Myeloma is clearly not one disease but several. In terms of treatment choices, it is increasingly evident that one size of treatment does not fit all. Moreover, as therapy is tailored to each individual patient, with the ability to mobilize and collect stem cells and retain them after successful induction/remission therapy, younger patients have choices.
Over the last decade, it has become clear that there are many different subsets of multiple myeloma, all with different biological drivers and a variety of patient-based characteristics that influence therapeutic efficacy. Careful assessment of both the underlying disease biology and the status of the patient are critical to determining the optimal type of therapy, as well as its duration, with the ultimate goal of improving long-term outcomes. It has also become clear that across the spectrum of multiple myeloma, there is wide variation in intrinsic genetics, disease characteristics, and the tumor microenvironment, all of which influence disease severity. The phenomenon of clonal tiding is also now better understood; while RNA and DNA sequencing have identified at least 20 different types of multiple myeloma, each of which is phenotypically different in its clinical behavior and its response to therapy, these are further complicated by intrinsic clonal heterogeneity. This diversity makes the choice of therapy and of combinatorial treatment challenging. However, to help us meet the challenge and find a real and lasting answer to this complex disease, there has been a dramatic improvement in the therapeutic options available. Specifically, there have been a total of 18 approvals of novel agents in the last 13 years-compared with none in the previous 30-with a record of 7 regulatory approvals last year alone. Moreover, the importance of optimal induction and the use of continuous therapy are now well established, and a role for maintenance therapy, either with or without autologous stem cell transplantation (ASCT), is emerging.[4,5]
Recent data have confirmed the superiority in the upfront setting of the combination of immunomodulatory drugs (IMiDs) with proteasome inhibitors (PIs) and dexamethasone, in comparison with a therapeutic doublet alone in the control group. Specifically, the phase III Southwest Oncology Group trial demonstrated highly significant progression-free survival (PFS) and overall survival (OS) benefits for this approach when comparing lenalidomide, bortezomib, and dexamethasone vs lenalidomide and dexamethasone in newly diagnosed multiple myeloma. While some recent phase III trials of ASCT have shown a PFS benefit and trends suggesting an OS advantage, the regimens used have involved only doublets or chemotherapeutic combinations such as melphalan, prednisone, and lenalidomide (MPR), and did not include PIs such as bortezomib.[7,8] Importantly, the interim analysis of the Intergroupe Francophone du Myelome/Dana-Farber Cancer Institute (IFM/DFCI) 2009 study that included 700 patients with multiple myeloma who were treated with 3 cycles of lenalidomide, bortezomib, and dexamethasone (RVD) followed by randomization to early vs delayed ASCT has demonstrated a PFS advantage of a median of 8.8 months compared with the control arm-although there is no apparent OS benefit, with 83% of patients who underwent delayed transplant alive at 4 years compared with 80% alive in the early transplant arm. Competing causes of mortality have included acute toxicities of ASCT as well as secondary leukemia (albeit at a very low rate), probably arising from the genotoxic consequences of exposure to high-dose melphalan. As patients live longer and an increasing proportion can reasonably anticipate a median survival in excess of 10 years, both long-term toxicities and important short-term side effects become key considerations. Furthermore, the ability to optimize continuous therapy (or maintenance) to ensure remission is a pertinent concern, given some of the challenges encountered with continuous therapy post ASCT in particular. It is also worth remembering that while ASCT in the French study improved median PFS by 8.8 months, several studies have shown that lenalidomide maintenance can improve PFS post ASCT by approximately 2.5 years, with recent meta-analyses demonstrating a significant OS benefit as well.
Immune function in multiple myeloma has become an important area of research, with the use of checkpoint inhibition in combination with IMiDs, as well as monoclonal antibodies (such as elotuzumab and daratumumab), showing remarkable promise. Next-generation PIs and IMiDs, together with the integration of second-generation novel-agent small molecules (such as histone deacetylase inhibitors), herald a dramatic era of continued progress. Participation in prospective trials evaluating the sequencing of treatments and the use of specific treatment modalities is vital. A pertinent example is the DETERMINATION study (ClinicalTrials.gov identifier: NCT01208662), which, similar to the IFM/DFCI 2009 study, is evaluating the role of early vs delayed ASCT and includes continuous maintenance treatment; this should help provide a better understanding of the role of patient and disease characteristics, as well as help in determining long-term outcomes in the context of US practice.
The advent of next-generation agents and their incorporation into the existing therapeutic paradigm of proteasome inhibition combined with immunomodulation promise to further enhance the quality and durability of responses-and as a result, higher rates of minimal residual disease negativity can reasonably be anticipated without transplant necessarily being part of an initial approach. Furthermore, in the absence of conventional chemotherapy, keeping ASCT in reserve with multi-novel agent combinations, including monoclonal antibodies, appears increasingly feasible, as initial treatment and salvage strategies continue to improve.
In conclusion, myeloma is clearly not one disease but several. In terms of treatment choices, it is increasingly evident that one size of treatment does not fit all. Moreover, as therapy is tailored to each individual patient, with the ability to mobilize and collect stem cells and retain them after successful induction/remission therapy, younger patients have choices. With the advent of highly effective monoclonal antibodies in particular, participation in studies is an obvious priority.
Financial Disclosure:Dr. Richardson serves on advisory committees for Celgene, Janssen, and Takeda.
1. Morgan GJ, Walker BA, Davies FE. The genetic architecture of multiple myeloma. Nat Rev Cancer. 2012;12:335-48.
2. Bahlis NJ. Darwinian evolution and tiding clones in multiple myeloma. Blood. 2012;120:927-8.
3. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter International Myeloma Working Group study. Leukemia. 2012;26:149-57.
4. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364:1046-60.
5. Stewart AK, Richardson PG, San-Miguel JF. How I treat multiple myeloma in younger patients. Blood. 2009;114:5436-43.
6. Durie B, Hoering A, Rajkumar SV, et al. Bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT): results of the randomized phase III trial SWOG S0777. Blood. 2015;126:abstr 25.
7. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371:895-905.
8. Gay F, Oliva S, Petrucci MT, et al. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015;16:1617-29.
9. Attal M, Lauwers-Cances V, Hulin C, et al. Autologous transplantation for multiple myeloma in the era of new drugs: a phase III study of the Intergroupe Francophone du Myelome (IFM/DFCI 2009 trial). Blood. 2015;126:abstr 391.
10. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770-81.
11. Laubach JP, Tai YT, Richardson PG, Anderson KC. Daratumumab granted breakthrough drug status. Expert Opin Investig Drugs. 2014;23:445-52.
12. Avet-Loiseau H, Corre J, Lauwers-Cances V, et al. Evaluation of minimal residual disease (MRD) by next generation sequencing (NGS) is highly predictive of progression free survival in the IFM/DFCI 2009 trial. Blood. 2015;126:abstr 191.