Treatment Options for Progressive Multiple Myeloma

Overview

When you learn that your multiple myeloma treatment did not work or that the cancer has relapsed after going into remission, it is a challenging period. Progressive multiple myeloma can definitely make you feel uncertain of your future. You are likely to feel scared, angry, or even confused by this diagnosis. It is perfectly normal to feel these emotions, but just because you have been given a verdict of progressive multiple myeloma, it does not mean that you will not be able to achieve remission again.

While there is no cure for multiple myeloma, it is possible to continue to live for a long time with the cancer while you control and manage your symptoms.

Here are some treatment options that help manage the disease and prolong your life span.

Treatment for Progressive Multiple Myeloma

Treatment for Progressive Multiple Myeloma

Some of the major therapies for progressive multiple myeloma include:

Immunomodulatory Drugs

Also known as biological therapies, immunomodulatory medications are designed to activate your immune system and help it fight back against the cancer cells. These drugs are also known to work as anti-angiogenic. Angiogenesis is the process of generating new blood vessels in the body. These drugs are also going to improve the microenvironment of the bone marrow as well. Bone marrow microenvironment is the place where the myeloma cells live.(1)

The exact manner in which these immunomodulating agents work on the immune system is not entirely clear, but there are three major immunomodulating drugs that are used in the treatment of multiple myeloma.

The three major immunomodulatory drugs used to treat multiple myeloma include:

  1. Thalidomide (brand name: Thalomid)
  2. Lenalidomide (brand name: Revlimid)
  3. Pomalidomide (brand name: Pomalyst)

Thalidomide was the first of these agents to be developed, but it caused severe birth defects when it was taken during pregnancy. The problem is that the other immunomodulating drugs are also related to thalidomide, and due to this, there is a concern that these drugs may also cause severe congenital disabilities. This is the reason why all of the three immunomodulating drugs can only be gotten through a special program that is run by the pharmaceutical companies that manufacture them.

These drugs are also known to significantly increase the risk of developing blood clots, and this is why they are usually prescribed along with a blood thinner or aspirin.
Let us take a closer look at these three drugs:(2)

Thalidomide: The medicine is available under the brand name Thalomid, and it was first used decades ago for the treatment of morning sickness in pregnant women. It was found that Thalomid caused severe birth defects, after which it was withdrawn from the market. A couple of years later, it again became available as a treatment for multiple myeloma. Some of the common side effects of thalidomide can include fatigue, drowsiness, painful nerve damage known as neuropathy, and severe constipation.

The neuropathy caused can be quite severe, and it is not necessary that this goes away after the medication is stopped. There is also a higher risk of developing serious blood clots that begins in the leg and can also travel to the lungs.(3)

Lenalidomide: This is available under the brand name Revlimid and is quite similar to thalidomide. The drug works well in the treatment of multiple myeloma. There are many side effects associated with this drug as well, the most common ones being thrombocytopenia (a condition characterized by low platelets in the blood), and low white blood cell counts. Revlimid can also cause painful nerve damage, similar to Thalidomide. The risk of developing blood clots is not as high as it is with thalidomide, but there is still some risk attached. In patients who have been in remission from their myeloma after undergoing initial treatment or a stem cell transplant, Revlimid can be prescribed for maintenance therapy to prolong the period of remission.(4)

Pomalidomide: Available under the brand name Pomalyst, pomalidomide is also related to thalidomide and is successfully in the treatment of multiple myeloma. Some of the common side effects associated with this drug include low red blood cell counts (anemia) as well as low white blood cell counts. There is a small risk of nerve damage with this drug as compared to the other two immunomodulating agents, but there is a higher risk of developing blood clots.

Protease Inhibitors

Protease inhibitors are a class of antiretroviral drugs. Protease inhibitors are part of targeted therapy as they hone in on specific abnormalities that are present in the multiple myeloma cancer cells.(5) These abnormalities allow the cancer to thrive, survive. The drugs prevent them from growing and thriving. Protease inhibitors ultimately cause the myeloma cells to die off eventually.

Some examples of these drugs include:

  • Bortezomib (brand name: Velcade)
  • Carfilzomib (brand name: Kyprolis)

Protease inhibitors are sometimes also administered after a chemotherapy session, but in low doses to ensure that no new tumors grow back again.

Velcade is usually the one that is mostly prescribed. It can be injected under the surface of the skin or directly into a vein. Kyprolis is administered through an IV, and another drug called ixazomib (brand name: Ninlaro) is taken in a pill form.

