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from previous page drug-based induction with proteasome inhibitor-based induction prior to transplant, bortezomib-based regimens are often preferentially used first-line. 16
Once an adequate response has been achieved( partial response or better, see table 7), the patient undergoes stem cell collection, then chemotherapy conditioning, usually with high-dose melphalan, and infusion of stem cells.
If an adequate response is not achieved, salvage therapy with a different regimen is often advised. After an autologous stem cell transplant, maintenance therapy is often recommended.
In Australia, the only current option for maintenance is thalidomide. While lenalidomide has been shown to improve both progression-free and overall survival, it is not approved in Australia for this indication. 18, 19 A second transplant may also be considered in certain patients who have had a suboptimal response to the first transplant and / or those with high-risk disease. 20
The superiority of autologous stem cell transplant over a nontransplant approach, in terms of both progression-free survival and overall survival, has been known since the 1990s. This has been reaffirmed in the era of new generation immunomodulatory drugs and
21, 22
combination therapy.
While the average time to progression for patients following autologous stem cell transplant is 2-4 years for younger patients, this time has been shown to be less in older cohorts. 23
Treatment of patients ineligible for transplant
There are a number of induction therapy options available in Australia for those who are ineligible for transplant, with the choice often dependent on patient fitness for treatment. In Australia, current first-line options are generally either lenalidomide or bortezomib. Thalidomide-based induction could be used in patients in whom there is a contraindication to lenalidomide or bortezomib. 3
The duration of therapy is largely dependent on the regimen used— immunomodulatory drug-based regimens are typically continued until progression or significant toxicity, while proteasome inhibitor-based regimens are continued until the patient reaches a plateau phase.
Other options available include more traditional chemotherapy agents, such as the final two shown in table 6. Doses can be attenuated in unfit elderly patients, such as reducing bortezomib to a weekly dose( which reduces risk of neuropathy), low-dose thalidomide and lower-dose dexamethasone.
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Response
Stringent complete response
Complete response
Very good partial response
Partial response
No change or stable disease
Progressive disease
Table 7. Evaluation of treatment response Criteria
Normal free-light chain ratio and absence of clonal plasma cells in bone marrow by immunohistochemistry( in addition to complete response criteria)
No detectable paraprotein and disappearance of any soft tissue plasmacytomas and < 5 % plasma cells in bone marrow
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Response to treatment / monitoring Following induction therapy or autologous stem cell transplant, patients require regular monitoring, usually monthly. Monitoring should include serum and / or urinary paraprotein levels and serum free light chains, FBC, serum calcium and renal function. 16
Treatment responses are classified
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based on size of reduction or rise in paraproteins, and are shown in table 7. 24
Relapsed myeloma There is no one standard treatment for patients who have relapsed following autologous stem cell transplant or initial induction therapy. Many, but not all, patients will require immediate treatment at first relapse. Indications to start treatment include new or increase in size of bone lesions, hypercalcaemia, worsening anaemia and worsening renal function, as well as significant biochemical relapse such as doubling of the paraprotein in less than two months.
In patients with a long first remission following induction, repeating the initial regimen may be considered. An alternative strategy is to switch to a regimen containing medications with different mechanisms of action.
The major options in Australia are the immunomodulatory drugs( lenalidomide, and pomalidomide in those who have failed lenalidomide),
Greater than 90 % reduction in paraproteins or paraproteins detectable but too low to measure
Greater than 50 % reduction in paraproteins Not meeting criteria for disease response or progression
Adapted from: Rajkumar, S. et al. 2011 39
At least a 25 % increase in paraproteins( increase of at least 5g / L), development of new bone lesions or plasmacytomas, or hypercalcaemia
Table 8. Common side effects of myeloma agents Medication
Common side effects
Thalidomide Somnolence Peripheral neuropathy Increased risk of venous thromboembolism( VTE) Myelosuppression Constipation Autonomic neuropathy( less common) Bradycardia
Lenalidomide Neuropathy( lower risk than thalidomide) Constipation Fatigue Myelosuppression Increased risk of VTE( lower than thalidomide)
Bortezomib
Sensory neuropathy Autonomic neuropathy Thrombocytopenia Reactivation of varicella zoster virus
Cyclophosphamide, melphalan( alkylating agents)
Nausea Myelosuppression
bortezomib,‘ traditional’ chemotherapy agents including alkylating agents and anthracyclines, and corticosteroids. 25
Patients who have had an autologous stem cell transplant who have had a long progression-free survival can be considered for a second transplant. 16 Most patients should also be considered for a clinical trial. Therapeutic decisions are often based, again, on patient fitness, and also timing of relapse post treatment.
