General MM

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

Treatment

Study

Key results

IMiDs

T vs no maintenance

T vs no maintenance

 

R vs placebo

 

 

R vs observation

 

IMWG meta-analysis5

Myeloma IX6

 

CALGB 100104, IFM2005-027, and GIMEMA RV-MM-PI-2098

 

 Myeloma XI9, EMN02/HO95, and RV-MM-EMN-44110

 

35% reduction in risk of progression or death with T compared to no maintenance

T did not provide a PFS benefit and had an adverse impact on OS in patients with high-risk cytogenetic abnormalities

 

PFS: R provided significant benefit with an HR of 0.47–0.57. OS: significant improvement in the CALGB and GIMEMA studies with R

 

R provided higher rates of conversion from MRD-positive to MRD-negative status of ~27–48%

PIs

V vs T

 

VT vs T vs IFN

 

 

Ixazomib vs placebo

 

HOVON-65/ GMMG-HD4 

 

GEM05MENOS65

 

TOURMALINE-MM3

 

V maintenance was better tolerated than T (11% vs 30% discontinuation due to toxicity)

 

For VT vs T vs IFN: Improvement in CR rate (21% vs 11% vs 17%) and PFS (50.6 vs 40.3 vs 32.5months)

Ixazomib maintenance provided a PFS benefit compared to placebo (26.5 vs 21.3 months; HR 0.72) and response improvement (46% vs 32%)

CR, complete response; HR, hazard ratio; IFN, interferon; IMiD, immunomodulatory drug; MRD, measurable residual disease; OS, overall survival; PFS, progression-free survival; PI, proteasome inhibitor; R, lenalidomide; T, thalidomide; V, bortezomib; VT, bortezomib + thalidomide

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

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

Treatment

Study

 

Key results

R vs observation post-CTD/CRD

 

 

MPR-R vs MPR-placebo vs MP-placebo and R vs no maintenance post-MPR/ASCT

 

MPT-T vs MPR-R and MPT-T vs MPR-R

 

VMP vs VTP induction, VT vs VP maintenance

 

VMPT-VT vs VMP

 

Fixed-duration V post-Vd induction vs VTD vs VMP

 

 

Ixazomib vs placebo post-ITd

 

Dara-VMP plus dara maintenance vs VMP

Myeloma XI

 

 

 MM01511 and GIMEMA-RV-MM-PI-2098

 

 HOVON87/NMSG1812 and E1A0613

 

 

GEM05MAS6514

 

 GIMEMA-MM-03-05

 

 UPFRONT15

 

 

 HOVON-126/NMSG21#13

 

 ALCYONE 

Significant improvement in PFS (HR 0.44) and PFS2 (HR 0.72), but no OS benefit observed (HR 1.02) in the R maintenance group vs observation

 

Prolonged PFS in the R maintenance group vs observation post-MPR induction; the GIMEMA-RV-MM-PI-209 study observed a better 5-year OS rate with MPR-R

 

No differences in efficacy between MPR-R and MPT-T regimens. Higher toxicity in the T-containing arms

 

Increases in CR rate from 24% after induction up to 42%, higher for VT vs VP (46% vs 39%)

 

 Improved 3-year PFS (56% vs 41%; HR 0.67) in the VT maintenance group vs no maintenance

 

Improved response with V maintenance following V-based induction in approximately 19% of responding patients, overall

 

No response benefit with ixazomib maintenance compared to placebo (10% vs 13%)

 

Improved 2-year PFS in dara-VMP plus dara maintenance group vs VMP alone (63% vs 36%; HR 0.43)

CRD, cyclophosphamide + lenalidomide + dexamethasone; CTD, cyclophosphamide + thalidomide + dexamethasone; dara, daratumumab; ITd, ixazomib + thalidomide + dexamethasone; MP, melphalan + prednisone; MPR, melphalan + prednisone + lenalidomide; mPR(-R), lower-dose melphalan + prednisone + lenalidomide (+ lenalidomide maintenance); MPT(-T), melphalan + prednisone + thalidomide (+ thalidomide maintenance); R, lenalidomide; V, bortezomib; Vd, bortezomib + dexamethasone; VMP(T), bortezomib + melphalan + prednisone (+ thalidomide maintenance); VP, bortezomib + prednisone; VT, bortezomib + thalidomide; VTD, bortezomib + thalidomide + dexamethasone; VTP, bortezomib + thalidomide + prednisone

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
References
  1. Gay F et al. From transplant to novel cellular therapies in multiple myeloma: European Myeloma Network guidelines and future perspectives. Haematologica. 2018 Feb; 103(2):197–211. DOI: 3324/haematol.2017.174573

  2. Dimopoulos MA et al. Developments in continuous therapy and maintenance treatment approaches for patients with newly diagnosed multiple myeloma. Blood Cancer J. 2020 Feb 13; 10(2):17. DOI: 1038/s41408-020-0273-x

  3. McCarthy PL et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J Clin Oncol. 2017 Oct 10; 35(29):3279–3289. DOI: 1200/JCO.2017.72.6679

  4. Nooka AK et al. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia. 2014 Mar; 28(3):690–693. DOI: 1038/leu.2013.335

  5. Ludwig H et al. IMWG consensus on maintenance therapy in multiple myeloma. Blood. 2012 Mar 29; 119(13):3003–3015. DOI: 1182/blood-2011-11-374249

  6. Morgan GJ et al. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5; 119(1):7–15. DOI: 1182/blood-2011-06-357038

  7. Attal M et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May 10; 366(19):1782–91. DOI: 1056/NEJMoa1114138

  8. Palumbo A et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4; 371:895–905. DOI: 1056/NEJMoa1402888

  9. Holstein SA et al. Summary of the Second Annual BMT CTN Myeloma Intergroup Workshop on minimal residual disease and immune profiling. Biol Blood Marrow Tr. 2019 Mar; 25(3):e89–e97. DOI: 1016/j.bbmt.2018.11.001

  10. Gambella M et al. Minimal residual disease by flow cytometry and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction in patients with myeloma receiving lenalidomide maintenance: a pooled analysis. Cancer. 2019 Mar 1; 125(5):750–760. DOI: 1002/cncr.31854

  11. Palumbo A et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012 May 10; 366(19):1759–1769. DOI: 1056/NEJMoa1112704

  12. Zweegman S et al. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3; 127(9):1109–1116. DOI: 1182/blood-2015-11-679415

  13. Stewart AK et al. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOGE1A06) in untreated multiple myeloma. Blood. 2015 Sep 10; 126(11):1294–1301. DOI: 1182/blood-2014-12-613927

  14. Mateos MV et al. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27; 120(13):2581–2588. DOI: 1182/blood-2012-05-427815

  15. Niesvizky R et al. Community-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol. 2015 Nov 20; 33(33):3921-3929. DOI: 1200/JCO.2014.58.7618

Download this article:

You can now download this article in Adobe PDF® format.

Download as PDF
Was this article informative? Thank you for your feedback!