Myeloma FAQ

So, we've been working on this class of drugs [JAK inhibitors] now for about 5 or 6 years, both in our research laboratory and clinically. And we've uncovered a series of mechanisms that suggests that these drugs are going to be very active, probably not only in myeloma, which we've now shown, but in lots of other cancers as well. And what we've uncovered is that these drugs actually enhance the immune response to the cancer, also help overcome resistance by blunting down proteins that lead to resistance in other drugs in myeloma like Revlimid, or lenalidomide.

So, we began work in the clinic early on, like 5 years ago, by using these drugs to treat highly, heavily previously treated patients with myeloma. And those patients were then given lenalidomide, ruxolitinib, and a steroid called methylprednisolone.

And what we learned is we had very high responsesopens in a new tab or window; about half the patients responded to some degree. And in that process, we also learned those patients were resistant to the lenalidomide. So, the rux [ruxolitinib] helped overcome that. So, then we decided to do the next step, we used a drug without lenalidomide. Let's see if it works without it. And it did, and we published that workopens in a new tab or window. But in that process, we decided: can we resurrect responses by adding the lenalidomide back to people who fail ruxolitinib and methylprednisolone? These are all pills. They're well tolerated. And we did, and we got very long remissions with simply the use of these pills.

How does it actually work to stimulate the immune system? Well, believe it or not, it knocks out the checkpoint inhibitor proteins, just like those drugs that are on TV every night like pembro [pembrolizumab] (Keytruda), all those drugs. This does the same thing, but it's just a pill. And by knocking out the checkpoint inhibitor proteins, the immune responses are enhanced. And we've shown that T-cell responses indeed are enhanced, in the test tube anyway. When you put ruxolitinib on the myeloma bone marrow, boy, the killing is markedly enhanced with T-cell effects from the enhancement from rux. It's really good.

And so, this is now leading us to use these drugs with all sorts of other drugs that have been used effectively to treat myeloma. We're trying to start a series of new trials, and we're about to start one in the next few weeks with a drug that's been used for myeloma called selinexor [Xpovio]. And hopefully we'll be able to start that soon.

We also have been able to identify a predictor for whether you're going to respond or not. It's serum B-cell maturation antigen, which is becoming more and more widely used to monitor myeloma, but it also could be used to predict whether you're going to respond to treatments. And it looks like it does that in the face of ruxolitinib in myeloma. So, we're excited, the future looks bright for these drugs in myeloma.

Symptoms of Myeloma may include:

• Back pain
• Bone pain
• Fatigue
• Weakness
• Shortness of breath
• Susceptible to infections
• Anemia
• Nausea
• Inability to urinate
• Heart rhythm disturbances

If myeloma is suspected, a variety of lab tests may be run, including:

• Bone tests
• Kidney tests
• Blood tests
• Platelet tests
• Antibody tests
• X-rays

Multiple myeloma is a bone marrow-based cancer of a type of white blood cell called a plasma cell. The job of a plasma cell is to make antibodies. What happens in myeloma is unfortunately billions of these cancer cells take over the bone marrow and prevent it from functioning properly.

This impairs the production of blood cells, including red blood cells, white blood cells and platelets:

1. Red Blood Cells: When you don’t make red blood cells, you become anemic, and you can become tired and short of breath.
2. White Blood Cells: If you cannot make white blood cells, you lose the ability to fight off infections.
3. Platelets: When you don’t make platelets, you can bleed. Most commonly, you don’t make red blood cells; and, thus, are anemic. Less often, you have low white blood counts and platelets.

Normally, each healthy plasma cell makes one type of antibody, and we normally have many plasma cells making lots of different types of antibodies. This allows you to make all kinds of antibodies that will help you fend off the many viruses and bacteria from causing infections. However, in myeloma, the malignant plasma cells are all of one type and lots of this protein ends up circulating in the blood. Unfortunately, certain types of these “circulating myeloma-produced antibodies” can clog up the kidneys and cause them to fail to function.

Because the bone marrow resides next to the bone, the myeloma-infested bone marrow often can wreak havoc on the bones. What does that mean? Bone loss! And when you lose bone, you are at high risk of developing fractures. You can also have bone pain. So, patients may present with fractures and bone pain. Also, loss of bone may lead to high calcium levels which can have a major negative impact on kidney function, produce serious heart rhythm disturbances, and impaired function of your brain.

