The initial management of multiple myeloma in the era of novel agents: 2021 and beyond

Multiple myeloma (MM) diagnostics and therapeutics have improved dramatically over the past two decades, with increased adoption of advanced imaging techniques, improved prognostic risk stratification tools, including fluorescence in situ hybridization (FISH) studies and minimal residual disease (MRD) testing, and the development of highly effective novel agents including next-generation immunomodulatory drugs (IMIDs), proteasome inhibitors (PIs), and monoclonal antibodies (MoABs). These drugs have further added to and move beyond previously established and effective therapies such as autologous stem cell transplantation (ASCT). Over and above these mainstay agents and the highly effective combinations derived therefrom, there are now several next-generation approved agents with novel mechanisms of action, including histone deacetylase inhibitors (panobinostat), nuclear transport inhibition (selinexor) and the first approved anti-B-cell maturation antigen (BCMA) antibody-drug conjugate (belantamab mafodotin). With emerging data demonstrating the benefit of BCMA-directed chimeric antigen receptor T-cell (CAR Tcell) therapy, the therapeutic landscape of MM therapy is growing rapidly. However, despite these highly effective therapies, and the remarkable improvements in prognosis as a result, MM remains incurable and it is, thus, inherently difficult to create a one-size-fits-all approach in management guidelines. This is particularly related to the heterogenous behavior of MM, including the broad spectrum of risk in any individual with the disease; the variability in depth and durability of response to current treatment approaches; the more advanced age of patients at diagnosis, often with numerous comorbid conditions and the unique toxicity profiles of available agents and combinations, recognizing that, generally, these approaches have proved manageable. However, specific agents or treatment modalities may not be appropriate for certain patients. Sive et al. have nonetheless very comprehensively reviewed the most up-to-date MM literature and have created a robust and thoughtful set of evidence-based guidelines for evaluation and initial treatment, intensification, consolidation and maintenance. These range from the use of proper diagnostic tools, including incorporation of serum-free light chain analysis, and the use of advanced imaging with positron emission tomography/computed tomography and/or whole body magnetic resonance imaging, with the former also allowing for detection of extramedullary disease (EMD). Detection of EMD is important initially because it is increasingly prevalent in the heavily pre-treated relapsed and refractory MM (RRRM) population. Results of FISH testing are now incorporated into the revised international staging system (R-ISS), allowing for useful prognostication at the time of diagnosis and at relapse. For example, genomic analysis with bi-allelic TP53 inactivation and amplification of 1q21 (≥4 copies) comprise an ‘ultra’ high-risk population with a severely adverse prognosis. Similarly, the presence of t(11;14) represents a subgroup of MM with unique biology and intermediate outcomes that is prime for targeting with BCL-2 inhibitor venetoclax, thus informing therapeutic choice. Amongst the broad array of treatment options discussed, the lenalidomide, bortezomib and dexamethasone (RVd) platform in newly diagnosed multiple myeloma (NDMM) has become a new standard of care for induction therapy globally, based first on the striking and consistent quality of responses seen with this triplet, as well as the highly significant progression free (PFS) and overall survival (OS) advantage demonstrated in the Phase 3 SWOG S0777 trial. This has been further strengthened by the successful translation of this platform into real-world practice, not least based upon its favourable tolerability and generally manageable side effect profile. A good example of this is the dose-modified RVd-lite regimen, which is particularly useful in transplant-ineligible Correspondence: Omar Nadeem, Jerome Lipper Multiple Myeloma Center, Hematologic Malignancies, Dana-Farber-Cancer Institute, Boston, MD, USA. E-mail: omar_nadeem@dfci.harvard. edu commentary