Treatment of Multiple Myeloma

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What is Multiple Myeloma?

The myeloma is a disorder in which plasma cells (developed from B-Cells, which secretes antibodies or immunoglobulins in response to a specific antigen) become abnormal (cancerous) and start dividing without control. The abnormal plasma cells get crowded in the red bone marrow causing a reduction in the number of RBCs and WBCs and destruction of the bone tissue along with the bone marrow tissue. The overall incidence of myeloma has been increasing slightly during the last decade, while the mortality rate has been decreasing during the same period. Clinically multiple myeloma is defined as the presence of following abnormalities:

  • Abnormal/Clonal plasma cells in bone marrow >/=10%
  • Presence of serum or urinary M proteins (an abnormal protein secreted by abnormal plasma cells instead of functional antibodies secreted by normal plasma cells) also known as myeloma protein or monoclonal protein (except in patients with non-secretory multiple myeloma)
  • Indication of end-organ damage such as hypercalcemia (serum calcium >/=11.5 mg/dL), renal insufficiency (serum creatinine >2 mg/dL or creatinine clearance <40 mL/min), anemia (low count of RBCs or hemoglobin <10 g/dL), and bone lesions attributable to the plasma cell disorder.

What are the other Plasma Cell Disorders?

Following are some disorders that arise from uncontrolled proliferation of plasma cells, and thus, these are closely related to multiple myeloma:

  • Solitary Plasmacytoma: It involves single bone lesion with the presence of abnormal plasma cells but the absence of any symptoms and end-organ damage. In case a single lesion is detected in soft tissue the condition is termed as an extramedullary plasmacytoma. M protein may be present in some cases with absence of any end-organ damage indication.
  • Monoclonal gammopathy of undetermined significance (MGUS): MGUS is an asymptomatic benign condition with abnormal plasma cells in bone marrow (<10%) and M protein is present in serum (<3 g/dL) but indications of end-organ damage are absent. It is postulated that virtually all cases of myeloma arise from MGUS. However, all cases of MGUS do not ultimately progress to multiple myeloma. MGUS do not require a treatment but patients with MGUS are followed-up closely for progression of the condition to multiple myeloma or any other aggressive disease.
  • Smoldering multiple myeloma: It is an asymptomatic pre-malignant condition characterized by the abnormal plasma cells in bone marrow (>/=10%) and presence of M protein in serum (>/=3 g/dL) but the absence of any indication of end-organ damage.
  • Light chain amyloidosis: Similar to secretion of antibodies by normal plasma cells. Abnormal plasma cells secrete M protein with a heavy and a light chain. Sometimes, the abnormal plasma cells secrete more light chain than the heavy chain. These light chain proteins can build-up in different organs and known as amyloid. This amyloid deposition in different organs may cause their enlargement and/or organ dysfunction. The most commonly affected organs by amyloidosis are the heart, kidneys, and peripheral nerves.

Risk Factors for Multiple Myeloma

Exposure to radiation

exposure to radiation History of radiation exposure is the most potent risk factor for the development of multiple myeloma. Even an exposure to low level of radiation also carries an increased risk of developing multiple myeloma.

Industrial/Occupational exposure

environmental exposure to certain chemicals Regular exposure to heavy metals like nickel, or harmful gases/fumes, especially benzene and petroleum products has been indicated to increase the risk of multiple myeloma.

Family history

family history of myeloma Higher incidences of multiple myeloma are observed in individuals with a history of multiple myeloma in close relatives.

Plasma cell disorders

People with certain plasma cells disorders, for example, MGUS are considered to be at higher risk of disease progression to multiple myeloma. Thus, such individuals should be followed-up closely.

Race

Incidence of multiple myeloma is twice as common as in African Americans than in Caucasians.

Age and gender

Myeloma is more common at an older age with highest incidences observed in individuals aged between 65 and 74 years. Multiple myeloma is more common among higher age individuals and among males compared to youngsters and females, respectively.

Signs and Symptoms

  1. Pain in the affected bone.
  2. Osteolytic bone lesion or fracture in the affected bone.
  3. Fatigue and weakness attributable to anemia, other anemia-related symptoms may include shortness of breath and dizziness.
  4. Recurrent infections like pneumonia due to low WBC count (leukopenia).
  5. Increased bleeding tendency due to low platelet count (thrombocytopenia).
  6. Unexplained weight loss.
  7. High blood level of calcium (hypercalcemia) that may lead to several symptoms like increased thirst and urination, dehydration, abdominal pain, severe constipation, loss of appetite, weakness, drowsiness, and kidney problems leading to kidney failure.
  8. Spinal cord compression due to multiple myeloma affecting the spine, which may cause severe pain in the back, leg’s muscle weakness and numbness in legs.
  9. Neuropathic pain due to nerve damage.
  10. Increased blood viscosity due to the presence of abnormal M protein in high concentration. This may impair the kidney function leading to kidney failure.

Investigations for Diagnosis and Staging

Blood Tests

blood tests for multiple myeloma Blood tests can provide very important information that provides direction to the diagnostic workup of multiple myeloma and help in selecting an appropriate treatment approach. Following are the commonly employed blood test for the diagnosis of the multiple myeloma.

Complete blood cells count (CBC)

This test provides information on the level of RBCs, WBCs, and platelets. In most cases of Multiple myeloma, low level of these formed elements is observed.

Serum protein electrophoresis (SPEP)

In this test, the type of M protein is determined in serum. About 70% of patients with multiple myeloma have elevated levels of monoclonal IgG, about 20% have IgA, and about 1% to 2% have no detectable M protein (non-secretory multiple myeloma). Immunofixation is another test which helps in determining the class of heavy and light chain constituting the M protein.

