CLINICAL, ECONOMICAL AND ETHICAL ASPECTS ASSESSING THERAPY OUTCOMES IN PATIENTS WITH MULTIPLE MYELOMAS OF HIGH CYTOGENETIC RISK

According to European authors, patients with multiple myeloma (MM) and high cytogenetic risk have shorter values of progression free survival (PFS) and overall survival (OS) as compared with standard hazard. More frequent hospitalizations mean potentially high expenses associated with management of patients with unfavorable cytogenetic risk. Cost and availability of treatment of oncological patients relate to one of pressing ethical issues. Another important aspect of this issue consists in an effective use of available approved modes of therapy in patients with various survival prognosis, which is especially critical for early lines of therapy. It has been proven that early administration of more effective modes based on individual characteristics both of a patient, and a disease will improve the total survival of patients. This will result in reduction of economic resources spent on selecting new modes of treatment in patients with a disease recurrence and correction of possible adverse effects and hospitalization.

Multiple myeloma (MM) is currently one of the most widely spread malignant vascular system tumors and, in spite of a significant number of accessible therapeutic options, patients' outcomes require improvement [1].
In patients with MM, various cytogenetic and molecular genetic breakages of tumor cells are met rather frequently and determined as the most important factors influencing the course and prognosis of MM (table 1) [2]. Depending on the effect produced on survival, high risk cytogenetic disturbances are detected (resulting in reduced overall survival) [1].
Determination of a high-risk myeloma has evolved over time and includes cytogenetic and clinical biomarkers (table 2) [3].
Due to a rather bad prognosis in a high-risk disease, there still remains a purpose of developing new treatment options for patients from a high-risk group. Thus, it's important to provide clear recommendations related to treatment of high-risk multiple myeloma to improve general therapy outcomes. The simplest approach to risk stratification is represented by the International Staging Scale that uses two available laboratory values (serum β2 microglobulin and serum albumin) (table 2) [3].
For a more exact prognosis, tumor load (stage) and disease biology (presence of molecular and genetic high-risk pathologies or increased level of LDH) should be assessed. The factors are estimated within the reviewed staging system (R-ISS) to develop a single prognostic index. To ensure consistency, only widely accepted cytogenetic markers such as trisomy, t (11;14), t (6;14), t (4;14), t (14;16), t (14;20), del 17p, + 1q are used in R-ISS [4]. The model of risk stratification called Mayo stratification (mSMART) and developed at Mayo clinic, which divides patients into two groups with high and standard risks, provides additional information for prognosis and selection of a therapeutic strategy (table 3) [5].
The prognostic value of (high-risk) cytogenetic abnormalities in MM is evident (table 4) [5,6]. However, limited data of real practice (mainly of European origin) are currently available. They describe clinical and economical models of treatment and ОБЗОР ЛИТЕРАТУРЫ outcomes for patients with MM with high cytogenetic risk. Results of international randomized clinical trials presenting effectiveness of novel agents and their combinations in patients with different cytogenetic risks are published (table 5) [7]. It is shown that some regimens are able to overcome the high cytogenetic risk and increase overall survival of patients with MM.
Results of retrospective analysis of 200 patients with MM recurrence risk in France have been published [8]. Outcomes of patients during second-line therapy were estimated after the first recurrence. 192 patients (96%) obtained second-line therapy following the recurrence: the most widely used regimens included lenalidomide (>50%). The rate of hospitalization was approximately twice higher among patients with high risk as compared with patients with standard risk. Based on Kaplan-Meier estimator, median (95% CI) of second-line progression-free survival (PFS) was 21.4 (17.5, 25.0) months    Among patients who initiated second-line treatment with bortezomib, third-line therapy with lenalidomide was the most widely spread regimen. Relatively small number of patients received bortezomib during third-line therapy after withdrawal of lenalidomide during the second-line therapy. The majority of patients cancelled treatment (n = 176.92%) by the moment when the study was completed. The principal reasons were disease progression (37%), lack of maximum response without expected additional profit (33%), and loss of response (13%). Duration of second-line treatment is commonly less than one year. It displays not satisfactory results for this line of therapy and requires to select a therapy regimen for every separate patient considering cytogenetic risk, starting from first-line therapy.
Thus, patients with high cytogenic risk had shorter values of PFS and OS as compared with standard one. More frequent hospitalization meant potentially high expenses associated with management of patients with high genetic risk. The data show that systemic collection and analysis of results obtained during the Russian real clinical practice of treatment of patients with MM are necessary for subsequent clinical and economical assessment of therapy outcomes in patients with high cytogenic risk of MM recurrence and possible correction of first-line treatment regimens.
Multiple myeloma is an incurable disease. Implementation of novel drugs into practice resulted in a significantly improved survival in the presence of multiple myeloma. This is associated with implementation of novel agents (proteasome inhibitors such as carfilzomib and ixazomib; monoclonal antibodies such as daratumumab and elotuzumab) into clinical practice [9][10][11][12][13]. In addition to new regimens, regimens with two medicinal agents used within a limited period of time, are increasingly replaced with regimens consisting of three or four medicinal preparations continuously used until progression. This improves survival even more [14]. Within 5 years, expected survival almost doubled from 38% in 1989-2000 to 64% in 2008-2016.
Some novel drugs and their combinations display high effectiveness in patients with high cytogenetic risk. However, a lack of recommendations regarding different therapy regimens depending on cytogenetic risk is a serious problem both for doctors, and for patients with myeloma. Implementation of novel agents and improved overall survival result in higher expenses on treatment of oncological patients [15,16].
The growing expenses are only partially associated with the incidence rate [17]. As compared with medicinal agents used for other indications, oncological drugs are more costly in absolute and relative terms [18]. These growing expenses cause concern as they compromise availability of effective therapy for patients.
For instance, among patients newly diagnosed with MM in the USA, healthcare expenditure per one patient a month increased from 3,263 US dollars in 2000 to 14,656 US dollars in 2014 [19].
Clinical and economical aspects of treatment of patients with MM raise a number of ethical questions. Cost of therapy is one of them. Providing treatment to people with limited resources forms the basis of any healthcare system. Growing worldwide cost of drug therapy of oncological diseases combined with insufficiently effective therapy outcomes raise questions about how effectively the existing therapy regimens are used in patients with different survival prognosis. This is especially true for early therapy lines because administration of more effective regimens based on individual characteristics both of the patient, and the disease, will sooner or later contribute to increased overall survival of patients. In future, this will reduce economical resources spent on selection of new regimens for a patient with disease recurrence, and correction of possible adverse effects and hospitalization.
For instance, the mean assumed threshold of economical effectiveness among oncologists was 280,000 US dollars per quality-adjusted life year (QALY). It is much higher than 50,000 US dollars per QALY regularly used by healthcare experts [20]. At least one oncologist in this study noted that addition of one day of life would justify expenses in the amount of 70,000 US dollars per year which is equivalent to 25 mln US dollars per QALY.
At disease onset, assessment of prognostic factors (including pathogenetic risk) in a patient with MM should be of fundamental importance while selecting therapy and will ultimately promote better overall survival. It will reduce a number of hospitalizations and expenses on correction of adverse events. Implementation of novel agents into clinical practice and increased cost of management of patients with oncological diseases (including the ones with multiple myeloma) raise ethical issues of therapy availability and need of patients in the most effective regimens based on their individual and disease characteristics.