State of the art clinical trials

Professor Sagar Lonial (Atlanta, USA) opened the UKMF by discussing the latest evidence in the management of myeloma, with comment from session chair Professor Gordon Cook (Leeds, UK).

Interviewer: Hannah Chatfield. Article: Maria Dalby.

https://vimeo.com/330372557

Novel combination therapies and risk-adapted maintenance treatment have radically improved outcomes in MM in recent years; although the condition remains incurable, patients are living longer and healthier lives thanks to having access to a wide range of effective treatment options, and MM is now regarded as a chronic rather than a palliative condition. Professor Sagar Lonial (Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA) was the first speaker in this year’s UK Myeloma Forum at the BSH Annual Scientific Meeting and delivered an overview of the state of the art in clinical trials in newly-diagnosed and relapsed MM. In his presentation, Professor Lonial highlighted the unmet need for patients with quad- and penta-refractory MM.

In patients with newly-diagnosed MM who are eligible for autologous stem cell transplantation (ASCT), triplet induction therapy has consistently shown superior clinical benefit over doublets in terms of response rate and survival. The addition of monoclonal antibody daratumumab in this setting has been shown to improve the speed and depth of response and appears to be overall well tolerated. In Professor Lonial’s centre, triplet induction therapy with a proteasome inhibitor and an IMiD is the standard first-line treatment in transplant-eligible patients with newly diagnosed MM, followed by maintenance therapy with lenalidomide in patients with standard-risk cytogenetics or with bortezomib or VRd in high-risk patients. In older and frailer patients who are not eligible for ASCT, lenalidomide in combination with dexamethasone (Rd) has replaced melphalan-based induction therapy in the wake of the FIRST study which showed significantly prolonged PFS and OS with continuous Rd compared with melphalan, prednisone and thalidomide (MPT). Adding a proteasome inhibitor has improved PFS and OS yet further, and dara-Rd has become a new standard treatment for transplant-ineligible frail patients following the MAIA study which was published at ASH 2018.¹ MAIA showed significantly greater depth of response, PFS and MRD negativity rate when adding daratumumab to Rd compared with Rd alone¹. Under the treatment algorithm in Professor Lonial’s centre, transplant-ineligible patients who are not considered frail receive either dose-adjusted VRd or IRd induction followed by RVd or bortezomib maintenance therapy depending on their cytogenetic risk.  

At relapse, selecting a triplet therapy is complicated by the fact that most major studies involve regimens with a lenalidomide backbone and thus have no relevance for patients who have relapsed on lenalidomide-based maintenance therapy. Only the PANORAMA-2 study (Vd plus panobinostat)² and CASTOR (Vd plus daratumumab)³studies have validated a bortezomib triplet regimen in RRMM. At early relapse, Professor Lonial’s treatment algorithm recommends combination therapy based either on pomalidomide or a proteasome inhibitor. Pomalidomide has been documented in a range of combinations including Vd, carfilzomib plus dexamethasone, and clarithromycin plus dexamethasone, with clinical benefit in terms of overall response rate in patients with up to six prior lines of therapy. In the OPTIMISMM study adding pomalidomide to Vd resulted in significantly superior PFS to Vd alone.⁴ Likewise in the ELOQUENT-3 study, pomalidomide and dexamethasone in combination with monoclonal antibody elotuzumab significantly prolonged PFS compared with Pd alone,⁵ and experience from Professor Lonial’s centre indicates that the combination pomalidomide, dexamethasone and daratumumab can prolong PFS and OS in both standard- and high-risk patients who relapse early.⁶ In Professor Lonial’s opinion, combining an IMiD with a monoclonal antibody is likely to have a synergistic effect on the innate immune system, and pomalidomide-based combinations have become an option of choice in patients who progress on lenalidomide maintenance therapy.

However, although there are now plenty of treatment options for newly-diagnosed MM and at early relapse, patients do become refractory over time and multi-refractory MM poses a considerable challenge in clinical practice. Patients who have become refractory to lenalidomide, bortezomib, carfilzomib and pomalidomide (quad-refractory) and also to daratumumab (penta-refractory) have a median OS of 11 months and a median PFS of only three to four months. In these patients, novel agents targeting different mechanisms may hold the key to prolonging survival and allow patients to benefit from additional lines of treatment or be eligible for clinical trials.