Chemotherapy

Chemotherapy is one of the most well-known and also the standard treatment for cancer. Chemotherapy works by seeking out and then destroying the cancer cells that are present in your body. The cancer-fighting drugs go into your bloodstream and reach all the parts of the body. Chemotherapy is usually a good choice for destroying myeloma cells, and you are likely to get the therapy as either an injection in your veins or you can even take it in pill form.

Doctors may use chemotherapy as the primary treatment, or you might even have it before you have stem cell transplant. You may also get it after a transplant for reducing the likelihood of the cancer cells to grow back.(6)

In advanced myeloma, chemotherapy is typically used for easing your pain and controlling the symptoms.

The commonly used chemotherapy drugs for treating multiple myeloma include:

  • Melphalan (brand name: Alkeran)
  • Cyclophosphamide (brand name: Cytoxan)

These two drugs have been around for many years, and they work by sticking to a cancer cell’s DNA, thus preventing it from spreading any further. Both of these medications can be taken intravenously, but it has been observed that when taken in pill form, they tend to cause fewer side effects. It is necessary to take these drugs on an empty stomach as this ensures that the right amount of the medication gets into your blood.

There are also some other chemotherapy drugs for the treatment of multiple myeloma. These include:

  • Vincristine (brand name: Oncovin)
  • Bendamustine (brand name: Treanda)
  • Panobinostat (brand name: Farydak)
  • Doxorubicin (brand name: Adriamycin)
  • Etoposode (brand names: Toposar and Etophophos)

Another drug known as liposomal doxorubicin (brand name: Doxil) is also prescribed for multiple myeloma and administered intravenously to patients, but this is not as commonly prescribed as the other drugs discussed above.

Sometimes, chemotherapy is also used in combination with other medications or therapies, for example, a round of chemotherapy might be accompanied by a prescription of low dose protease inhibitors to prevent the growth of any new tumors.(7)

The important factor to consider before undergoing chemotherapy is that while the chemo drugs successfully kill the cancer cells, but they can also damage normal cells, and they also have a lot of side effects. These side effects of chemotherapy typically depend on which type of drugs you have been prescribed and also for how long you have been taken them for. Some of the common side effects of chemotherapy include:

Most of these side effects are temporary and tend to disappear after the treatment is completed.

Corticosteroids

Corticosteroids are drugs that are used for boosting and regulating the immune system. They also help control inflammation. These medications have shown decent promise as a treatment for progressive multiple myeloma. The most common corticosteroids include dexamethasone (brand name: Decadron) and prednisone (brand name: Deltasone).(8)

Corticosteroids can be used either alone as a standalone treatment or in combination with other drugs as part of your overall treatment plan. Corticosteroids are also helpful in decreasing nausea and vomiting that might be caused by chemotherapy.

However, this is not to say that corticosteroids do not have side effects. Some of the common side effects of corticosteroids include:

  • Trouble sleeping
  • High blood sugar
  • Increased weight gain and appetite
  • Sudden changes in mood, with some people becoming ‘hyper’ or irritable

When corticosteroids are used for an extended period of time, they can end up suppressing the immune system, thus increasing the risk of developing some severe infections. These drugs are also known to weaken your bones.

You will notice that most of the side effects tend to go away on there over time once the treatment is stopped.

Corticosteroids such as dexamethasone are helpful in the treatment of myeloma because they are able to stop white blood cells from traveling to other areas where the cancer cells are already causing damage. This reduces the amount of inflammation in those areas and also alleviates the pain and pressure in that area.(9)

If prescribed in high doses, dexamethasone can also successfully kill the myeloma cancer cells. When the drug is combined with other myeloma drugs, it can also increase the efficiency of those drugs, making them work even better.

Some of the other agents that are frequently used with dexamethasone include chemotherapy drugs such as doxorubicin, vincristine (brand name: Oncovin), and some immunomodulators as well.

It has been observed in some cases that dexamethasone and some other corticosteroids prove to be the most effective single agent for treating multiple myeloma, but only when prescribed in high doses. However, the risk of side effects of the drug at such high doses is also double.

Histone Deacetylase (HDAC) Inhibitors

HDAC inhibitors are yet another group of drugs that are helpful in multiple myeloma. These drugs affect the genes that are active or turned on inside the cells. These medications interact with the proteins present within the chromosomes known as histones.

The most common HDAC inhibitor is panobinostat (brand name: Farydak). This is used for treating patients who have already undergone treatment with bortezomib and any immunomodulating drug. It is available in the form of a capsule and needs to be taken three times a week for a period of two weeks, and then a week off. This cycle is then repeated once again.

