Multiple myeloma — diagnosis and treatment | Lesson

Multiple myeloma is the second commonest haematological cancer and is characterised by the proliferation of malignant plasma cells in the bone marrow. Patients are often asymptomatic at presentation. Complications include cytopaenias, renal failure, bony lesions with pathological fractures and hypercalcaemia. Work up requires establishing the presence of a paraprotein, bone marrow examination, biochemistry and radiological investigations. Monoclonal gammopathy of uncertain significance (MGUS) is a pre-cancerous condition and is often seen prior to the diagnosis of overt myeloma.

Case Study

A 58 year old female presented with a 3 month history of fatigue and back pain. She had recently had a mechanical fall and fractured her right radius. Her bloodwork was remarkable for a serum creatinine of 294umol/L, a total protein of 108g/L with an albumin of 36g/L, a corrected calcium of 2.95mmol/L and a haemoglobin of 9.4g/dL.

This clinical scenario should immediately prompt a search for myeloma. While there are other causes for back pain, hypercalcaemia, renal failure and anaemia, the finding of a markedly increased total protein is a red flag in the context of the other features. The albumin is normal, suggesting that there is either a polyclonal gammopathy or a high intact paraprotein. An SPEP and SFLC should be ordered promptly. While waiting for this result, which can take a few days, imaging would be prudent. The history of a fracture, especially if associated with minimal trauma, could suggest a pathological fracture. MRI is most sensitive for the detection of bony lesions. Alternative modalities are low dose CT and PET/CT. Plain films are the least sensitive but because of cost and availability are still used commonly in the investigation of MGUS. As the clinical scenario is highly suggestive of myeloma, a bone marrow examination at this early stage should also be performed. A marrow aspirate can be examined on the same day and a diagnosis made without waiting for an SPEP or SFLC result. The renal failure, if relatively recent, could, potentially be reversible if myeloma is established and therapy is started urgently. A marrow sample for cytogenetic analysis should be taken as this has prognostic and therapeutic importance.

An MRI of the lumbosacral spine shows multiple compression fractures with lytic lesions seen in several vertebrae. The bone marrow aspirate showed an infiltrate of plasma cells that accounted for 70% of nucleated cells.

The diagnosis of myeloma requires an infiltrate of greater than 10% clonal plasma cells in the bone marrow. This can be demonstrated on either the aspirate or trephine biopsy sample but the trephine can take some time to prepare for assessment and specific stains may be required. Clonality can only be determined on a trephine biopsy with immunohistochemistry. Is this case, the diagnosis is incontrovertible because of the heavy infiltrate but when a low percentage of cells is seen, clonality assessment is important.

A diagnosis of myeloma with bony and renal involvement is now established. A course of oral high dose dexamethasone is commenced and continued for 4 days. Intravenous fluids are started and bisphosphonate therapy with a dose of pamidronate is given.

This patient has symptomatic myeloma and there is a clear indication for treatment because of end organ damage. All the typical ‘CRAB’ features are present with hypercalcaemia, renal and bony involvement and anaemia evident. High dose corticosteroid therapy is a useful emergent approach and can be a first step for debulking the plasma cell mass and potentially improving the renal failure and hypercalcaemia. It is also useful for management of bony pain.

The hypercalcaemia corrects and creatinine normalises. She is started on bortezomib and lenalidomide therapy (RVD) and is managed in the haematology day ward after discharge.

Bortezomib was the first proteasome inhibitor developed to treat multiple myeloma. This class of drug is highly effective and safe to use in renal impairment making it a very useful component in the management of this malignancy. It is usually combined with a immunomodulating drug (IMiD) such as lenalidomide along with dexamethasone for maximal efficacy and is, therefore, termed a triplet combination. Triplets have generally been shown to have higher response rates than doublets or 2 drug regimens. Maximal effect is usually seen after 4 to 6 cycles of therapy. 

Complications of myeloma

Hypercalcaemia occurs in up to 10% of cases at presentation. This finding should alert the clinician to consider myeloma in the differential diagnosis. Symptoms include confusion, weakness, nausea and vomiting. Intravenous fluids, bisphosphonates and occasionally dialysis are mainstays of treatment.

Skeletal complications include pathological fractures, spinal cord compression and bony pain. Prophylactic bisphosphonate infusions decrease the risk of fractures and improve pain. Radiotherapy and occasionally vertebroplasty are useful in spinal cord compression.

Renal impairment is common and is seen in up to 50% of patients. Multiple aetiologies contribute including light chain nephropathy, hypercalcaemia, nephrotic syndrome, amyloidosis and medications. Avoidance of dehydration is crucial and adequate fluid intake for a patient with myeloma is 3L per day.

Patients with myeloma are at a higher risk of infection estimated at a 7-fold increase compared with matched controls in one large population based study. Some chemotherapies cause neutropaenia which predisposes to bacterial and fungal disease. The newer drugs require the concomitant use of antiviral prophylaxis because of the risk of reactivation herpes simplex and herpes zoster viruses. Patients can be hypogammaglobulinaemic at baseline and replacement therapy is indicated in the setting of recurrent infections.