In addition, patients may develop infections because they don’t make any other antibody than the one type that is produced by the malignant myeloma cell. All of these other antibodies are necessary to fight infections caused by all kinds of viruses and bacteria.

In addition, patients can also have low blood cell counts. So, myeloma is most often identified because routine laboratories may show either a low red blood cell count, i.e., anemia, or a high total protein count from all of the monoclonal (one type) antibody in their blood.

In terms of symptoms, back pain or bone pain is often present, and then X-rays are performed. Often, the patient is found to have holes in the bones, so-called lytic lesions, or fractures which is suggestive that they have multiple myeloma.

Other complaints may be fatigue or tiredness from low blood counts or the myeloma itself which can produce substances which make you tired. You may also come in with bone pain or fractures. Sometimes, patients present with kidney failure and the symptoms of that also may be fatigue or nausea, vomiting or inability to have any urine output, which in that case means it is very severe.

How does the doctor actually make the diagnosis of myeloma or, in fact, rule it out? There are a series of tests that are done in order to establish the diagnosis and determine its severity.

Tests that can be used to diagnose Multiple Myeloma:

1. First, the blood test and urine tests are done to determine whether the patient is anemic, if the kidneys are not functioning normally, and if the calcium level is increased. When bone loss is severe, calcium levels can get very high in the blood. In addition, doctors measure the levels of protein of the myeloma-related protein, the monoclonal antibody which is also called the M-protein, in the blood and urine. Certain levels help doctors make the diagnosis.
2. Recently, we have used a test called the “serum free light chain assay” that can measure a part of the antibody in the blood. These tests together help establish whether the patient has a monoclonal antibody. Determining the amount helps determine whether it is enough to call it “myeloma” or its premalignant version which is called monoclonal gammopathy of undetermined significance or “MGUS.”
3. A bone marrow examination in which a small amount of bone marrow is removed from the lower back or upper hip, the iliac bone in the lower back, determines whether abnormal plasma cells are present. The percentage of plasma cells in the marrow will help determine whether the patient has MGUS or myeloma. If 10% or more of the cells are plasma cells, then the patient has multiple myeloma.
4. In addition, further testing is done on the bone marrow to determine whether the abnormal plasma cells show “chromosomal or genetic abnormalities“ which can help tell us the relative severity of the disease. These results may be helpful in making decisions about how much treatment is necessary to control the myeloma effectively, and what specific drugs may work better for your type of myeloma.
5. Last but not least, X-rays are performed to look for holes in the bone, lytic lesions, which may have resulted from too much bone loss, and fractures. Additional imaging is often done through MRIs or PET CT scans which are able to identify lesions more precisely and sensitively, and whether those holes or lesions in the bones may lead to problems that would require surgical intervention or radiation therapy.

So, the next question the myeloma patient has is “Do I need treatment?”

Many patients with myeloma need very little treatment as this disease can progress very slowly. While the patient’s myeloma requires no treatment, we are continuing to make many discoveries with new drugs that we can hopefully have available in the clinic by the time the patient would need to undergo treatment with these drugs for their myeloma.

One must be careful not to “over treat” a disease that unfortunately remains incurable in the vast majority of patients today. So, the decision to treat is the first one.

Treating MGUS:

It turns out that most individuals with a monoclonal antibody or M-protein in their blood and/or urine don’t have myeloma. They, in fact, have a disorder called “MGUS” or “monoclonal gammopathy of an undetermined significance” in which the amount of abnormal protein is lower and the percentage of plasma cells in the bone marrow is lower- < 10%.

They also don’t have evidence of low blood counts or anemia. They don’t have significant bone disease (fractures or holes in their bones), high calcium levelsin the blood, or kidney disease. Those patients can generally be watched and do not require treatment.

Although, if they have evidence of bone loss such as osteopenia or osteoporosis, they may require treatment with drugs to strengthen their bone such as bisphosphonates including zoledronic acid or an antibody treatment called denosumab.

