The ongoing therapeutic revolution in multiple myeloma care can be traced to the turn of the millennium with the unanticipated discovery in 1999 that the cereblon binding small molecule thalidomide had profound clinical effectiveness and, simultaneously, the emergence of a new class of targeted therapies inhibiting the proteasome, both of which ultimately target ubiquitinated protein degradation. These contemporaneous discoveries forever changed the landscape of multiple myeloma care, substantially extending survival. Foreshadowing this seismic change, Nobel Prize winning work on the proteasome ubiquitin pathway had stimulated the development of highly specific proteasome inhibitor small molecules, particularly PS-341 (later named bortezomib). An abundance of the proteasome in hematologic malignancies had been recognized and thus PS-341 was logically being explored in relevant preclinical models. Concurrent with phase I trials, which were soon to prove the significant clinical relevance of preclinical models, the laboratory of Dr. Kenneth Anderson and colleagues at Dana-Farber, in partnership with Dr. Julian Adams and scientists at ProScript (later Millennium Pharmaceuticals) first demonstrated that the proteasome inhibitor PS-341 inhibited growth, induced apoptosis, and overcame drug resistance in human multiple myeloma cells. This landmark paper in Cancer Research set the stage for a paradigm shift in how multiple myeloma was managed across all stages of the disease, which changed the lives of patients worldwide.
A first mention of the proteasome in multiple myeloma appears in 1993, describing elevated levels of the proteasome in hematologic malignancy (1). By 1999, scientists at a small biotech company, ProScript Inc. (later Millennium Pharmaceuticals), led by Dr. Julian Adams had published on a novel reversible inhibitor of the 26S proteasome named PS-341 (2), and this agent had been shown to have the ability to both modulate NFκB and to demonstrate cytotoxicity in preclinical cancer models including prostate cancer and Burkitt lymphoma. Phase I testing had begun in a basket trial of blood cancers, but evidence to support the specific use in multiple myeloma was lacking. It was Hideshima and colleagues (3) who first brought widespread attention to the potentially dynamic role of proteasome inhibitors (PI) specifically in multiple myeloma in the April 2001 issue of Cancer Research.
Contemporaneously in the clinic, treatment options remained limited in that era to steroids and conventional nonspecific cytotoxic chemotherapeutic agents, particularly the alkylators melphalan and cyclophosphamide. The role of thalidomide had also only recently been serendipitously discovered and the start of what was to be a revolution in care was in its formative years.
In their landmark study, Hideshima and colleagues systematically demonstrated the anti-multiple myeloma effect of PS-341, now known as bortezomib (Velcade). For the first time, this publication demonstrated that PS-341 was capable of inhibiting the growth and inducing apoptosis of multiple myeloma cells. The median inhibitory concentration (MIC) in several cell lines and patient-derived multiple myeloma cells was achieved at less than 10 nmol/L concentrations, which was a clinically achievable level. In contrast, the MIC for normal peripheral blood mononuclear cells was 100 nmol/L, suggesting preferential cytotoxicity in multiple myeloma cells. This study also demonstrated the synergistic effect of combining PS-341 with steroids and that the effect is not impacted by exogenous IL6, which is an inhibitor of dexamethasone-induced apoptosis. PS-341 was capable of inducing apoptosis irrespective of p53 mutation status, an effect seen in both chemoresistant multiple myeloma cell lines and patient cells. Finally, the authors also showed that PS-341 blocked the activation of MAPK in multiple myeloma cells adherent to marrow stromal cells, which further highlighted its inhibitory effects on tumor cell growth and proliferation. This preclinical study was the first of its kind to demonstrate the detailed mechanisms behind the antitumor effects of proteasome inhibition in controlling multiple myeloma cell growth.
