Immunotherapy and Targeted Therapy in Multiple Myeloma Treatment

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What is the current treatment strategy for the management of Multiple Myeloma (MM)?

Multiple myeloma (MM) is an aggressive cancer type with comparatively high mortality rate even with modern treatment modality. The selection of treatment for MM depends on many factors like the stage, risk stratification (i.e., high- or standard-risk disease), patient’s kidney function, age, and presence of comorbidities.

Stem cell transplantation (SCT) is the only curative treatment currently available for MM. Thus, almost all patients with MM are assessed to determine eligibility for autologous/allogeneic SCT. The patients who are found eligible for SCT are generally treated with initial induction therapy consisting of 3 or 2 drugs for three to four months. Induction therapy not only helps in achieving a low level of cancerous cells in the bone marrow and peripheral blood but also helps in mitigating the disease symptoms and end-organ damage. After induction therapy, patients may undergo autologous SCT or continue the same therapy followed by maintenance therapy (usually with lenalidomide) until relapse. For patients who cannot undergo SCT, treatment with a triplet regimen (usually include a corticosteroid, an immunomodulatory drug, and a targeted drug) or doublet regimen (for frail patients) followed by lenalidomide-based maintenance therapy is generally recommended.

The selection of second-line treatment generally depends on the risk stratification, initial treatments received, and the duration of response with initial treatment.

What is the role of Immunomodulatory Drugs in the treatment of MM?

The immunomodulatory drugs are believed to modify the function of the body’s immune system that identifies and kills the cancer cells. The exact mechanism of action for these drugs is unclear. These drugs are generally associated with an increased risk of blood clots; thus, prophylactic treatment with anticoagulant drugs is generally recommended. These drugs can cause birth defects if consumed by pregnant women and thus are contraindicated in pregnant and nursing women.

Following three drugs comes under this category:

Thalidomide: It was the first immunomodulatory drug introduced in ‘60s for treating morning sickness in pregnant women. The drug was removed from the market due to its tendency to cause birth defects in the newborns. Later, the drug was reintroduced for treating multiple myeloma. In combination with dexamethasone (a corticosteroid), it is indicated for the treatment of patients with newly diagnosed MM. The addition of bortezomib significantly improved treatment response and is generally recommended for young patients or those who are otherwise healthy. Side effects of thalidomide include fatigue, constipation, skin problems, drowsiness, serious blood clots, and nerve damage (neuropathy) that can be severe.

Lenalidomide: It is an analog of thalidomide, which has improved efficacy and safety than thalidomide. In combination with dexamethasone and bortezomib, it is considered the preferred treatment option for the treatment of patients with newly diagnosed MM who are eligible/non-eligible for SCT. In the case of frail patients, it can be given only with dexamethasone. As a single agent, it is considered the preferred maintenance treatment in patients who have responded to initial treatment. In combination with dexamethasone and any of the drug among carfilzomib, ixazomib, daratumumab, and elotuzumab, it is considered the preferred treatment option for patients with relapsed/refractory MM.

Lenalidomide should be used cautiously for patients with renal impairment because it is mainly excreted via the kidneys. It has less tendency (compared to thalidomide) for causing neuropathy but has a similar tendency for blood clotting.

Side effects associated with lenalidomide include diarrhea, fatigue, constipation, low level of certain white blood cells (neutropenia), platelets (thrombocytopenia), and red blood cells (anemia), nerve damage, dizziness, decreased appetite, and blood clots.

Pomalidomide: It is another analog of thalidomide that has more efficacy than the parent compound to treat relapsed/refractory MM. It is approved by the US Food and Drug Administration (FDA) for the treatment of patients with MM who have received at least two prior lines of therapy, including bortezomib and lenalidomide, and have progressed on or within 60 days of the last therapy completion. In combination with dexamethasone, it has shown significant efficacy for the treatment of patients with relapsed/refractory disease. The addition of cyclophosphamide, daratumumab, or bortezomib further increases the response rates.

The drug is considered safe for patients with moderate to severe renal impairment. Side effects associated with the drug include fatigue, neutropenia, anemia, thrombocytopenia, blood clots, constipation, nausea, diarrhea, back pain, fever, breathlessness, and increased incidence of infections. The severity of neuropathy is lower compared to other immunomodulatory drugs.

What is the role of proteasome inhibitors in the treatment of MM?

Proteasome inhibitors work by inhibiting an enzyme complex called proteasome that brings about the degradation of abnormal proteins and thus plays an important role in controlling cell division. The myeloma cells make a lot of abnormal proteins that get accumulated due to proteasome inhibition and lead to the death of myeloma cells. These drugs have become an integral part of MM treatment strategy since their introduction.