Treating Smoldering Myeloma:

Next, there is a group of patients who have what we call “smoldering myeloma.” This group represents about 10 to 15 percent of newly diagnosed myeloma patients. They meet the diagnostic criteria for myeloma because they have at least 10 percent monoclonal plasma cells in their bone marrow.

They do have myeloma, but they don’t have any clinical manifestations of the disease to make it necessary for them to need treatment.

Smoldering Myeloma patients don’t have:

• High calcium levels in the blood
• Kidney failure
• Low red blood cell counts or anemia.
• Fractures or lots of holes in their bones.

They also don’t feel poorly from what may be the myeloma-related effects of the disease. In fact, they’re living a life that has not been impacted by the disease.

Those patients generally may benefit simply from treatment with bone strengtheners like bisphosphonates or denosumab if they have evidence of bone loss without many lytic lesions but do not require any other therapy.

Treating Multiple Myeloma:

However, most patients with myeloma come in with one of the signs or symptoms that shows that they need treatment.

They feel poorly and they may also have bone pain associated with holes in their bones or a fracture related to their myeloma. Sometimes, the calcium levels are elevated which may lead to serious problems if left untreated. Patients may be weak and feel tired. They may have kidney failure and low blood counts that may also be making them feel weak and tired.

Patients with any of these problems require treatment. Therapy can take on many variations depending on the patient’s specific type of myeloma, other medical problems, work, and lifestyle.

So now that the doctors have decided that you need treatment for your multiple myeloma, how do they decide what treatment should be given?

The choice of a specific treatment will be based on 2 main factors:

1. The characteristics of the disease. One of those that is very important, of course, are the characteristics of the disease.
   • Blood & Plasma cells: Is the bone marrow very involved with a lot of plasma cells resulting in anemia or other low blood counts? Are there cells in the blood that are of the myeloma type? When the plasma cells are in the blood and have gotten outside the bone marrow, so-called “plasma cell leukemia,” that is a very serious form of myeloma which requires more intensive treatment.
   • Bones: How involved are the bones? Are there just a few small holes in the skull which may not be serious? Or are there lots of holes throughout the skeleton and fractures? Does the patient have bone pain as well as fractures from the bone loss?
   • Genetic Abnormalities: What are the genetic abnormalities in the cancer cells? They may suggest this is a poor risk patient that may require more aggressive treatment. Notably, we also now have drugs today that can target myeloma with specific genetic abnormalities.
   • Kidneys: What is your kidney function?
   • Lifestyle: What is your lifestyle and work style? Are you a very active person? Are you running marathons or are you bedridden from the effects of myeloma and were very active just a few months ago?
   • Other Medical Conditions: We also want to know what your other medical conditions are. Maybe you already have kidney disease from diabetes or high blood pressure? Maybe you have heart failure? These can impact the choices that the doctor will make to treat your multiple myeloma.
2. Previous Treatments. If you have been previously treated, doctors also want to know what treatments you have received before. They specifically want to know how well they worked and how they were tolerated.
   • Did the drugs cause side effects?
   • Did you feel poorly on it?
   • Were you nauseated?
   • Did you have to stay at home because you were so “wiped out” from the treatment?
   • Was it lowering your blood counts which caused delays in further treatment?
   • Was it affecting your liver or kidney function?

All of these should be considered in terms of how doctors decide on your regimen. Treatment choices have become more complicated thanks to the great increase in therapeutic options available today compared to just a few years ago when the choices were so limited.

So, what are the treatment options today for myeloma patients? There are so many more options than just a few years ago.

1. Chemotherapy
2. Steroids
3. More recently, we have immunomodulatory drugs (IMiDs), such as:
   • Thalidomide
   • Lenalidomide or Revlimid
   • Pomalidomide or Pomalyst, is now available for treating myeloma patients who have failed other therapies including other IMiDs.
4. We also have available three drugs with similar mechanisms of action called proteasome inhibitors (PIs):
   • First, we had Velcade or bortezomib which became available in the early 2000’s.
   • More recently, a second drug in this class has become available called carfilzomib or Kyprolis.
   • A third drug in this drug class that can be taken by mouth, orally, called ixazomib, is now used for treating MM patients.
5. In addition, we now have several immune-based therapies that are available.
   • Monoclonal antibodies target the myeloma.
   • Bispecific antibodies target the myeloma and bring immune cells called T-cells to the myeloma tumor cells so that it more effectively attacks the myeloma.
   • Also, immune type cellular therapy with T- lymphocytes which are altered to be able to target the myeloma cell are also now being used to treat myeloma patients.
   • Drugs including selinexor or Xpovio that prevent substances from getting out of the nucleus are also being used effectively to treat myeloma; these drugs are especially effective when used in combination with other agents.
   • Venetoclax or Venclexta is a pill that is highly effective in a subset of myeloma patients whose cancer cells show a specific genetic abnormality.

