Treatment at third or subsequent relapse
For patients who relapse a third time or more, various options may be available, including some recently NHS-approved treatments described below. Note panobinostat/bortezomib, outlined above for second relapse can also be used at this stage, as can ixazomib, lenalidomide and dexamethasone. DT-PACE outlined in the primary refractory section is also an option at third or subsequent relapse. Entry into a clinical trial should be considered wherever possible.
Pomalidomide
Pomalidomide (Imnovid®) is the third member of the immunomodulatory drug class. Like thalidomide and lenalidomide, it is significantly more active when combined with dexamethasone and/or other anti-myeloma drugs.
Pomalidomide was approved in January 2017 as a treatment, in combination with dexamethasone, for patients who have had at least three previous lines of treatment including both a proteasome inhibitor and an iMID. It is now also available from second line in Scotland. Pomalidomide, bortezomib and dexamethasone triplet therapy (PVD) is a particularly good option for those with cardiac issues who cannot tolerate certain myeloma drugs, and as all drugs can be taken at home it offers far fewer hospital trips. This makes it an attractive treatment regimen particularly for older/frailer patients.
In 2020, a triplet combination of isatuximab, pomalidomide and dexamethasone (IsaPD) was made available through the CDF for myeloma patients in England and Wales who have received at least three previous lines of treatment, including lenalidomide and a proteasome inhibitor (bortezomib, carfilzomib or ixazomib).
As with isatuximab, thalidomide and lenalidomide, pomalidomide must not be taken during pregnancy or without effective methods of contraception.
Efficacy
The approval of pomalidomide as a treatment for relapsed/refractory myeloma was based on the results of the MM-003 trial, a phase 3 clinical trial. The two-arm, randomised trial compared PFS of patients treated with pomalidomide and low-dose dexamethasone with those treated with high dose dexamethasone only (placebo arm).
The results of the trial showed a significant prolonged PFS in patients treated with pomalidomide-dexamethasone combination (4 months) compared to the placebo group (1.9 months) with limited additional side effects.
Administration
Pomalidomide is taken orally, normally for 21 days followed by a 7 day rest period. This constitutes one 28 day (4 week) cycle.
Common side effects
| Treatment | Potential side effects |
|---|---|
| Pomalidomide | Gastrointestinal disturbances, fatigue, peripheral neuropathy, VTEs, thrombocytopenia and/or neutropenia |
In common with other immunomodulatory drugs, the use of pomalidomide carries an increased risk of thrombosis and prophylactic low-molecular weight heparin or oral anticoagulants such be considered
Pomalidomide is being investigated in combination with other anti-myeloma drugs including bortezomib, carfilzomib, ixazomib, daratumumab, checkpoint inhibitors and bendamustine, predominantly in the relapsed and/or refractory setting.
Daratumumab
Daratumumab is available as a fourth line treatment option for patients in England and Wales and for patients in Scotland. Daratumumab is available for use as a monotherapy (on its own, not in combination with other drugs) in patients who have had three previous lines of treatment, including a proteasome inhibitor and an iMID, and whose myeloma progressed on their last treatment.
Selinexor
Selinexor and dexamethasone (SD) is an innovative option for patients at fifth line and beyond. According to the STORM clinical trial, average survival is nearly 8.5 months. It is now available to people who have received at least four treatments and whose myeloma has become resistant to a minimum of two proteasome inhibitors – e.g. bortezomib, carfilzomib and ixazomib – as well as two immunomodulatory agents such as lenalidomide, thalidomide or pomalidomide and an anti-CD38 monoclonal antibody like daratumumab or isatuximab.
Bispecific antibodies
Bispecific antibodies (or T cell engagers) are a novel targeted approach to specifically kill myeloma cells. They work by binding to antigens presented on the surface of T cells and myeloma cells and therefore bring the two together, initiating an immune response. There are several bispecific antibodies currently available through clinical trials for relapsed/refractory myeloma and two available across the UK on the NHS from 2025, Elranatamab (Elrexfio®) and Teclistamab (Tecvayli®).
These drugs offer great hope to those who are entering later lines of therapy where options are fewer. Talquetamab (Talvey®) works via the same mechanism though binds to another protein, GPRC5D on myeloma cells. In late 2025, talquetamab was approved for use on the NHS in England and Wales.
These bispecific antibody drugs are available for patients who have received at least three previous lines of treatment including an immunomodulatory agent such as lenalidomide (Revlimid®), a proteosome inhibitor such as bortezomib (Velcade®) or an anti-CD38 antibody like daratumumab (Darzalex®).
The EMMBRAce Project website provides a range of resources designed to help healthcare providers implement bispecific antibody therapies.
Efficacy
Elranatamab and teclistamab both work by binding to BCMA on myeloma cells and CD3 on T cells. In late 2024 following results of the MagnetisMM-3 and MajesTEC-1 trials, respectively, elranatamab and teclistamab were approved by NICE and the SMC as monotherapies for relapsed and refractory myeloma patients who have had three or more lines of treatment including an immunomodulatory drug, a proteosome inhibitor and an anti-CD38 antibody. Talquetamab was licenced in the UK based on results from the phase 1-2 MonumenTAL-1 trial.
Administration
Elranatamab, teclistamab and talquetamab are administered subcutaneously. Two step-up doses will be given in the first week and then a full dose once a week until around 6 months when it may be reduced to once every 2 weeks.
Side effects
All T cell engagers can cause side effects. These include cytopenia, infections, anaemia, gastrointestinal problems, fatigue, headaches and peripheral neuropathy.
More serious side effects particularly during the initial doses of treatment include Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANs) that can lead to feelings of confusion and delirium, and cytokine release syndrome (CRS) causing flu like symptoms, dizziness, shortness of breath and a fast heart rate.
Patients should be asked to stay close to their hospital for at least the first 3 doses of treatment, and to immediately contact their team if any side effects of ICANs, CRS or infection arise. Nurses must educate patients to recognise which side effects require immediate help and how to contact the appropriate out of hours service.
Nurses must be familiar with the specific protocols for the assessment and management of CRS and ICANS following bispecific therapies at their hospital. Examples can be found in the ‘Consensus framework for the optimal delivery of bispecific antibodies for patients with multiple myeloma’ developed as part of the EMMBRAce project.
Some centres now offer these treatments on an ambulatory care basis, where patients come to the unit for their first 3 doses and are sent home in between with an alert card, thermometers and blood pressure monitors, and phoned daily by the ambulatory care team. This reduces the infection risks that arise by patients being in hospital, saves bedspace and allows patients to stay at home where they may feel more comfortable.
Further reading
Beyond third/fourth relapse
This is a distressing time for patients and families, particularly if and when there are no further approved treatments available. Clinical trials should always be considered. Nurses play a crucial role in ensuring patients and their families are kept informed with what is available and in supporting them through this period.
Sensitive and compassionate support is crucial for patients when there is no further anti-myeloma treatment available and a palliative approach has been recommended. This is discussed in greater detail in Module 10 – Living well with myeloma.