Treatment options at first relapse
Clinical trials
Whenever possible, it is important patients are offered the opportunity to participate in a clinical trial. In the last two decades, trials investigating the development of new drugs for myeloma in the UK have increased substantially. As a result, patients have more options available to them at relapse. Current clinical trials can be viewed on our Myeloma Trial Finder.
Second SCT
Treatment at first relapse will depend on whether patients are suitable for a second SCT and if they have enough stem cells available. A second SCT may be considered at this stage in patients:
- Previously treated with standard chemotherapy and SCT
- Progressive disease ≥ 24 months from the time of first transplant
- Adequate hepatic, renal, pulmonary and cardiac function
The transplant process is described in detail in Section 6.
If a second SCT is not appropriate patients will receive a second line treatment regimen, the most common of which are described below. ill receive a second line treatment regimen, the most common of which are described below.
Daratumumab
Daratumumab (Darzalex ®) was the first human anti-CD38 monoclonal antibody to be approved as a treatment for myeloma.
Monoclonal antibodies target specific proteins expressed by myeloma cells and induce cell death either directly or through various immune response mechanisms. CD38 is a surface protein found on most, if not all, myeloma cells. Direct binding of daratumumab to CD38 triggers the immune system to attack the myeloma cells, resulting in rapid cell death through various immune-mediated mechanisms.
Daratumumab in combination with bortezomib and dexamethasone (DVd) is now available at first relapse for patients in England, Wales and Scotland and is one of the most preferred options at second line. It is an option for patients both eligible and non-eligible for SCT.
Efficacy
The approval of daratumumab as a treatment for relapsed myeloma was based on the results of two single-arm clinical trials, MMY2002 (SIRIUS) and GEN501. The CASTOR phase 3 trial demonstrated a superior overall response rate (ORR) and PFS for daratumumab, bortezomib and dexamethasone (DVd) compared to bortezomib and dexamethasone (Vd).
Administration
Daratumumab is given by intravenous infusion or subcutaneous injection in 21/28 day cycles, usually once weekly for weeks 1 to 8 and then reducing to every two weeks or less for the following cycles. The exact schedule will be decided by the healthcare team and will usually continue until there is disease progression. Dose adjustments due to side effects and infusion-related reactions may occur.
Side effects
Side effects of using daratumumab are described previously.
Bortezomib
As discussed above, for patients who are not suitable for a second SCT, one option at first relapse includes bortezomib. Although approved for use as a monotherapy in this setting, bortezomib is mostly given with dexamethasone and can also be combined with a chemotherapy agent such as cyclophosphamide (VCD). More recently, it is combined with dexamethasone and daratumumab as described above.
Efficacy
The approval of bortezomib as a treatment for relapsed myeloma was based on the pivotal APEX trial, where 669 patients with relapsed or refractory myeloma (one to three prior lines of treatment) were randomised to receive either bortezomib or high-dose dexamethasone. An Independent Data Monitoring Committee stopped the study early due to the superiority of bortezomib over high-dose dexamethasone in this patient population.
Median survival was 29.8 months for bortezomib versus 23.7 months for dexamethasone, a six-month benefit, despite substantial crossover from dexamethasone to bortezomib which means the benefit of bortezomib is likely underestimated. The overall response rate for bortezomib was 43% compared to 18% for dexamethasone.
Administration
Exact dosage and length of treatment is dependent on various factors, side effects and the exact treatment combination being used. For bortezomib it is important to note that at least 72 hours must elapse between treatment doses.
The response to treatment is carefully assessed and determines how many cycles are given. Common side effects of bortezomib are described previously.
Lenalidomide
Lenalidomide in combination with dexamethasone is an option at second line for patients who previously received bortezomib at first line. Lenalidomide-containing treatment regimes are not usually suitable for patients who have received lenalidomide maintenance treatment after first-line HDT-SCT and subsequent relapse, as they would be considered to be lenalidomide-refractory and their myeloma would be unlikely to respond to further lenalidomide treatment.
Carfilzomib
Carfilzomib was the first of the second-generation proteasome inhibitors to be developed as a treatment for myeloma. Designed to target a different area of the proteasome to bortezomib, results from clinical trials have shown that it produces effective and durable responses including in those refractory to bortezomib treatment.
In 2021, carfilzomib was made available on the NHS for use in combination with lenalidomide and dexamethasone (KRD) for patients at second line who have been previously treated with bortezomib. It is also available at second, third and fourth line as a dual therapy with dexamethasone.
Efficacy
The approval of carfilzomib as a treatment for relapsed/refractory myeloma was based on the results of a phase 3 clinical trial, the ENDEAVOR trial. The two-arm, randomised trial compared the PFS and OS of myeloma patients treated with carfilzomib and dexamethasone to those treated with bortezomib and dexamethasone. Participating patients had relapsed after one to three previous myeloma treatments. The results of the trial showed a significantly improved PFS and OS in the carfilzomib group compared to the bortezomib group.
Administration
Carfilzomib is given by intravenous infusion on 2 consecutive days, each week for 3 weeks (days 1, 2, 8, 9, 15, and 16) followed by a 12-day rest period (days 17 – 28). The exact dosing schedule thereafter will depend on tolerability and specific combination being used. When administering carfilzomib, nursing staff should consider providing antiviral prophylaxis for herpes zoster infection.