Serum free light-chain (FLC) assay

In this test, the level of FLCs of M protein, that is kappa (k) and lambda (l), is estimated. These light chains are not firmly bound to intact (whole) M protein. This test is very useful in some cases like light-chain only disease, non-secretory myeloma, renal disease, and amyloidosis.

Beta-2 microglobulin (b2M)

b2M is a protein expressed on the surface of abnormal myeloma cells and it keeps shedding into the blood. High level of b2M indicate worse prognosis and decreased renal function. Apart from above blood tests, few blood analyses like the level of creatinine, blood urea nitrogen (BUN), calcium, albumin, C-reactive protein, lactate dehydrogenase (LDH), and erythrocyte sedimentation rate (ESR) tests may also be employed.

Bone Marrow Aspiration and Biopsy

bone marrow aspiration and biopsy Biopsy samples contain a tiny piece of tissue collected from the bone with the help of a biopsy needle. The biopsy sample is then tested in a laboratory and can provide very useful information about the myeloma cells such as percentage of plasma cells, clonality of plasma cells, and the presence of specific defective genes or proteins.

Following are various techniques used for collecting this information:

Flow cytometry

In this technique, the biopsy sample is first treated with some fluorescent antibodies that get attached to certain specific proteins (antigens) on the surface of cells. The treated sample is then analyzed using a laser beam and a detector attached to a computer. This test can detect different types of cells in the biopsy sample along with the quantification of each type of cells.

Cytogenetic Testing

In this technique, chromosomes are evaluated for certain defects which are very common in multiple myeloma. The sample cells are first grown into the culture medium and are observed under a microscope after adding certain reagents that bind only to a specific portion of a chromosome. This test enables detection of chromosomal abnormalities like translocation, amplification, or deletion. The presence of certain chromosomal abnormalities is linked to the poor prognosis of the disease, for example, deletion: 17p13, translocations: t(4;14), t(14;16), and chromosome 1 amplification.

Fluorescent in situ hybridization (FISH)

In this technique, a fluorescent RNA probe is used which binds to a specific portion of a chromosome in the sample cells. Then, the sample can be examined under a microscope to determine the presence of certain chromosomal abnormalities like translocation, addition, or deletion. This technique is very sensitive, fast, and accurate. Thus, this technique is preferably used for detecting chromosomal abnormalities.  

Imaging Tests

These tests help in scanning larger body area to diagnose the extent of involvement of bones. Alternatively, these tests are employed after treatment to evaluate the treatment efficacy and to detect any signs of disease progression/recurrence.

Radiographic Examination

This is usually the first imaging test which is employed when a multiple myeloma (or any other bone abnormality) is suspected.  This test can provide information on the bone lesion compared to the nearby bone on x-ray film. Any abnormality observed during this test warrant detailed investigations to establish the diagnosis of multiple myeloma.

Computed tomography (CT) scan

In this technique, detailed cross-sectional images of body organs are generated using x-rays. This technique can also be utilized for scanning the complete body instead of simple radiography. This technique can sometimes be used to guide a biopsy needle to collect biopsy samples from the affected bone or soft tissue.

Magnetic resonance imaging (MRI) scan

Whole body MRI is sometimes recommended for the diagnosis of any bone lesions in the skeletal system, which might be missed on plain radiography. This technique can be used when detailed imaging is required, for example in case of spinal cord compression.

Positron emission tomography (PET) scan

This technique is considered sensitive to diagnose multiple myeloma and to assess response to treatment. This technique can also be combined with CT scan (PET/CT) to accurately diagnose the extent of disease in distant body parts and soft tissue involvement.

Urine Tests

urine electrophoresis Similar to blood tests, some urine tests are also commonly employed in the diagnostic work-up of multiple myeloma. The most commonly employed urine tests include a 24-hour urine protein electrophoresis and immunofixation for the determination of M protein excreted in the urine. This can help in excluding/detecting non-secretory myeloma. These tests can also reveal renal damage, especially presence of glomerular versus tubular lesions. It can also be used for response assessment after starting treatment.

Revised International Staging System (RISS) for Myeloma

It is the most commonly used system for staging multiple myeloma.

Following table describes the characteristics of multiple myeloma according to different RISS stages:

Stage I

Serum beta-2 microglobulin <3.5 mg/L; Serum albumin level >/=3.5 g/dL; Absence of high-risk cytogenetic abnormalities; and Serum LDH level </= Upper limit of normal

Stage II

Neither Stage I nor Stage III

Stage III

Serum beta-2 microglobulin >/=5.5 mg/L; and Either Presence of high-risk cytogenetic abnormalities; or Serum LDH level > Upper limit of normal

Role of Targeted Therapy in Multiple Myeloma Treatment

targeted therapy for multiple myeloma

Proteasome Inhibitors

Proteasome inhibitors work by inhibiting an enzyme complex called proteasome that brings about the degradation of abnormal proteins and thus palys 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

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 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 nerve damage. Some patients may develop shingles (herpes zoster) while on treatment with this drug and may require prophylactic antiviral treatment.

Carfilzomib

carfilzomib It is a second-generation proteasome inhibitor that selectively and irreversibly inhibits the proteasome function. It confers better response rate than bortezomib but survival benefit is not yet verified.

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

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.

Monoclonal Antibodies

Daratumumab

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

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.

Histone Deacetylase (HDAC) Inhibitors

Panobinostat

It 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.

Role of Immunomodulator Drugs in Multiple Myeloma Treatment

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. 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

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 is not suitable 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. The most common 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

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 nerve damage is lower compared to other immunomodulatory drugs.

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