Updated ESMO Clinical Practice Guidelines

In January 2017, the European Society of Medical Oncology (ESMO) issued an update of their Clinical Practice Guidelines for Multiple Myeloma (MM), which was published in the March edition of Annals of Oncology. This document built on the previous draft published in 2013. These guidelines comprise comprehensive recommendations covering diagnosis, staging and risk assessment, treatment and response evaluation, and follow-up, and now also include recommendations for supportive care. Since 2013 many advances have been made in all of these areas and therefore a re-evaluation of the previous guidelines was required.

Key Updates in 2017 Guidelines:

• The criteria for diagnosis of MM was updated in 2014 by the International Myeloma Working group (IMWG) to include new parameters:
  • Measurement of renal insufficiency by assessing creatine clearance using validated equations such as Modification of Diet in Renal Disease (MDRD) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
  • Lytic lesions are to be defined by CT in addition to conventional X-ray
  • Other biomarkers of malignancy eg. ≥60% clonal BM plasma cells, involved/uninvolved serum FLC ratio ≥100 and ≥1 focal lesion on MRI studies (each focal lesion must be ≥5mm in size) are also to be assessed
• Staging and diagnosis now includes use of the Revised International Staging System (R-ISS), which expands on the previous ISS by adding in parameters for cytogenetics (using FISH analysis) and lactate dehydrogenase (LDH) (see previous MMHub article)
• The benefit of gene expression profiling to identify patients with high risk cytogenetics is mentioned, but is not yet adapted for routine use
• Assessment of elderly patients is to be carried out on an individual basis, with age, comorbidities, cognitive and physical conditions assessed to determine a frailty score, to predict risk of toxicity and mortality rate
• Response evaluation is to include a depth of response analysis using minimal residual disease (MRD) taking into account the statistical correlation between a negative MRD and achieving complete response (CR), progression free survival (PFS) and overall response (OS)
• Treatment for elderly patients that are transplant ineligible includes the use of continuous lenalidomide plus low-dose dexamethasone (Rd), which now has full EMA approval
• Other regimens for elderly pts - bortezomib, cyclophosphamide and dexamethasone (VCD) and addition of bortezomib to Rd - were noted to be in current use with high response rates, but do not yet have full EMA approval
• For younger patients, standard of care remains induction therapy followed by autologous stem cell transplant (ASCT), but a longer induction regimen of 4-6 courses is now recommended (previously 3-4)
• Further clinical data now supports the preferential use of triplet drug regimens for induction therapy, and it was noted that in Europe, VTD (bortezomib, thalidomide and dexamethasone) and VCD (bortezomib, cyclophosphamide and dexamethasone) are preferred; RVD (lenalidomide, bortezomib and dexamethasone) is expected to be widely used once approval is granted
• For elderly pts systematic maintenance therapy is not recommended, but for post-transplant pts lenalidomide is recommended, following significant improvements in PFS
• Significant treatment advances in front-line therapies available for relapsed and refractory MM (RRMM) pts include triplet combinations now approved by the EMA:
  • Panobinostat in combination with bortezomib and dexamethasone (pts who have received at least two prior regimens)
  • Carfilzomib in combination with lenalidomide and dexamethasone (pts who have received at least one prior therapy)
  • Elotuzumab, in combination with lenalidomide and dexamethasone (pts who have received at least one prior therapy)
• Other new therapies for pts with RRMM who have received at least one prior therapy include:
  • Carfilzomib in combination with dexamethasone alone
  • Elotuzumab in combination with lenalidomide and dexamethasone
  • Ixazomib in combination with lenalidomide and dexamethasone
• Daratumumab is also approved for treatment of RRMM pts with disease progression and who previously received a proteasome inhibitor and an immunomodulatory agent
• Daratumumab combined with bortezomib-dexamethasone, or lenalidomide-dexamethasone will be considered following regulatory approval
• The most significant update of the new guidelines is the inclusion of a new supportive care section, which details advances in treatment options for bone disease and spinal cord compression, anaemia, bone marrow failure and infections, and renal failure:
  • Bone disease can be treated with pamidronate and zoledronic acid; pts with moderate renal function impairment should receive a reduced dose of zoledronic acid (max 3mg) and pamidronate 4 hr infusion; pts with hypercalcaemia should receive zoledronic acid
  • Treatment with bisphosphonates not recommended for ≥2 years due to osteonecrosis of the jaw
  • Denosumab (anti-RANKL) will benefit pts with renal impairment once approved
  • Orthopaedic surgery and radiotherapy recommended for pts with pathological fractures or at risk of long bones
  • Pts with vertebral compression fractures may benefit from vertebroplasty or kyphoplasty
  • Spinal cord compression requires immediate treatment with high-dose dexamethasone and simultaneous local radiotherapy; surgery may be carried out if bone fragments occur within the spinal route
  • Recombinant human erythropoietin and darbepoetin alfa are recommended for the treatment of myeloma-associated anaemia
  • Granulocyte colony-stimulating factor (G-CSF) may be required to treat chemotherapy-induced severe granulocytopaenia
  • Infections can be treated with broad spectrum antibiotics
  • Vaccinations for Influenza and pneumococcal are recommended; acyclovir or valacyclovir for prevention of herpes-zoster virus for pts receiving inhibitor-based therapies   
  • Pts with renal failure should be treated with bortezomib-based therapies (in combination with dexamethasone with/without thalidomide or doxorubicin or cyclophosphamide)
  • Pts on IMiD therapy should receive aspirin (100 mg) to prevent venous thromboembolism

In summary, the updated guidelines build on the significant advances made in drug combination regimens for all classes of MM patient (transplant-eligible, transplant-ineligible and elderly) and include additional guidelines for supportive care. The goal of personalized medicine has still not been reached, but with the R-ISS and advances in cytogenetics, this may be on the horizon sooner rather than later.