Side effects
| Treatment | Potential side effects |
|---|---|
| Carfilzomib | Gastrointestinal disturbances (constipation, diarrhoea, nausea, vomiting), peripheral neuropathy (less common compared to bortezomib), dyspnoea, tachycardia, cardiac failure, infections, VTEs, fatigue, anaemia, bleeding |
| Lenalidomide | Gastrointestinal symptoms including diarrhoea, fatigue, increased thrombotic risk, peripheral neuropathy, low blood counts (neutrophils and platelets), skin rashes, birth defects |
| Dexamethasone | Stomach irritation, increased appetite, fluid retention, swelling in feet and hands, changes in blood sugar levels, infections, mood swings, insomnia, muscular problems, eye complications |
Carfilzomib is also being investigated in other settings. In the Myeloma XI trial, it was used as induction treatment in combination with cyclophosphamide, lenalidomide and dexamethasone (KCRD).
Selective Inhibitor of Nuclear Export (SINE) compounds
This class of drugs act to block the action of an intracellular protein called exportin-1 (XPO-1).
XPO-1 is highly expressed in myeloma cells, where it facilitates the transport of various proteins between cellular compartments. The myeloma cells exploit XPO-1 to export tumour suppressor proteins from the nucleus, effectively inactivating them and promoting uncontrolled proliferation. Inhibiting this process with a SINE (Selective Inhibitor of Nuclear Export) compound restores the function of tumour suppressors, ultimately leading to myeloma cell death.
Selinexor (Nexpovio®) is the first SINE to be approved in the UK. In combination with bortezomib and dexamethasone, SVD is approved for people at second line whose myeloma has become resistant to daratumumab and lenalidomide and for patients at third line whose cancer is resistant to lenalidomide.
Efficacy
Data from the STORM clinical trial for SD showed that over a quarter of patients responded well to treatment and had an average remission of nearly three months. Data from the BOSTON clinical trial showed that 76% of patients responded well to SVD and had an average remission of over 13 months. This was around four months longer than patients receiving bortezomib and dexamethasone alone.
Administration
Selinexor is administered orally, once or twice a week.
Side effects
| Treatment | Potential side effects |
|---|---|
| Selinexor | Thrombocytopenia, peripheral neuropathy, headaches, fatigue, anaemia, neutropenia, gastrointestinal toxicities, appetite loss and cataracts |
Selinexor can also cause hyponatraemia which can cause patients to feel confused, weak and nauseous. Sodium levels should therefore be monitored regularly and salt tablets or fluids can be given to increase the level as necessary. As with all new drugs, new side effects are possible and should be noted and treated accordingly.
Antibody-drug conjugates
Building on the success of monoclonal antibodies, antibody-drug conjugates have been developed to target myeloma cells more precisely. These conjugates use the same or similar targets as monoclonal antibodies but use these to specifically deliver other drugs directly to the myeloma cell. One example is to combine a chemotherapy drug with a monoclonal antibody. An advantage of these conjugates is the ability to use stronger chemotherapy agents which would otherwise be more toxic to the patient.
Belantamab mafodotin (Blenrep®) acts to direct the chemotherapy mafodotin to myeloma cells by binding to the protein BCMA which is expressed at high levels on their surface. Across the UK, belantamab mafodotin is now available at second line in combination with bortezomib and dexamethasone (BVD). In January 2026, belantamab in combination with pomalidomide and and dexamethasone (BPD) was approved in England and Wales for patients at second line who have previously received lenalidomide.
Efficacy
The approval of belantamab mafodotin follows two key clinical trials: DREAMM-7 and DREAMM-8. In DREAMM-7, patients receiving BVD had a nearly tripled median PFS compared to a daratumumab-based comparator (36.6 months vs 13.4 months) and a statistically significant improvement in overall survival after 18 months (84% vs 73%).
Administration
Belantamab mafodotin is usually given via IV infusion every 3 weeks, though the exact dose and schedule may vary with each individual.
Side effects
| Treatment | Potential side effects |
|---|---|
| Belantamab mafodotin | Keratopathy, blurred vision, dry eyes, infusion reactions, nausea and diarrhoea, anaemia, fatigue, thrombocytopenia, abnormal levels of some enzymes in the blood |
Generally, belantamab mafodotin is relatively well tolerated. However as with many myeloma treatments there are reported side effects as outlined in the table above. One of the more serious side effects of belantamab mafodotin is keratopathy (changes to the cornea), leading to blurred vision, dry eyes or in some cases a loss of vision that can take several months to improve. Patients should be given eye drops to prevent dry eyes, have regular eye check-ups, and be advised not to wear contact lenses while on treatment. If the effects are severe, patients should not drive and changes to the treatment dosage/a postponement in treatment should be considered alongside a ophthalmology referral. A patient support programme is being established with to support management of eye-related toxicities.
As this is a relatively new drug, nurses should also be aware and encourage patients to discuss any additional side effects so they can be recorded and managed effectively and as soon as possible.