Treatment at second relapse
The standard anti-myeloma treatment at second relapse, has for several years, been lenalidomide. However, with the approval of new drugs recently other options are now available in this setting.
Again, wherever possible, it is important patients are offered the option of entering into a clinical trial.
Lenalidomide
Lenalidomide is licensed for use in combination with dexamethasone and approved by NICE for use on the NHS throughout the UK for patients who have had two prior treatments for their myeloma, have relapsed and require treatment. It has also more recently been approved as a triplet combination with ixazomib and dexamethasone (IRd), with evidence showing those receiving IRd live longer than Rd alone (see section on ixazomib below).
Efficacy
The approval of lenalidomide as a treatment for relapsed myeloma was based on the results of two pivotal randomised controlled trials, MM-009 and MM-010. Both international trials compared the combination of lenalidomide and dexamethasone with dexamethasone alone in patients who had refractory or relapsing myeloma and had previously received between one to three prior treatments. The results of both studies showed that patients benefitted significantly from receiving lenalidomide and dexamethasone compared to patients receiving dexamethasone only. The median OS for the combined studies was 38 months for dexamethasone, versus 32 months for lenalidomide plus dexamethasone. In both trials, 47% of patients of the dexamethasone arm crossed over to receive lenalidomide. As these patients were still assigned to the dexamethasone arm, the difference in outcomes between the arms is likely to be under-estimated.
Side effects of lenalidomide use are described previously. Since there is an increased risk of thromboembolic events, particularly when combined with a steroid, patients receiving lenalidomide are usually given thromboprophylaxis with an anticoagulant.
Ixazomib
Ixazomib (Ninlaro®) is the first oral proteasome inhibitor to be used in myeloma. Despite sharing some chemical similarities with bortezomib and carfilzomib and working via a similar mechanism to induce myeloma cell death by preventing the breakdown of wanted protein by the proteasome, it is a distinctly different drug. Following roll out through the CDF in 2017, in 2023, NICE approved the use of ixazomib in combination with lenalidomide and dexamethasone (IRd) for myeloma patients who have received two or three prior lines of treatment. This is the first all-oral triplet combination for myeloma that includes both a proteasome inhibitor and an iMID, making it a convenient new option for patients.
Efficacy
The approval of ixazomib as a treatment for relapsed/refractory myeloma was based on the results of the TOURMALINE-MM1 (TMM1) trial. The two-arm, randomised trial compared PFS of patients treated with lenalidomide and dexamethasone only (placebo arm) with those treated with the triple combination (ixazomib, lenalidomide and dexamethasone). The addition of ixazomib was associated with significantly longer progression-free survival.
Administration
Ixazomib is given orally once a week. The recommended starting dose may need to be adjusted depending on side effects. During treatment, it is advised to offer the patient antiviral prophylaxis to decrease the risk of herpes zoster reactivation.
Side effects
| Treatment | Potential side effects |
|---|---|
| Ixazomib | Gastrointestinal disturbances, peripheral neuropathy (monitor for symptoms), rashes, neutropenia, thrombocytopenia, fluid retention, back pain |
Panobinostat
Panobinostat (Farydak®) is the first histone deacetylase (HDAC) inhibitor to be approved as a treatment for myeloma. HDAC inhibitors are a relatively new class of anti-cancer drug and work by blocking the actions of HDAC proteins. They cause key genes, responsible for cell cycle progression and cell proliferation, to be switched off, which ultimately leads to myeloma cell death. Currently, HDAC inhibitors are not used on their own but always in combination with another agent as they are most effective in combination.
Panobinostat was approved in January 2016 in the UK in combination with bortezomib and dexamethasone for relapsed and/or refractory myeloma patients who have received at least two previous lines of treatment including bortezomib and an IMiD. However, it is mainly used only after three lines of therapy, one of which usually includes lenalidomide. Sometimes it is reserved until later in the treatment pathway.
Efficacy
The approval of panobinostat as a treatment for relapsed/refractory myeloma was based on the results of the PANORAMA-1 study, a phase 3 clinical trial.
Administration
Panobinostat is administered orally. In combination with bortezomib and dexamethasone, patients take panobinostat on days 1, 3, 5, 8, 10 and 12 of a 21-day (3 week) cycle, for up to 16 cycles. Exact dose and scheduling of all three drugs depends on a number of factors including age and tolerability.
Side effects
| Treatment | Potential side effects |
|---|---|
| Panobinostat | Gastrointestinal disturbances, cardiac arrhythmia, thrombocytopenia, fluid retention, anaemia, neutropenia, fatigue and insomnia, hypotension |
Patients should be advised to avoid pomegranate and pomegranate juice, grapefruit and grapefruit juice and starfruit when taking panobinostat as these can all interfere with the way the drug works. Taking Panobinostat in the morning can minimise the relatively common side effect of insomnia.
Current and future directions
Further investigations with panobinostat are ongoing to identify effective combinations with other anti-myeloma drugs such as ixazomib, carfilzomib and lenalidomide in relapsed and/or refractory patients. It is also being tested in the front-line setting.
Further reading
Laubach et al. (2021) Efficacy and safety of oral panobinostat plus subcutaneous bortezomib and oral dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma (PANORAMA 3): an open-label, randomised, phase 2 study. doi.org/10.1016/S1470-2045(20)30680-X.
Selinexor
As outlined in the first relapse section, in combination with bortezomib and dexamethasone, SVD is approved across the UK for people at third line whose cancer is resistant to lenalidomide.