Some of the side effects of HDAC inhibitors include severe diarrhea, fatigue, nausea and vomiting, loss of appetite, weakness, swelling in the legs or arms, and fever.
Farydak can also affect your blood cell counts and also the level of some minerals in the bloodstream, including sodium, potassium, and calcium.

Some of the less, but still serious, side effects of Farydak can include internal bleeding, liver damage, and changes in your heart rhythm. Any such change in the heart rhythm can prove to be life-threatening.(10)

Monoclonal Antibodies

Antibodies are proteins that are manufactured naturally by your body’s immune system for fighting off infections. Monoclonal antibodies are man-made versions of these antibodies that are designed for attacking a specific target, including the proteins present on the surface of myeloma cancer cells.

The commonly used monoclonal antibody for the treatment of multiple myeloma is daratumumab (brand name: Darzalex). This drug attaches to the CD38 protein,(11) which is generally found on the myeloma cancer cells. The drug is believed to kill cancer cells directly and also boosts the immune system so that the body attacks them naturally as well. This drug is typically used in combination with other types of cancer drugs, although it can also be used as a standalone medication in patients who have earlier already undergone many different treatments for their myeloma. The drug is administered as an infusion into a vein.

The drug Darzalex is known to cause a reaction in some people either while it is being administered or within a few hours after being given. The side effects that occur within a few hours after administration usually tend to be severe. Some of the symptoms of a severe side effect can include:

Other side effects of this drug can include:

  • Nausea and vomiting
  • Fatigue
  • Back pain
  • Fever
  • Cough

The drug is also known to lower blood cell counts, increasing the risk of bruising/bleeding and infections.

Another monoclonal antibody that is used for treating multiple myeloma is Elotuzumab (brand name: Empliciti). This drug attaches to the SLAMF7 protein present on the myeloma cancer cells. It is believed that this drug helps the immune system attack the myeloma cancer cells. Empliciti is primarily prescribed to patients who have already undergone other treatments for myeloma, and it is administered as an infusion straight into the vein.(12)

Empliciti can cause an adverse reaction in some people, and the symptoms can include:

  • Chills
  • Fever
  • Feeling dizzy or lightheaded
  • Wheezing
  • Trouble breathing
  • Rashes all over the body
  • Runny or stuffy nose
  • Tightness in the throat
  • Shortness of breath

Other commonly observed side effects of this drug include:

  • Fever
  • Loss of appetite
  • Fatigue
  • Severe diarrhea or constipation
  • Cough
  • Nerve damage that leads to numbness/weakness in the hands and feet
  • Upper respiratory tract infections
  • Pneumonia

Stem Cell Transplant

One of the more advanced treatments for multiple myeloma, a stem cell transplant involves giving high-dose chemotherapy for killing off the cells in the bone marrow. The patient then receives new and healthy blood-forming stem cells. During the initial years following the development of stem cell transplants, these new stem cells were derived from the bone marrow, due to which the process was earlier known as bone marrow transplant. With the advent of technology, now these stem cells are collected from the blood itself and is sometimes also known as a peripheral blood stem cell transplant.

Stem cell transplant is a fairly common treatment for multiple myeloma. Before the transplant procedure takes place, drug treatment is used for reducing the number of myeloma cancer cells present in the patient’s body.(13)

There are two types of stem cell transplants (SCT) – autologous or allogeneic.

Autologous Stem Cell Transplant

During an autologous stem cell transplant, doctors use the patient’s own stem cells. The stem cells are removed from the patient’s bone marrow or from peripheral blood before the transplant process. These cells are then stored until they are required for the transplant. After this, the patient with myeloma gets treated with high-dose chemotherapy or other treatments, sometimes with radiation therapy as well, in an attempt to kill off the cancer cells. Once this procedure is completed, the stored stem cells are then given back to the patient into their bloodstream through a vein.(14)

An autologous stem cell transplant is considered to be the standard treatment for patients who have multiple myeloma. Although this type of transplant can make the cancer go away for some time (even years), but it does not actually cure the cancer, and patients often find the myeloma returning.

Some doctors also recommend that patients who have multiple myeloma undergo two autologous transplants, at least 6 to 12 months apart.(15) This approach to autologous transplant is known as tandem transplant.(16)

Studies have shown that tandem transplant may prove to be more beneficial for some patients rather than a single transplant. The disadvantage of tandem transplant is that is causes more severe side effects, and due to this, it is considered to be a riskier procedure.

Allogeneic Stem Cell Transplant

In this type of stem cell transplant, the patient is given blood-forming stem cells from a donor. The best treatment results are observed when the donor’s cells are closely matched to the patient’s cell type. Preferably the donor should be related to the patients, such as a sibling.

