37-0.74]). The most commonly reported adverse reactions to pomalidomide in clinical studies were anemia (45.7%), neutropenia (45.3%) and thrombocytopenia (27%), fatigue (28.3%), pyrexia (21%), peripheral edema (13%), and infections including pneumonia (10.7%). Peripheral neuropathy adverse reactions were reported in 12.3% of patients, and venous embolic or thrombotic (VTE) adverse reactions were reported in 3.3% of patients. Pomalidomide is expected to be teratogenic. This paper summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu).

The diagnosis of multiple myeloma requires the presence of monoclonal bone marrow plasma cells, a monoclonal (M) protein in serum and/or urine and evidence of end-organ damage from the plasma cell proliferative disorder. Initial therapy for transplant-eligible patients includes thalidomide, bortezomib or lenalidomide, all with dexamethasone. Stem cells for a possible autologous stem cell transplant (ASCT) should be collected if the patient is considered eligible for an ASCT. Initial therapy for patients ineligible for an autologous stem cell transplant includes melphalan and prednisone as well as thalidomide, bortezomib or lenalidomide. More than 100 agents are in phase I, II or III clinical trials. The most promising are carfilzomib and pomalidomide.

WHAT IS KNOWN AND OBJECTIVE:

Given the increasing healthcare costs and the recent introduction of novel agents in the treatment for multiple myeloma (MM), an incurable haematologic malignancy, more efficient use of existing resources is fundamental. The objective of this study was to systematically review economic evaluations of the use of novel agents in MM and assess their reporting quality.

METHODS:

A literature search was performed in PubMed/Medline, Latin American and Caribbean Health Sciences Literature, Cost-Effectiveness Analysis Registry and the National Health Services Economic Evaluation Database for economic evaluations up to June 2015. The search strategy included Medical Subject Headings terms or text words related to MM, economic evaluations and drugs. Full economic evaluations of bortezomib, thalidomide or lenalidomide in patients with MM that were published in English, Portuguese or Spanish were included. Two independent authors performed study selection, data extraction and quality assessment using 24 items from the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement.

RESULTS AND DISCUSSION:

Of the 132 potentially relevant records identified, eight satisfied the inclusion criteria. Most studies were cost-effectiveness analyses combined with cost-utility analyses (n = 6) from the public payer perspective (n = 4) and were performed in Europe (n = 6) on patients with refractory or relapsed MM (n = 5). All studies were based on economic models, with four of them using discrete event simulation. We found bortezomib-based therapies to be one of the more commonly selected treatment strategies for comparison (n = 7). Overall, the intervention was more effective and costlier than the alternative strategy (average of $54 630 per life year; $68 261 per quality-adjusted life year-QALY). The CHEERS' total score was 14·6 (SD = 2·6) with the most frequent problems being the lack of precision measures for all model parameters, no evaluation of heterogeneity of the results by subgroup analyses and no description of the role the funder in the identification, design, conduct and reporting of the analysis.

WHAT IS NEW AND CONCLUSION:

Most analyses of the novel therapeutic agents determined that they were cost-effective in MM at a threshold of up to $100 000/QALY. Nevertheless, the poor reporting quality of the economic studies requires improvement to ensure greater transparency.

We conducted a retrospective analysis of lenalidomide with dexamethasone for patients with relapsed/refractory multiple myeloma (RRMM) who were treated within the Korean patient access program. Lenalidomide has been approved for RRMM for several years in Europe and North America, but has not been accessible to Asian patients in the past. Between 2008 and 2012, 110 patients from 20 hospitals were enrolled. The overall response rate (ORR) was 43.6 % with 15.4 % of very good partial response (VGPR) or better. The median time to progression (TTP) in this heavily pretreated patient population was 8.0 months, and median overall survival (OS) was 23 months. Hematologic toxicities, fatigue, anorexia, and constipation were the most common adverse events. The number of previous treatment lines, previous exposure to thalidomide, refractoriness to thalidomide and bortezomib, pretreatment white blood cell count (WBC), platelet count, t(14;16), and 17p deletion were significant prognostic factors for TTP, and creatinine clearance, refractoriness to thalidomide and bortezomib, performance status, platelet count, and 17p deletion were significant for OS in univariate analysis. In multivariate analysis, WBC and platelet count were significant prognostic factors for TTP and performance status for OS. For Korean myeloma patients, lenalidomide showed considerable efficacy, and toxicities were comparable to the data published in Europe and North America.

This reference is based in information provided by a systematic review (Picot J, Cooper K, Bryant J, Clegg AJ. The clinical effectiveness and cost-effectiveness of bortezomib and thalidomide in combination regimens with an alkylating agent and a corticosteroid for the first-line treatment of multiple myeloma: a systematic review and economic evaluation. Health technology assessment (Winchester, England). 2011;15(41):1-204) reporting unpublished data obtained by the authors. This record has been prepared by collaborators of Epistemonikos.

Multicentre RCT in the UK.

POPULATION:

Aged at least 18 years. Newly diagnosed symptomatic multiple myeloma or non-secretory multiple myeloma.

INTERVENTION:

Thalidomide: 50 mg daily for 4 weeks, increasing every 4 weeks by 50-mg increments to 200 mg daily
+
Cyclophosphamide: 500 mg once a week, on days 1, 8, 15 and 22 of each cycle
Dexamethasone: 20 mg daily on days 1–4 and 15–18 of each cycle
Cycle length 4 weeks, to maximal response, but with a minimum–maximum number of cycles of 6–9

COMPARISON:

Six to nine cycles of melphalan 7 mg/m2 and prednisolone dose 40 mg on days 1–4 of a 4-week cycle

OUTCOMES:

Primary: overall survival, progression free survival, response; Secondary: quality of life, skeletal-related events, height loss, toxicity, proportion receiving bortezomib-dexamethasone as 'early rescue' on induction chemotherapy, or at relapse