There are lots of other agents now in development, including novel antibodies and other targets that we will discuss in more detail as we address specific drug classes and options.

A key point we’ve learned over the last few years is that progressing or not being responsive to one drug does not mean that the same drug will not work when combined with another agent that’s shown effectiveness for treating myeloma patients. We’ve learned that with the PIs.

For example, when the PI Velcade is used and fails to work with a drug like cyclophosphamide or Cytoxan, then the patient may respond when Velcade is combined with other drugs known to be active for myeloma such as pegylated liposomal doxorubicin (Doxil) and steroids.

The same is also true with IMiDs including thalidomide, Revlimid and Pomalyst. What we have learned more recently that even drugs in the same class that the patient has failed can produce responses when another drug from the same class is used. For example, Velcade failures with an alkylating agent Cytoxan may respond to another alkylating agent called bendamustine when combined with Velcade.

Even more startling is that patients failing one immunomodulatory agent such as Revlimid in combination may show responses when the same combination is used with simply substitution of another drug in that class such as Pomalyst or thalidomide. Similarly, we have shown that patients failing the PI Velcade often respond to the same combination when Velcade is replaced with another drug in the same class specifically carfilzomib or Kyprolis.

In the past, it was believed that patients who had class resistance- i.e., patients failing drugs in the same class would be unlikely to respond when it was used in a new combination.

Clearly, this is not the case for myeloma patients as demonstrated now in many recently completed clinical studies as discussed above. Thus, the number of treatment choices for myeloma patients today is so much greater than even a few years ago not only because of the increasing number of drugs but also the ability to combine these agents more effectively.

Let’s talk about specific drug classes starting with the oldest agents known as chemotherapy. Some specific drug classes are effective in myeloma, including the alkylating agents and anthracyclines.

• Alkylating Agents. The oldest drugs are the alkylating agents, including melphalan or Alkeran, cyclophosphamide or Cytoxan, and bendamustine or Treanda or Bendeka. These drugs are not particularly active alone but when used in combination with some other agents we will describe below are very active. Partner drugs for alkylating agents include steroids, IMiDs, PIs, and monoclonal antibodies.

  These drugs when used at lower doses have very few side effects and uncommonly lower blood counts. Occasionally, nausea can occur, but these drugs are generally very well tolerated when given for a few days every month. They can be quite effective for a long period of time.

  However, only when combined with other agents and classes of drugs used to treat myeloma today do they show significant clinical benefits for myeloma patients. Sometimes, patients may develop leukemia from being treated with these drugs but most often that is following their use at very high doses as part of the stem cell transplant procedure.

• Anthracyclines. The other major chemotherapy class of drugs used to treat myeloma today is an anthracycline.

  The oldest drug in this class was doxorubicin but in the last few years a newer and safer version has been developed which is a chemically modified form of doxorubicin known as pegylated liposomal doxorubicin called Doxil or Lipodox. It’s like having the drug in a fat globule. Using this form, it can be given safely and is very effective for treating myeloma patients.

  When given alone, it has limited clinical activity but when combined with steroids and especially PIs such as Velcade or Kyprolis, it’s quite active. Also, the same is true when these drugs are given with IMiDs especially Revlimid and more recently Pomalyst.

  Possible Side Effects:

  When Doxil or Lipodox is administered in the standard way as an infusion once every three or four weeks, these drugs can cause significant side effects in terms of causing mucositis so that the inside of the mouth can hurt and blister, and lead to red-hot hands and feet that can also blister especially on the palms and the bottoms of your feet. This can be quite troubling for patients.