One such agent is selinexor, an oral selective inhibitor of the nuclear export protein XPO1. In the STORM study, penta-refractory patients treated with selinexor in combination with dexamethasone achieved an overall response rate of 26.2%, with 39.3% having at least a minimal response. Median PFS and OS in patients who had at least a minimal response were 4.6 months and 15.6 months, respectively. In the phase-1 STOMP study selinexor in combination with Vd achieved an overall response rate of 74% in patients with more than four prior lines of therapy. A randomised phase 2 study called BOSTON is currently in progress.

Another novel agent that is attracting interest in RRMM is venetoclax, specifically for patients with Bcl-2-dependent MM. This subset of MM is known to express the t(11;14) mutation, and a phase 1 study of venetoclax as monotherapy in RRMM showed an overall response rate of 40% among patients with t(11;14) cytogenetics, compared with 6% in patients without t(11;14) cytogenetics. Other phase 1 studies have indicated even higher overall response rates when combining venetoclax with dexamethasone or Vd, and a phase 2 study which combined venetoclax with carfilzomib and dexamethasone showed 100% overall response in patients with t(11;14) cytogenetics.⁷

The third and in Professor Lonial’s opinion possibly the best novel target in RRMM is B-cell maturation antigen (BCMA). BCMA is uniquely expressed on plasma cells and therefore presents a near-perfect target in MM, either through bispecific T-cell engagers (BiTEs) such as AMG 420, antibody drug conjugates (ADCs) such as GSK2857916, or CAR-T cell therapy including bb2121. Early-phase clinical studies have shown that these agents are very potent for inducing an overall response in patients with multi-refractory MM, with manageable safety profiles.

In Professor Lonial’s view, an important challenge for the future of MM treatment will be to identify targets not only within the biology of the plasma cells, which is where all therapeutic targets can be found at the moment, but also within the biology of cancer itself. A study is currently in progress at Professor Lonial’s centre where patients with high-risk MM will undergo gene expression profiling and then receive treatment with mutation-driven agents, such as MAP kinase inhibitors in patients with RAF/RASmutations or venetoclax in patients with t(11;14) cytogenetics. Patients who fail to respond to single-agent therapy will receive additional ixazomib and pomalidomide. Professor Lonial’s vision of the future of MM treatment is an algorithm where patients who are newly diagnosed receive biology-based treatment, to reduce the number of clones down to a level where MRD can be targeted with mutation-based treatment.

References

1. Facon T, Kumar SK, Plesner T, et al. Phase 3 Randomized Study of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplant (MAIA). Blood 2018;132:LBA-2-LBA-2.
2. San-Miguel JF, Hungria VT, Yoon SS, et al. Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial. Lancet Haematol 2016;3:e506-e515.
3. Spencer A, Hungria VTM, Mateos M-V, et al. Daratumumab, Bortezomib, and Dexamethasone (DVd) Versus Bortezomib and Dexamethasone (Vd) in Relapsed or Refractory Multiple Myeloma (RRMM): Updated Efficacy and Safety Analysis of Castor. Blood 2017;130:3145-3145.
4. Richardson PG, Rocafiguera AO, Beksac M, et al. Pomalidomide (POM), bortezomib, and low‐dose dexamethasone (PVd) vs bortezomib and low-dose dexamethasone (Vd) in lenalidomide (LEN)-exposed patients (pts) with relapsed or refractory multiple myeloma (RRMM): Phase 3 OPTIMISMM trial. J Clin Oncol 2018;36:8001.
5. Dimopoulos MA, Dytfeld D, Grosicki S, et al. ELOTUZUMAB PLUS POMALIDOMIDE/DEXAMETHASONE (EPD) VS PD FOR TREATMENT OF RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): RESULTS FROM THE PHASE 2, RANDOMIZED OPEN-LABEL ELOQUENT-3 STUDY. 23rd Congress of the European Hematology Association. Stockholm, Sweden, 2018.
6. Nooka AK, Kaufman JL, Hofmeister CC, et al. Daratumumab in multiple myeloma. Cancer 2019.
7. Costa LJ, Stadtmauer EA, Morgan GJ, et al. Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Journal of Clinical Oncology 2018;36:8004-8004.