Allogeneic transplants are known to be a risky procedure as compared to autologous transplants, but they are better at fighting the myeloma. This is because the donor or transplanted stem cells are more likely to destroy the myeloma cells. This is known as a graft versus tumor effect.(16)

In studies undertaken of multiple myeloma patients, those who underwent allogeneic transplants were observed to get worse in the short term than the patients who got autologous stem cell transplants. At present, allogeneic stem cell transplants are not considered to be the standard treatment for multiple myeloma, but they might be undertaken as part of a clinical trial.(17)(18)

Side Effects of Stem Cell Transplant

Like any other treatment procedure, stem cell transplant also has its share of side effects. The early side effects from a stem cell transplant are very much similar to those experienced from radiation therapy and chemotherapy, except that these are much more severe. One of the most severe side effects of stem cell transplant is low blood counts, which can drastically increase the risk of developing severe infections and internal bleeding.

The most serious side effect from allogeneic stem cell transplants is known as graft versus host disease, or GVHD. This condition occurs when the new immune cells taken from the donor consider the patient’s tissues to be foreign and start attacking them. It is possible for GVHD to affect any part of the body, and the condition can prove to be life-threatening.(19)

Radiation Therapy

Radiation therapy is another treatment option available for progressive multiple myeloma. This procedure makes use of high-energy rays to kill off the cancer cells. Radiation is typically used for treating areas of bone that has been damaged by myeloma and have not responded to other medications or chemotherapy. These affected areas are also causing pain or are near breaking. Radiation is also the most commonly used treatment for solitary plasmacytomas.(20) Solitary plasmacytomas is a rare condition that is very similar to multiple myeloma, except instead of having myeloma cells present in the bone marrow, people who have solitary plasmacytomas have tumors composed of plasma cells growing on a single restricted part of the body. Usually, these tumors grow in a bone, but they can also grow on an organ.

If your doctor concludes that the myeloma has severely weakened the bones in your back or the vertebral bones, and these can collapse putting pressure on the spinal nerves and spinal cord, then prompt treatment with radiation treatment and/or surgery is needed to prevent long-term complications such as paralysis. Some of the symptoms that indicate this condition include sudden weakness in leg muscles, a sudden change in sensation, including the onset of tingling or numbness, or having an unexpected problem with urination or bowel movements. This condition should be considered to be a medical emergency, and you should seek immediate medical assistance.(21)

The type of radiation therapy that is usually used for treating multiple myeloma or even solitary plasmacytoma is known as external beam radiation therapy. This type of radiation therapy is directed at the cancer cells from a machine from outside the body.

Undergoing radiation therapy is very much similar to having a diagnostic x-ray, except that each treatment session lasts longer, and the course of the treatment tends to continue for many weeks.

Some of the commonly observed side effects of radiation therapy include:

  • Nausea and vomiting
  • Fatigue
  • Diarrhea
  • Low blood counts

Skin changes in the area being treated, which can range from redness to blistering as well as peeling of the skin

These symptoms are known to improve once the treatment has been stopped.

Conclusion

Once you have been diagnosed with multiple myeloma, you will be seeing a full team of doctors, including an oncologist. An oncologist is a doctor who specializes in the treatment of cancer. Your health care team will help you navigate you through all the possibilities, information, and realities related to your disease. Together with your doctor, you will find a treatment plan that maintains an aggressive approach towards treating the cancer while also managing the symptoms.

References:  

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  2. Zhu, Y.X., Kortuem, K.M. and Stewart, A.K., 2013. Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma. Leukemia & lymphoma, 54(4), pp.683-687.
  3. Singhal, S., Mehta, J., Desikan, R., Ayers, D., Roberson, P., Eddlemon, P., Munshi, N., Anaissie, E., Wilson, C., Dhodapkar, M. and Zeldis, J., 1999. Antitumor activity of thalidomide in refractory multiple myeloma. New England Journal of Medicine, 341(21), pp.1565-1571.
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  8. The Myeloma Crowd. (2019). How Corticosteroids (Like Dexamethasone) Work to Fight Myeloma – The Myeloma Crowd. [online] Available at: https://www.myelomacrowd.org/myeloma-101-dex/ [Accessed 30 Aug. 2019].
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  19. Clinicaltrials.gov. (2019). Allogeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma – Full Text View – ClinicalTrials.gov. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT01453101 [Accessed 30 Aug. 2019].
  20. Komanduri, K.V., Couriel, D. and Champlin, R.E., 2006. Graft-versus-host disease after allogeneic stem cell transplantation: evolving concepts and novel therapies including photopheresis. Biology of Blood and Marrow Transplantation, 12(1), pp.1-6.
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