  We now know that these side effects can be greatly reduced and pretty much eliminated when we simply give the drug at lower doses more often--twice weekly for two weeks per month or simply once weekly.

  The other side effect that may occur after long term treatment with anthracyclines is heart failure. The drugs are now given for a limited length of time to avoid development of this cumulative dose-related complication.

  However, it is important for patients to have their heart function checked with heart tests called an echocardiogram or MUGA scan before they begin this type of treatment.

One of the most active drugs to treat myeloma today remains a steroid. These are not the same steroids that Barry Bonds used; these are the steroids that, in fact, are commonly used to calm down inflammation.

These are called glucocorticosteroids. They are also known as corticosteroids, drugs such as prednisone, methylprednisolone or Medrol, and dexamethasone or Decadron. These can be given orally or intravenously to treat myeloma patients.

We know that steroids directly can kill the myeloma cells but equally important they can make the “soil that it grows in, the bone marrow, less hospitable for the myeloma to grow.” It’s no longer fertile but instead barren soil and the myeloma cells die! As a result, the patient responds and feels better.

So, steroids remain an excellent drug choice for myeloma patients today. Also, they are very inexpensive and easily and effectively combined with all of the other active drugs used to treat myeloma such as chemotherapy agents, PIs, IMiDs, and monoclonal antibodies. They are, in fact, among the most active drugs to treat myeloma and they are certainly by far the cheapest. The problem is that their dosing and schedules can have a major impact on their tolerability and even different ones can have marked differences in potency and side effects.

Even if they are an old drug, steroids really do work especially when used in combination with other drugs. These drugs are also used to reduce the occurrence and severity of infusion reactions that commonly occur when patients are treated with the first dose of a variety of immune-based therapies including antibodies.

We have learned that when you combine these drugs with other types of agents, you can use much lower doses effectively without all of the side effects that we used to see before we had the opportunity to combine these drugs with all of the new types of drugs to treat myeloma patients. Because of their anti-inflammatory effects, these drugs can also help reduce bone pain.

Possible Side Effects:

Patients may also develop cataracts after long-term usage. Some patients don’t like being on steroids. However, it turns out the dose and type of drug and schedule is especially important in terms of a patient’s ability to stay on these drugs with minimal negative effects.

In our own practice, we believe that when being treated with dexamethasone through intravenous administration rather than orally causes fewer side effects such as less inability to sleep, so-called insomnia, decreased hyperactivity, and reduced negative effects on mood.

We also believe that when given in a pill form that the steroid methylprednisolone or Medrol seems to be better tolerated particularly when given at lower doses every other day than dexamethasone at much higher doses administered once weekly.

Studies done recently showed that the amounts of steroids that we used to treat myeloma until recently were too much. These led to poor outcomes for patients because of the many side effects that patients experienced. Many patients discontinued the treatment with a negative impact on their treatment responses and overall outcomes.

Steroids also can also lead to more infections, blood clots, increased blood sugar or worse control of diabetes mellitus, fluid retention, increased appetite, weight gain, and muscle weakness.

The results of a randomized trial showed us that “less” was, in fact, “more” as patients were able to remain on their treatment resulting in improved outcomes at, in fact, lower doses of steroids. With lower doses and differences in doses (lower), types and routes of administration, patients can live happier and more fulfilling lives while on these drugs.

Another class of drugs commonly used to treat myeloma today are proteasome inhibitors (PIs). We call these drugs chemosensitizers. They make the other drugs work just that much better including the chemotherapy drugs, immunomodulatory agents, some of the immune-based therapies, and steroids. These drugs, in fact, make other drugs to treat myeloma much more effective.

Benefits:

We know they both directly eliminate myeloma cells and also make the bone marrow in which myeloma cells grow less hospitable to support the myeloma!

They have a multitude of different ways in which they accomplish these goals, but essentially, they shut down a system which is kind of like the garbage disposal in the cell which eliminates all of the toxic proteins in the cell. When the garbage disposal is closed for business by the PI, toxic proteins accumulate, and those proteins lead to the death of the myeloma cell. The good news is that myeloma cells are much more sensitive to the impact of blocking the proteasome than other types of cells in the body.