Role of allogeneic stem cell transplant The role of allogeneic stem cell transplantation is controversial, with high transplant-related mortality and graft-versus-host-disease rates. It may be considered as a treatment option at some centres for young patients with high-risk disease who are willing to accept the toxicities for the possibility of
26, 27
improved long-term survival. Clinical trials are underway to further investigate the role of allogeneic stem cell transplantation in the treatment of myeloma.
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Agents in the clinical trial stage Carfilzomib and ixazomib are new-generation proteasome inhibitors. These are approved by the US Food and Drug Administration, and have both been shown to be superior to lenalidomide in patients with relapsed-refractory
28, 29
myeloma.
Daratumamab is a monoclonal antibody against CD38 and has shown promising results in phase three trials in combination with standard agents. 30 Elotuzumab, a humanised IgG monoclonal antibody directed against a signalling molecule expressed on myeloma and natural killer cells, has been shown to improve progression-free survival and overall survival in refractory myeloma. 31 Panobinostat is a deacetylase inhibitor that affects the growth of myeloma cells, and increases progression-free survival in relapsed refractory myeloma. 32
None of these is currently funded by the PBS.
Common side effects Side effects of the commonly used agents in myeloma are listed in table 8. Some side effects can be managed with simple measures, such as moving the timing of administration to night-time if there is somnolence or fatigue.
However, more severe side effects, such as neuropathy or myelosuppression, often require that the drugs be discontinued, or at the very least the dose reduced.
Radiation therapy and surgery Radiation therapy remains an important part of the management of myeloma, with up to two-thirds of patients requiring this modality during the course of their disease. 33
Traditional indications are palliative, and include large osteolytic lesions, prophylactic treatment of lytic lesions in long bones at risk of pathological fracture, post-fracture pain, spinal cord compression, extramedullary disease and solitary plasmacytoma.
The use of radiation therapy is seen at two peaks in the course of the disease— the first at diagnosis, when urgent debulking may be needed, such as in impending spinal cord compression; and then second, late in the course of disease when there is disease progression. 31
Radiation therapy is able to offer exceptional pain control, without the side effects of potent analgesics that may be needed otherwise. 34
The need for surgery in myeloma has reduced in recent years because of the efficacy of systemic therapy.
However, it is recommended for those with pathological fractures of long bones, unstable spinal fractures, and for those with spinal cord compression with bone fragments. 35
End stage disease / palliative care With new treatments effectively rendering multiple myeloma a chronic disease, it is becoming more important to effectively manage symptoms, and for clinicians to recognise when a patient has advancing and untreatable disease.
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A referral to a palliative care service at this point allows the team to become familiar with the patient, and vice versa; this may occur even if the patient is receiving‘ active’ treatment. 36
However, earlier referral in the case of difficult to manage symptoms or psychological distress is also appropriate.
Supportive therapy Bone disease To reduce skeletal-related events prescribe a bisphosphonate, either zolendronic acid or pamidronate, monthly in those with bone disease. 33
Venous thromboembolism Myeloma itself increases the risk of VTE, and treatment with immunomodulatory drugs increases this further.
Prophylaxis, with aspirin for low-risk and low molecular weight heparin for higher-risk patients with myeloma, is recommended. 36
Anaemia While erythropoiesis-stimulating agents have been shown to reduce transfusion requirements in anaemic myeloma patients, they are not approved in Australia for this indication, and their long-term impact in myeloma is still unknown. 33
Infections Infections are the main cause of death in patients with myeloma. 34
• Patients with recurrent severe infections and documented hypogammaglobulinaemia may be eligible for monthly intravenous immunoglobulin 37
• Antimicrobial prophylaxis should follow institutional guidelines, however general recommendations include:
• Prophylaxis against zoster reactivation( valaciclovir or famciclovir) for those receiving proteasome inhibitors
• Pneumocystis jiroveci pneumonia prophylaxis( trimethoprim / sulfamethoxazole first line) for those on high dose corticosteroids that is equivalent to 20mg of prednisone daily for at least four weeks. 34
• Vaccinations: vaccinate all patients against hepatitis B, pneumococcus and influenza. Avoid live vaccines. 34
Pain management Pain is one of the most common symptoms experienced by myeloma patients, and management includes a multi-modal approach using both pharmacological and non-pharmacological( radiotherapy, surgery, psychological techniques) strategies. 38
While most of these symptoms can be managed by GPs and haematologists, there are certain warning signs that should prompt a referral to specialist pain services— including increasing pain, opioid intolerance, additional psychological stresses or existential problems, or opioid-induced hyperalgesia. 36
References
Available on request from howtotreat @ adg. com. au
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