Hyperviscosity syndrome is a rare but serious complication. The mechanism is related to a high paraprotein in the circulation which manifests as fatigue, confusion, blurred vision and neurological symptoms. Emergency plasmapheresis is indicted in these cases.

Thrombosis is usually seen in the setting of chemotherapy. The immunomodulatory drugs such as thalidomide and lenalidomide, particularly when used with corticosteroids, are thrombogenic. Prophylaxis with aspirin or low molecular heparins is mandatory when these agents are used.

Indications for treatment of myeloma

Myeloma does not always need to be treated. Smouldering myeloma is defined as the presence of the disease without end organ damage. This entity is simply observed, usually every 3 months, in clinic with an FBC, renal function, calcium and SPEP or SFLC depending on the type of paraprotein seen. If any new abnormalities are seen or if the protein levels are rising this should prompt restaging the patient with a skeletal survey and bone marrow examination. To diagnose smouldering myeloma there needs to be a careful assessment of whether bony lesions are present with a whole body MRI or low dose CT.

Symptomatic myeloma can only be diagnosed in the presence of end organ damage. These are:

  • Hypercalcemia with a serum calcium >0.25 mmol/L higher than the upper limit of normal or >2.75 mmol/L
  • Renal insufficiency with a creatinine clearance <40 mL per min or serum creatinine >177 µmol/L
  • Anaemia with a haemoglobin value of >2.0 g/dL below the lower limit of normal, or a haemoglobin value <10.0 g/dL
  • Bone lesions with one or more osteolytic lesions on skeletal radiography, CT, PET-CT, or MRI.

Newer parameters have recently been developed which should prompt a consideration to treat. If present, these have been shown to predict for a rapid progression to symptomatic myeloma. These are:

  • Clonal bone marrow plasma cell percentage ≥60%
  • Involved:uninvolved serum free light chain ratio ≥100
  • >1 focal lesions on MRI studies

Current management of symptomatic myeloma

The first decision will be to determine a patient’s eligibility for autologous transplantation with high dose melphelan as this dictates the induction chemotherapy given. Co-morbidities should be carefully assessed. Patients aged ≥ 65 should be considered but there is no strict age cut off for this procedure and chronological age should not always be a contraindication.

Treatment cycles start with induction followed by consolidation of a response. 

Maintenance chemotherapy is then given usually with an oral drug.

A triplet (3 drug) combination is administered in the day ward setting for 4-6 cycles, if transplant eligible, as induction therapy and the paraprotein followed with each cycle. Combinations of a proteasome inhibitor (commonest is bortezomib (Velcade), an immunomodulator (thalidomide or lenalidomide) and corticosteroids (usually dexamethasone) are used and various different protocols are available. A bone marrow assessment may be performed when the protein levels plateau.

Consolidation is usually with an autologous stem cell transplant, if the patient has been deemed transplant eligible. This procedure involves two phases. The first is termed a ‘stem cell harvest’ which uses drugs such as cyclophosphamide and G-CSF to stimulate the egress of bone marrow stem cells into the blood which are then collected using an apheresis machine. These are cryopreserved and stored until the transplant. The second phase involves the administration of a high dose of a chemotherapy drug (melphelan) followed by reinfusion of the stem cells. This is done as an inpatient.

Autologous stem cell transplant has been shown to prolong both event-free and overall survival in previously untreated patients with myeloma. There is ongoing controversy as to whether newer treatments will render this procedure unnecessary, however. The evidence for autografting was published prior to novel agents being developed and more lines of therapy are now becoming available. Novel agents include carfilzomib, pomalidomide, daratumimab and ixazomib. Many more drugs are currently in development.

Other useful modalities

All patients with symptomatic disease should be treated with intravenous bisphosphonate therapy. These drugs inhibit osteoclast activity and consequently bone resorption. They have been shown to prevent pathological fractures and improve bony pain. Zoledronic acid is most commonly used but should not be given to patients with renal impairment. Pamidronate is used in these cases. Administration is every month for 24 months in a day ward setting. Bisphosphonate therapy is not effective or indicated in smouldering myeloma or MGUS.

Radiotherapy is used in a subset of patients with myeloma. Indications are solitary plasmacytoma where there is a localised focus of disease with no demonstrable systemic component. Patients who have painful bony lesions that are refractory to chemotherapy respond well to radiotherapy and may need up to 10 cycles of treatment. This modality is also indicated in spinal cord compression where a vertebral collapse or enlarging plasmacytoma impinges on the cord. This is a medical emergency and requires urgent treatment. High dose steroids are given until radiotherapy is available.

While surgery generally has no role in the treatment of myeloma, an occasional patient may benefit from vertebroplasty. Painful malignant vertebral collapse can respond to this minimally invasive technique. This involves the injection of bone cement under fluoroscopic guidance into a collapsed vertebral body. This is often done in conjunction with a course of radiotherapy.