These drugs were first used to treat late-stage myeloma in which the patient had failed many other therapies but are now used often as part of the first treatment for myeloma. Their activity is much better when they are combined with steroids, chemotherapy, IMiDs, and more recently immune-based therapies such as some of the monoclonal antibodies.

1. Bortezomib or Velcade

   The first was bortezomib or Velcade two decades ago. Velcade has been demonstrated to be a highly effective drug which has been shown to certainly improve the quality and the length of myeloma patients’ lives today.

2. Carfilzomib or Kyprolis

   In 2012, a second PI was FDA-approved called carfilzomib or Kyprolis. This drug too is quite effective to treat myeloma and in the same class as Velcade. It has a similar mechanism of action, but it turns out the newer drug can overcome resistance to Velcade. Thus, it is a great option for patients who have failed Velcade.

   It also causes less neuropathy than Velcade; and, therefore, it is a good option for patients who have Velcade-induced neuropathy.

   Like Velcade, it is much more effective when combined with steroids, chemotherapy, or the immunomodulatory agents such as thalidomide, Revlimid, or Pomalyst. It also is highly effective when combined with monoclonal antibodies that target CD38 (see below).

   Notably, a small percentage of patients may develop worsening high blood pressure or heart failure while receiving Kyprolis. Thus, careful attention to symptoms related to heart failure such as new chest pain, shortness of breath or a new cough and should be mentioned to the healthcare professional.

3. Ixazomib or Ninlaro

   Recently, a third PI, ixazomib or Ninlaro, has been FDA-approved for treatment of patients who have received other therapies. It is a pill which makes it convenient but appears to be less active than the other two FDA-approved PIs. It is less likely to overcome resistance to patients who are failing the other PIs. Sometimes it can cause gastrointestinal problems. Its role as a convenient and long-term maintenance treatment for myeloma patients who have responded to treatment with a PI is being studied.

   Possible Side Effects:

   Today, it is uncommon that they’re used without one or several of these other drugs. The PIs can cause some side effects, most common of which is the development of peripheral neuropathy, which is manifest as numbness, tingling, and burning pain in the hands and feet and sometimes weakness in the arms and legs.

   These effects can be reduced if the drugs are given at lower doses using longer cycles and, in the case of Velcade, if the drug is given subcutaneously instead of intravenously. These three adjustments result in much less neuropathy; and, as a result, patients may remain on the drugs for longer periods of time. Often, this side effect can improve or even go away with these maneuvers. We’ve learned particularly when the drugs are combined with other agents, these lower doses and longer cycles can still allow these drugs to be quite effective with less side effects.

   The drugs can also increase your likelihood to develop the viral infection shingles, a serious skin infection, so we recommend that patients be given low doses of antiviral drugs, including acyclovir, Valtrex, or Famvir to reduce the chances of this occurring. If patients are treated with Velcade especially in combination with other drugs, it can also lead to reductions in blood counts, so it is important to carefully monitor the blood counts of patients who are receiving this treatment.

Another class of drugs that is highly effective for treating myeloma are the immunomodulatory agents. These are administered as pills.

Types of IMiDs:

1. First, thalidomide was used 20 years ago.
2. More recently lenalidomide or Revlimid was introduced.
3. Pomalidomide or Pomalyst is the most recently developed drug which has become available in the last few years.

How do IMiDs work?

• These drugs are called immunomodulatory agents because they help boost the immune system and take away the part of the immune system that suppresses it from eliminating myeloma.
• They reduce blood vessels that feed the myeloma.
• They can kill myeloma directly.
• They “make the neighborhood in which the myeloma cells grow less hospitable” for the cancer cells to increase.

Although somewhat active as single agents, their effectiveness is greatly boosted when they are combined with steroids. They also are more effective when combined with Velcade and Kyprolis as well as other chemotherapeutic agents.

More recently, they have been shown to have enhanced anti-myeloma effects when they are combined with a variety of monoclonal antibody treatments. The other good news is when they are combined, their doses can be reduced; and, as a result, they can have less side effects.

