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Recent therapeutic approaches in myeloma
Research highlights
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Treatment options for myeloma bone disease have increased during the last years.
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Denosumab is an RANKL inhibitor that has shown its noninferiority in SRE prevention compared to zoledronic acid.
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Denosumab may constitute a safer option for patients with impaired renal function, addressing an unmet medical need.
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Antisclerostin antibodies combined with zoledronic acid seem to be a promising future therapeutic approach.
Introduction
Multiple myeloma (MM) is a plasma cell neoplasm with an estimated incidence of 4/100,000/year in the United States and 4.5–6.0/100,000/year in Europe. It is the second most common hematologic malignancy and it accounts for 1%–1.8% of all cancers worldwide [ , ]. The median age at diagnosis is approximately 69 years, whereas the majority of individuals are diagnosed between the ages of 65 and 74 years. Despite the significant improvement in patient survival and quality of life over the last decades, only 10%–15% of the patients achieve or exceed the anticipated survival compared to matched general population [ ]. During the last years patient management and therapeutics are evolving rapidly with novel agents being constantly introduced in the treatment algorithm [ , ]. The availability of several different treatment regimens provides the opportunity for personalized therapeutics [ ], as well as facilitates the continuum of care during emergency situations, such as the COVID-19 pandemic [ ].
Overview of treatment approaches in multiple myeloma
Newly diagnosed patients
The primary element for guiding the treatment strategy in newly diagnosed patients with MM (NDMM) is the eligibility for autologous stem cell transplantation (ASCT).
For fit patients up to the age of 70–75 years without any impending comorbidities, induction treatment followed by high-dose therapy with melphalan (HDT) with ASCT is the recommended approach [ ]. Recently, two phase III trials compared upfront ASCT, after triplet novel agent-based induction, versus ASCT at the time of first relapse. Both showed that the progression-free survival (PFS) was improved among MM patients undergoing upfront ASCT [ ]. Although long-term PFS of more than 7 years can be achieved in up to 9% of NDMM patients [ ], optimizing the induction regimens, in order to increase the percentage of patients with minimal residual disease (MRD) negativity, and prolong PFS, and overall survival (OS), remains a challenge [ ]. Proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) are integral part of well-established three-drug combinations [ ]. The combination of bortezomib with lenalidomide and dexamethasone (VRd) seems to be more effective, although there is no direct comparison with alternative regimens including bortezomib with thalidomide and dexamethasone (VTd) and bortezomib with cyclophosphamide and dexamethasone (VCd) [ ]. More recently, anti-CD38 monoclonal antibodies have been introduced in the frontline setting. The addition of daratumumab to the VTd regimen (Dara-VTd) has resulted in deeper responses and significantly prolonged PFS compared with VTd in the randomized phase III CASSIOPEIA study [ , ]. Furthermore, the addition of daratumumab in the VRd regimen (Dara-VRd) provided higher response rates than VRd in the phase II GRIFFIN study [ ]. Regarding consolidation therapy, the benefit is rather debatable; however, it should be considered in patients with high-risk disease features [ , , ]. Several meta-analyses have confirmed the results of randomized trials showing that lenalidomide maintenance after ASCT offers both PFS and OS advantage over placebo [ ]. Maintenance with PIs, including bortezomib or ixazomib, is effective and it may be considered especially in case of lenalidomide intolerance [ , ].
Regarding elderly NDMM patients or those unfit for HDT/ASCT, the mainstay of upfront treatment consisted of either lenalidomide with dexamethasone (Rd) or bortezomib with melphalan and dexamethasone (VMP) [ , ]. More recently, the addition of bortezomib to Rd regimen (VRd) showed an OS advantage compared with Rd [ ]. Furthermore, two new standards of care have emerged following the addition of daratumumab to VMP (Dara-VMP) and Rd (Dara-Rd) based on the results from the ALCYONE and MAIA phase III randomized studies [ ].
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