Long-term treatment approaches for patients with newly diagnosed multiple myeloma

In the last two decades, survival rates for patients with multiple myeloma (MM) have improved substantially.¹ Long-term treatment approaches, such as continuous therapy and maintenance, can prolong disease control and improve progression-free survival (PFS) and, sometimes, overall survival (OS) compared to fixed-duration approaches. ‘Continuous therapy’ refers to administering a regimen, typically a doublet or triplet, until disease progression, whereas maintenance refers to the use of single-agent or doublet combinations following more intensive approaches like autologous stem cell transplant (ASCT), or doublet, triplet, or quadruplet induction therapies.²

Requirements for agents and regimens used in these contexts are²

• efficacy and effectiveness, with no impact on feasibility or efficacy of subsequent treatment at relapse

• tolerability and safety for a prolonged period of time, with no adverse impact on patients’ quality of life (QoL)

• minimal treatment burden for patients

The aims of such long-term approaches are to

• prolong disease control

• improve PFS and OS

• reduce clonal evolution

• achieve deep responses by negative measurable residual disease (MRD) status

In an article published in Blood Cancer Journal, Meletios A. Dimopoulos and colleagues reviewed the latest results in the field of long-term therapy approaches in newly diagnosed MM (NDMM). Here we present a summary of these results.²

Maintenance treatment post-ASCT²

Immunomodulatory drugs and proteasome inhibitors have been investigated as post-ASCT maintenance therapy, and key results from these studies are reported in Table 1. Of immunomodulatory drugs,  lenalidomide (R) has been approved by the United States Food & Drug Administration as maintenance treatment post ASCT. The approval was based on the meta-analysis³ of 1,208 patients who received R vs placebo/no maintenance post ASCT in the CALGB 100104, IFM2005-02, and GIMEMA RV-MM-PI-209 studies. The Connect® MM registry, a registry incorporating data from > 3,000 NDMM patients, reported the value of R maintenance post ASCT in the real-world setting, with an improved PFS (54.5 vs 30.4 months, HR 0.58) and 3-year OS (85% vs 70%; HR 0.45) compared to no maintenance. Of proteasome inhibitors, bortezomib (V) has been evaluated in two key phase III studies, and results are reported in Table 1. A single-center study suggested that VR and dexamethasone (d) consolidation and maintenance may have a specific role in the treatment of high-risk (del17p, del1p, t[4;14], t[14;16]) patients, with 96% achieving at least a very good partial response (VGPR), a median PFS of 32 months, and 3-year OS of 93% ⁴, though larger trials would need to confirm this.

Table 1. Data on IMiDs® and PIs as post-ASCT maintenance

Optimal duration of post-ASCT maintenance

The optimal duration of post-ASCT maintenance treatment and the depth of response required to stop maintenance are still under investigation. Some patients may derive benefits from shorter-term/fixed-duration maintenance, whereas others may require a longer treatment duration. For example, the GMMG-MM5 trial showed that, in patients stopping R maintenance at CR, the OS rates were reduced, with no significant differences in PFS. However, an increase in toxicity was observed with the use of continuous R maintenance therapy. Regarding the depth of response required to stop maintenance, data from Myeloma XI showed PFS benefits with R maintenance regardless of MRD status and an increase in MRD-positive to MRD-negative conversion with R vs observation (30% vs 4%)⁹, but further investigation is needed to determine whether MRD status can guide duration of post-ASCT maintenance.

Ongoing studies

• GEM2014MAIN study: ixazomib + Rd as maintenance
• ATLAS and FORTE studies: carfilzomib-R(d) vs R
• Cassiopeia: post-ASCT randomization to daratumumab maintenance vs observation
• EMN18: addition of daratumumab to ixazomib maintenance

Continuous frontline therapy in transplant-ineligible patients²

The use of continuous R and low-dose d as a standard-of-care upfront therapy is supported by the results of the FIRST trial, comparing continuous Rd vs Rd (18 cycles) vs melphalan-prednisone-thalidomide (MPT). In this trial, patients with standard-risk cytogenetic abnormalities showed PFS (HR 0.66) and OS (HR 0.69) benefits with continuous Rd, but patients with high-risk cytogenetics had similar outcomes with each therapy (PFS, HR 1.27; OS, HR 0.92).

The RV-MM-PI-0752 study, comparing continuous Rd with Rd followed by R maintenance (Rd-R), showed no significant differences in efficacy between regimens but lower rates of adverse events (AEs) and dose reductions in the Rd-R arm. The MAIA study of daratumumab-Rd vs Rd until progression demonstrated the efficacy and feasibility of continuous triplet therapy, resulting in a 44% reduction in the risk of progression or death. The triplet regimen of VRd has demonstrated benefits vs Rd in the SWOG S0777 study, but VRd was only given for eight cycles before continuing Rd until progression. To determine the benefit of prolonged PI therapy in addition to Rd, further comparative studies are required.

Ongoing studies

• TOURMALINE-MM2 and ELOQUENT-1 studies: ixazomib or elotuzumab plus Rd
• COBRA: carfilzomib-Rd vs VRd

Maintenance therapy post-induction in transplant-ineligible patients²

In addition to continuous Rd as post-induction maintenance therapy, the efficacy of R has been investigated in ‘continuous R’ settings involving R-based induction followed by single-agent R maintenance. Key studies on maintenance therapy post induction are reported in Table 2.

Table 2. Data on post-induction maintenance therapy

Tolerability and safety of long-term therapeutic approaches and impact on QoL²

It is important that agents used for continuous therapy are well tolerated, with no adverse impact on patient QoL.  Thalidomide and bortezomib continuous therapy appear to be associated with an increased risk of peripheral neuropathy, while continuous therapy with R resulted in increased rates of Grade 3–4 neutropenia, chronic diarrhea, and increased risk of second primary malignancies. However, the risk of using R maintenance is outweighed by the significantly reduced risk of disease progression. Regarding QoL, the data available suggest that these therapies do not have an adverse impact.

Another important factor to consider is the treatment burden, which can be higher with long-term approaches due to the need for trips to hospital for repeated intravenous or subcutaneous drug administrations. Considering that prolonged treatment is associated with improved PFS, the authors recommend that patients should continue therapy for as long as possible to achieve this PFS benefit; a way to improve the feasibility of these long-term therapeutic approaches may be switching from a parenterally administered therapy to an orally administered regimen — this is being explored with ixazomib in the MM-6 trial.

Conclusion²

• Data, reported on multiple agents and regimens, demonstrate the benefit of long-term therapeutic approaches on PFS in patients with NDMM
• When choosing a treatment, it is important to consider not only efficacy and safety but also QoL and treatment burden
• To determine the optimal treatment duration and dosing schedule in different patient populations, studies comparing different treatment durations and intensities are required
• Another important issue to be explored concerns the role of MRD evaluation in guiding decisions on the duration of treatment