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Bortezomib efficacy in I, II and subsequent therapy lines was studied at 51 multiple myeloma (MM) patients in Novosibirsk Hematological Center. The median of age was 66 years (39—87); patients have received from 4 to 12 therapy courses, totally — 363 courses. Total efficacy of the I line therapy was 80%. Complete remission has been achieved in 60% of patients. Efficacy of Bortezomib monotherapy and in combination with glucocorticoids in case of progression and refractory MM was 75,7%. Bortezomib was effective even at repeated administration to patients had receied it or other components of combined regimes earlier (total response — 46,2%). Bortezomib side effects were predicted and managed; most significant of them are gastrointestinal, hematologic, asthenia and peripheral neuropathia. Thus, bortezomib is highly effective drug, important in MM therapy as I and subsequent therapy line and result in significantly increase of overall survival.

Most clinicians consider performance status and comorbidities rather than chronological age in determining prognosis and treatment. Significant advancements in the treatment of myeloma have occurred including routine use of proteasome inhibitors and immunomodulatory drugs; however, the impact of comorbidity on clinical outcomes has not been fully investigated. Here, we performed a review of the literature utilizing PubMed search engines to identify all publications comparing influence of comorbidities on survival of patients with multiple myeloma. Comorbidities of patients with multiple myeloma have been demonstrated to affect progression-free survival and overall survival. Infections pose the greatest risk of early death in these patients. Cardiovascular and renal impairment is a dreaded complication in multiple myeloma and has been associated with decreased progression-free survival and overall survival. Cardiovascular complications associated with proteasome inhibitors and immunomodulatory drugs are an important component in supportive care of patients with myeloma. Conclusions. Comorbidity plays a critical role in the outcome of myeloma patients in terms of early mortality. The management of multiple myeloma patients with comorbidities is a challenge that should be addressed improving the measurement of comorbidity and the coordination of care.

The landscape of multiple myeloma treatment transformed at the last 15 years by the introduction of novel agents (bortezomib, lenalidomide) and wide application of autologous hematopoietic stem cell transplantation, which have prolonged the survival of multiple myeloma patients. Despite the fact that multiple myeloma remains an incurable disease due to the new options, the median overall survival of patients with multiple myeloma in Russia in 2006–2016 was about 55–68 months. Drug resistance and clonal evolution remain a problem. The novel proteasome inhibitors (carfilzomib, ixazomib) differ in chemical structure and pharmacological characteristics. Thereby the next-generation proteasome inhibitor (IPs)-based regimens (KRd (carfilzomib, lenalidomide, dexamethasone), IRd (ixazomib, lenalidomide, dexamethasone), and Kd (carfilzomib, dexamethasone)) are emerging as new standards for the treatment of patients with relapsed and/or refractory multiple myeloma. In a randomized trial phase 3 ENDEAVOR, carfilzomib demonstrated improved survival in direct comparison to bortezomib. The dose-dependent activity of carfilzomib demonstrated in the study of A.R.R.O.W. Аctivity of ixazomib is comparable to that of bortezomib, the oral method of administration and the absence of neurological toxicity, allow for long-term control of the disease. The new PIs are an important advance in relapsed and/or refractory multiple myeloma treatment, increasing survival, response rate and quality of life, even in subgroups of patients with poor prognosis. This review summarizes the main pharmacological properties, mechanisms of action and clinical outcomes of major clinical studies with these agents. A separate issue discusses the problem of overcoming new proteasome inhibitors of drug resistance to bortezomib.

Ixazomib (NINLARO, Takeda Pharmaceutical Company Limited) is the first oral proteasome inhibitor which approved in combination with lenalidomide and dexamethasone (IRd) for the treatment of patients with multiple myeloma who have received at least one prior therapy. Ixazomib is a boron-containing selective and reversible proteasome inhibitor that have high antitumor activity with excellent safety. This combination was approved based on the results from the phase 3, double-blind, placebo-controlled TOURMALINE-MM1 study, which demonstrated a 35% improvement in progression-free survival (PFS) for IRd versus placebo-Rd: median: 20.6 vs 14.7 months; hazard ratio (HR): 0.74, P = 0.012. PFS was improved in both high-and standard-risk cytogenetics subgroups with median PFS in high-risk patients 21.4 vs 9.7 months (HR 0.54; P = 0.021) and in standard-risk patients 20.6 vs15.6 months (HR 0.64; P = 0.007). The addition of ixazomib to Rd regimen was associated with minimal additional toxicity. Common grade ≥3 adverse events with ixazomib include gastrointestinal adverse events, rash, and thrombocytopenia. No significant inhibition of neuronal cell survival protease HtrA2/Omi was noted in response on ixazomib treatment in vitro that explains its minimal clinical peripheral neuropathy. The present review addresses the current knowledge regarding the clinical use of ixazomib in relapsed myeloma patient and the prospects for further expansion of therapeutic indications.