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The first medicine containing the boron element, bortezomib, was approved for clinical use just 18 years ago. The boronic acid substructure in bortezomib serves as an electrophilic functionality with high affinity for hydroxy groups, which are frequently found in catalytic sites of proteolytic enzymes, to create reversible covalent bonds with a slow dissociation rate. Today, boronic acid is considered an important molecule in the medicinal chemistry toolbox, which was promoted by the success of bortezomib and pioneering approaches to use boronic acid in the molecular design of serine protease inhibitors in the 1980s. In this review article, we first provide an overview of the development of bortezomib, and then summarize our achievements to construct boronic acid analogs of tyropeptin A, a naturally occurring proteasome inhibitor, with potent in vivo efficacy. Representative stereoselective synthetic methods of α-aminoboronic acid are also showcased.

The introduction of proteasome inhibitors (PIs), such as bortezomib (BTZ), and immunomodulatory drugs (IMiDs), including thalidomide (THAL) and lenalidomide (LEN), as first-line therapies in multiple myeloma (MM) has markedly improved the clinical outcomes of patients. However, MM remains incurable, and most patients eventually relapse. Moreover, prognosis is poor in patients who exhibit resistance to BTZ or LEN, and novel therapeutic approaches for such patients are urgently needed. Currently, the following six drugs are available for use in relapsed patients: second generation PIs (carfilzomib and ixazomib), an IMiD (pomalidomide), a histone deacetylase (HDAC) inhibitor (panobinostat), and two monoclonal antibodies (elotuzumab and daratumumab). The choice of treatment should be individualized based on certain factors, such as age, presence of comorbidities, frailty, cytogenetic risk, efficacy and toxicity of prior treatments, and the duration of the previous response. A course of triplet therapy containing two novel agents along with DEX is recommended, on first relapse, in fit and healthy patients, whereas doublet therapy is preferred for unfit or frail patients. Retreatment of relapsed/refractory MM (RRMM) with monoclonal antibodies and IMiDs is promising because these drugs have immunostimulatory effects. In addition, novel agents, including an anti-BCMA antibody-drug conjugate, are being studied. Clinical trials are needed to define the optimal treatment strategy for RRMM.

Recent progress in cancer therapy has improved the long-term outcomes of cancer patients, and it has increased the importance of managing cardiovascular complications associated with cancer and cancer therapies. In the field of hematology, there is a serious concern about cardiovascular complications associated with a variety of chemotherapeutic drugs, such as anthracyclines, BCR-ABL tyrosine kinase inhibitors, and proteasome inhibitors. Despite the recent accumulation of epidemiological and clinical data and the fact that these are molecularly targeted drugs, molecular mechanisms underlying the pathogenesis of cardiovascular toxicities associated with individual drugs remain to be precisely defined. Recently emerging "onco-cardiology" will extend the interdisciplinary collaboration between oncology, hematology, and cardiology specialists in clinical practice, research, and education in order to protect cancer patients and survivors from cardiovascular complications.

Multiple myeloma (MM) is a mature plasma cell neoplasm characterized by the excessive production of monoclonal antibodies and various cytokines. Therefore, MM cells are highly dependent on the ubiquitin-proteasome pathway and the well-differentiated unfolded protein response in the endoplasmic reticulum. Bortezomib, the first approved proteasome inhibitor (PI) for the treatment of MM, is widely used as a therapeutic agent for patients with MM, including newly diagnosed and relapsed/refractory (RR) cases. However, severe peripheral neuropathy and gastrointestinal disorders often occur during bortezomib treatment, which leads to inadequate treatment of MM owing to the interruption or reduction in bortezomib administration. Novel PIs, carfilzomib and ixazomib, have been developed as less toxic and more effective PIs than bortezomib, and these novel PIs are expected to be potent options for the treatment of RR MM. The use of novel PIs, which is based on the characteristics of each agent and the condition of each patient, is considered an effective treatment, and it can improve the outcomes in patients with RR MM, particularly those who cannot tolerate bortezomib.

Since the turn of the century, many agents against multiple myeloma (MM) have been introduced into daily clinical practice. The development of further agents is ongoing and some of these will reach the point of use in clinical practice in the near future. As various treatment options become available, the selection of an appropriate treatment strategy for an individual patient becomes more important. Treatment selection and decision making are based on the following two apparently opposite factors: 1) generalized findings and evidence from clinical trials, and 2) disease risks and background of individuals, which are diverse among patients. Proteasome inhibitors (PIs) are central players in MM treatment. In this review, we summarize evidence for the efficacy and safety of a first generation PI, bortezomib, and discuss its advantages in controlling disease risks and myeloma-defining events in patients with transplant-ineligible, untreated, newly diagnosed MM (NDMM). We also highlight on recent knowledge regarding the use of second generation PIs such as carfilzomib and ixazomib in the treatment of transplant-ineligible, untreated NDMM.