Treatment of multiple myeloma

Treatment is indicated in symptomatic myeloma (defined by the presence of myeloma-related organ or tissue impairment - ROTI) (1).

• the aim is to control disease, maximise quality of life and to prolong survival
• a combination of specific disease-directed therapy and supportive care is used
  • supportive therapy includes transfusion for anaemia, antibiotics for bacterial infection, plasmaphoresis for hyperviscosity and rehydration.
  • radiotherapy is used for the treatment of localised painful lesions
• treatment decision should be reviewed in an MDT and should take into account individual patient factors and patient choice (1)

Corticosteroids and chemotherapy are the mainstay of treatment, nevertheless multiple myeloma remains incurable possibly because the malignant plasma cell clone is more slowly dividing than normal haemopoietic tissue.

• administration of corticosteroids, usually dexamethasone or prednisolone, either alone or in combination with other agents (2)
  • single-agent dexamethasone is an option for patients who will go on to autologous transplantation or whose comorbidities prohibit aggressive treatment
  • response rate can be augmented by the addition of cytotoxic chemotherapy
    • agents such as doxorubicin and vincristine (combinations known as VAD or DVD), melphalan (usually given with prednisolone), or newer agents such as thalidomide or lenalidomide
      • myelosuppression is the most common dose-limiting toxicity for traditional cytotoxic chemotherapy agents, including oral and intravenous melphalan
        • efficacy of these agents has been improved with the development of techniques for mobilization, collection, cryopreservation, and re-infusion of hematopoietic stem cells
  • high-dose chemotherapy with autologous stem-cell support, also known as autologous transplantation, is now a part of standard initial treatment

First-line treatment (3)

• bortezomib is recommended as an option within its marketing authorisation, that is, in combination with dexamethasone, or with dexamethasone and thalidomide, for the induction treatment of adults with previously untreated multiple myeloma, who are eligible for high-dose chemotherapy with haematopoietic stem cell transplantation
• thalidomide in combination with an alkylating agent and a corticosteroid is recommended as an option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate
• bortezomib in combination with an alkylating agent and a corticosteroid is recommended as an option for the first-line treatment of multiple myeloma if:
  • high-dose chemotherapy with stem cell transplantation is considered inappropriate and
  • the person is unable to tolerate or has contraindications to thalidomide
    
    
• currently, treatment options for multiple myeloma include bortezomib or carfilzomib (both with dexamethasone) if a person has had thalidomide as the first treatment. For those who have had bortezomib first, carfilzomib is not a treatment option and retreatment with bortezomib is becoming routine
  • evidence shows, as a second treatment, daratumumab plus bortezomib plus dexamethasone improves how long people live for before the disease gets worse when compared with bortezomib plus dexamethasone (4)
    
    
• daratumumab is indicated (5):
  • in combination with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant
  • as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy
  • in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy
• note that hepatitis B virus reactivation has been reported in patients treated with daratumumab, including several fatal cases worldwide and advice is to screen all patients for hepatitis B virus before initiation of daratumumab; patients with unknown serology who are already on treatment should also be screened (5)
• carfilzomib is indicated in combination with either lenalidomide and dexamethasone or dexamethasone alone for the treatment of adult patients with multiple myeloma who have received at least 1 prior therapy
  • carfilzomib has been associated with new or worsening cardiac failure, decreased ejection fraction, pericarditis, atrial fibrillation, tachycardia, myocardial ischaemia, and myocardial infarction (6)

First autologous stem cell transplantation (3)

• consider using frailty and performance status measures that include comorbidities to assess the suitability of people with myeloma for first autologous stem cell transplant.
• do not use age or the level of renal impairment alone to assess the suitability of people with myeloma for first autologous stem cell transplant

Allogeneic stem cell transplantation

• take into account that only a small number of people with myeloma are suitable for allogeneic stem cell transplantation
  
  

Treatment monitoring is by serial measurements of immunoglobulin, beta2-microglobulin and haemoglobin levels, and reassessment of bony infiltration.

The neuropathy of multiple myeloma is poorly responsive to treatment.

Preventing bone disease (3)

• to prevent bone disease, offer people with myeloma:
  • zoledronic acid or
  • disodium pamidronate, if zoledronic acid is contraindicated or not tolerated or
  • sodium clodronate, if zoledronic acid and disodium pamidronate are contraindicated, not tolerated or not suitable

Primary plasma cell leukaemia (3)

• consider bortezomib-based and/or lenalidomide-based combination induction chemotherapy for people with primary plasma cell leukaemia
• consider high-dose melphalan-based autologous stem cell transplantation for people with primary plasma cell leukaemia if they are suitable

Notes:

• symptomatic treatment
  • addition of high-potency intravenous (IV) bisphosphonates to myeloma therapy has provided major symptomatic benefits to patients
    • may prolong time to disease progression, although not clearly overall survival 21)

Reference:

• (1) Bird JM et al. Guidelines for the diagnosis and management of multiple myeloma 2011. Br J Haematol. 2011;154(1):32-75.
• (2) Stoopler ET et al. Medical management update: multiple myeloma.Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007 May;103(5):599-609.
• (3) NICE (February 2016).Myeloma
• (4) NICE (April 2019). Daratumumab with bortezomib and dexamethasone for previously treated multiple myeloma
• (5) MRHA Drug Safety Update (August 2019). Daratumumab: risk of reactivation of hepatitis B virus
• (6) MRHA Drug Safety Update (August 2019). Carfilzomib:reminder of risk of potentially fatal cardiac events