Bortezomib: it was the first proteasome inhibitor approved for the treatment of MM. Effective as a single agent and in combination with other drugs. In combination with dexamethasone and lenalidomide, it is considered the preferred treatment option for the treatment of patients with newly diagnosed or relapsed/refractory MM. In the case of frail patients, it can be given only with dexamethasone. Daratumumab, panobinostat, and liposomal doxorubicin are other drugs that can be added to bortezomib + dexamethasone regimen to constitute other preferred treatment options for the relapsed/refractory disease. As a single agent, it can also be employed as maintenance therapy for patients who have achieved a response to initial treatment containing bortezomib, especially in the case of high-risk disease.

Bortezomib is specifically helpful in the treatment of patients with MM who have compromised kidney function. To reduce the severity of nerve damage, the subcutaneous route is the preferred over the intravenous route for the administration of bortezomib.

Side effects of the drug include nausea, vomiting, decreased appetite, fatigue, diarrhea, constipation, fever, skin problems, neutropenia, thrombocytopenia, and neuropathy. Some patients may develop shingles (herpes zoster) while on treatment with this drug and may require prophylactic antiviral treatment.

Carfilzomib: It is a second-generation proteasome inhibitor that selectively and irreversibly inhibits the proteasome function. It confers better response rate than bortezomib. It is approved by the US FDA for the treatment of patients with MM have received at least 2 prior lines of treatment including bortezomib and an immunomodulatory agent and who have progressed on or within 60 days of the last therapy completion. The addition of lenalidomide to carfilzomib + dexamethasone regimen further improves the response rate and is considered the preferred treatment option for otherwise healthy MM patients.

Side effects of the drug include fatigue, nausea, vomiting, diarrhea, shortness of breath, fever, and low blood counts. It may also cause reactivation of shingles or hepatitis. Carfilzomib has a lower tendency to cause neuropathy but may cause heart failure, liver/kidney failure, severe bleeding, and hypertension in some patients. Some cases of severe heart and lung toxicity, especially in elderly patients, have also been reported.

Ixazomib: It is another proteasome inhibitor that can be given orally. In combination with lenalidomide and dexamethasone, it is recommended for the treatment of patients with MM who have received at least 1 prior therapy or patients with newly diagnosed MM.

Side effects of the drug include nausea, vomiting, diarrhea, constipation, swelling in the hands or feet, back pain, nerve damage, and a lowered blood platelet count. As with other proteasome inhibitors, prophylactic treatment with antiviral drugs is recommended for patients receiving ixazomib.

When is Panobinostat recommended for the treatment of MM?

Panobinostat is a histone deacetylase (HDAC) inhibitor that, in combination with dexamethasone and bortezomib, has been approved by the US FDA for the treatment of patients with MM who have received at least 2 prior lines of therapies, including bortezomib and an immunomodulatory drug.

Side effects include severe diarrhea, fatigue, nausea, vomiting, loss of appetite, swelling in the arms or legs, fever, low blood cell counts, and abnormal blood levels of certain minerals (such as potassium, sodium, and calcium). Some cases of serious cardiac ischemic events and changes in heart rhythm have been reported with the drug.

What are different monoclonal antibodies used for the treatment of MM?

Following 2 monoclonal antibodies are currently approved for the treatment of MM:

Daratumumab: It is a monoclonal antibody that targets CD38 protein commonly found on myeloma cells and rarely on normal lymphoid and myeloid cells. This drug act by directly killing the myeloma cells or stimulating the immune system to attack and kill myeloma cells.

It is approved:

1) in combination with bortezomib, melphalan, and prednisone for the treatment of patients with newly diagnosed MM who are not candidate for SCT;

2) in combination with dexamethasone and lenalidomide or bortezomib for the treatment of patients with MM who have received at least 1 prior therapy;

3) in combination with dexamethasone and pomalidomide for the treatment of patients with MM who have received at least 2 prior lines of therapies including lenalidomide and a proteasome inhibitor; and

4) as a single agent treatment for patients with MM who have received at least 3 prior lines of therapies including a proteasome inhibitor and an immunomodulatory drug.

Adverse effects of the drug include infusion reactions, neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, nerve damage, and upper respiratory tract infection. This drug may cause infusion-related reactions and interference with red blood cells cross-matching in some patients.

Elotuzumab: It is a monoclonal antibody that targets SLAMF7 protein commonly found on myeloma cells and natural killer cells. It is approved in combination with dexamethasone and lenalidomide for the treatment of patients with MM who have received 1 to 3 prior lines of therapies. It is also approved in combination with dexamethasone and pomalidomide or bortezomib for the treatment of patients with MM who have received at least 2 prior lines of therapies including lenalidomide and a proteasome inhibitor.

Side effects associated with the drug include fatigue, loss of appetite, diarrhea, constipation, cough, nerve damage, upper respiratory tract infections, fever, and pneumonia. This drug may cause infusion-related reactions, severe infection, liver toxicity, and secondary cancers in some patients.

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