In 2004, the Nobel Prize in Chemistry was awarded to Aaron Ciechanover, Avram Hershko, and Irwin Rose for their discovery of ubiquitin-mediated protein degradation. Derived from this pioneering work, PIs were then developed to bind to the 26S proteasome (for bortezomib, specifically the chymotrypsin-like β5 catalytic subunit) and thus inhibit the degradation of ubiquitinated target proteins, inducing tumor cell apoptosis (4). Although the precise mechanisms remain to this day not completely clear, several of the downstream key proteins implicated in cell death include NFκB, p53, cyclin, and cyclin-dependent kinases (4). PIs also cause the accumulation of unfolded and misfolded proteins, which trigger the unfolded protein response and apoptosis. Adherence of multiple myeloma cells to the bone marrow stroma confers resistance to apoptosis and triggers NFκB-dependent transcription and secretion of IL6, which potentiates multiple myeloma cell survival. PIs downregulate the expression of VCAM-1 (5) and inhibit NFκB activation (6) to overcome these mechanisms and promote multiple myeloma cell death.
Capitalizing on the emerging science and fast following the preclinical data described above, with a clear signal now also emerging in clinical phase I drug testing (7), a practice changing phase II study (8) evaluated the efficacy of single agent bortezomib in patients with relapsed and refractory multiple myeloma. The results showed an overall response rate of 35% and a median time to first response of 1.3 months in these heavily treated patients. Ten percent of patients achieved a complete response, a rare occurrence in that era. This led to the approval of bortezomib by FDA in May 2003 as a single agent for use in relapsed multiple myeloma. In rapid succession, bortezomib was then studied in previously untreated multiple myeloma in the phase III VISTA (9) trial, leading to FDA approval in 2008 for newly diagnosed patients. Since then, bortezomib has been incorporated as the backbone of most major multiple myeloma regimens in various combination with immune modulators (thalidomide, lenalidomide, pomalidomide), alkylators (cyclophosphamide and melphalan), and more recently with mAbs (daratumumab and isatuximab) and novel agents such as selinexor across the spectrum of the phases of this disease. The lack of renal excretion makes bortezomib a safe option in patients presenting with renal failure. In addition, the switch from intravenous to subcutaneous formulation and less frequent administration on a weekly schedule have improved convenience and reduced the troublesome incidence of peripheral neuropathy, the most common dose-limiting side effect with this drug. This has facilitated widespread adoption based not only on efficacy but also better patient tolerance and adherence.
Importantly, the widespread success of bortezomib led to the development of new PIs for the treatment of multiple myeloma. Carfilzomib (Kyprolis), a potent second-generation irreversible PI, was a welcome addition to the anti-multiple myeloma therapeutic arsenal. Carfilzomib was approved by the FDA in 2012 for relapsed multiple myeloma. Later, a combination of carfilzomib with lenalidomide and dexamethasone (KRd) was found to be superior to standard of care along with better health-related quality of life in the phase III ASPIRE trial (10), which led to its expanded approval. Another offspring of bortezomib, ixazomib (Ninlaro) is an oral PI, and is often used in combination with lenalidomide or pomalidomide and steroids as an all-oral regimen in elderly and frail patients who may not prefer frequent visits to an infusion center.
Two decades removed from the landmark study by Hideshima and colleagues, PIs have been integrated into the treatment of multiple myeloma at every stage of the disease in different combinations and are now also integrated into the treatment armamentarium of other hematologic malignancies such as Waldenstrom macroglobulinemia, mantle cell non–Hodgkin lymphoma, and primary amyloidosis. As the first systematically conducted preclinical study of proteasome inhibition in multiple myeloma, the landmark study of Hideshima and colleagues will be remembered as a practice changing advancement that launched a paradigm shift away from conventional cytotoxic chemotherapy toward specifically targeted therapeutic combinations in multiple myeloma and improved survival for patients with myeloma worldwide.
G. Lancman reports personal fees from Janssen, Sanofi, Takeda, FORUS, and Pfizer outside the submitted work. A.K. Stewart reports personal fees from Janssen, Pfizer, Amgen, GSK, and Sanofi outside the submitted work. No disclosures were reported by the other author.