Possible Side Effects:

• The major side effect of thalidomide is peripheral neuropathy which manifests as numbness, tingling, and sometimes burning pain. Unfortunately, in contrast to Velcade-induced peripheral neuropathy, these effects are often irreversible.
• All of these drugs can also cause constipation but also diarrhea after long term use. The latter adverse event can often be improved with the use of bile acid binding agents such as cholestyramine.
• The drugs certainly can increase the risk of blood clots especially when combined with steroids and some types of chemotherapy including Doxil or doxorubicin.
• Also, rashes can occur early in the treatment but often resolve quickly after a short break in their usage.
• The drugs are very active and can be given for a long period of time but there seems to be small risk of secondary cancers especially skin cancers and more rarely some types of leukemia. The risk of secondary cancers is more often observed among those who receive these drugs who have also been previously treated with an alkylating agent such as melphalan. Their ability to lengthen lives in myeloma patients far outstrips their low risk of the patient developing another type of cancer.
• Side effects of these drugs may also include tiredness as well as inability to think clearly. But lowering the dose certainly helps overcome those effects, and when these drugs are given in the evening that can help as well.

Other Considerations:

Since the drugs are cleared in the kidney, patients may require a reduction in the dose if they have reduced kidney function. We know that’s true with both Revlimid and Pomalyst. Importantly, the drugs certainly can be given safely and be effective for patients with poor kidney function but should be administered at lower doses for those individuals.

The drugs also increase the risk of blood clots especially when combined with steroids. In terms of reducing the risk of blood clots, patients should take a baby aspirin daily in order to help prevent this problem from occurring. Patients with a prior history of blood clots or other risk factors for clots may need to take other stronger medications that reduce clots such as Eliquis, Pradaxa or Xarelto to prevent these types of complications.

Overall, IMiDs are a highly active class of drugs and even more effective when combined with the other classes of drugs used to treat myeloma including chemotherapy, steroids, PIs, and monoclonal antibodies.

Recently, a variety of immune-based therapies have been shown to be highly effective for treating myeloma patients. The types of treatment and their target proteins vary but they all show encouraging effectiveness although their side effects differ.

First, monoclonal antibodies that target surface proteins highly expressed on myeloma cells made their way into the clinic. Specifically, both CD38 and SLAMF7 serve as targets for these antibodies. These proteins are highly expressed on the outside of myeloma cells, but on few other types of cells in the patient. This “targeting” of the treatment with these monoclonal antibodies to the tumor cell without impacting other types of cells makes these drugs ideal.

They elicit an immune response that results in the elimination of myeloma cells. The antibodies have also been shown to boost immune responses in quite different ways. Treatments targeting CD38, daratumumab (Darzalex or Faspro) and isatuximab (Sarclisa), rid the bone marrow of cells that turn off the immune response unleashing an enhanced way for the bone marrow to be rid of myeloma cells. The antibody targeting SLAMF7, elotuzumab (Empliciti), turns on a type of white cell called a natural killer cell that can bolster the immune response in its attempt to kill the tumor cells.

Elotuzumab or Empliciti with dexamethasone has been reported to be only active when combined with either the IMiD Revlimid or Pomalyst. However, this drug may also be active in some patients when the two drugs are used without these IMiDs. Without the IMiD, this combination is much better tolerated with few side effects. However, this monoclonal antibody is much more effective when it is used in combination with an IMiD. The drug is administered intravenously. Empliciti has minimal side effects with a small minority of patients experiencing what are termed infusion related reactions consisting of flu-like symptoms during the first infusion which are rarely of any significance.

Both the CD38-targeting monoclonal antibodies daratumumab and isatuximab have shown activity for treating myeloma in many clinical settings.

Daratumumab may be administered either intravenously (Darzalex) or subcutaneously (Faspro) whereas isatuximab (Sarclisa) is only given intravenously. Both antibodies are active when combined with oral dexamethasone. Sarclisa improves the effectiveness of other myeloma drugs including Pomalyst and Kyprolis. Daratumumab has shown to increase the effectiveness of many other anti-myeloma drugs, including not only Pomalyst and Kyprolis but also Revlimid and Velcade.

Moreover, this latter anti CD38 monoclonal antibody has been shown to improve outcomes for patients in not only the previously treated setting but also for patients who have received no prior treatment when it is combined with dexamethasone and Revlimid, and also when Velcade is added to those two drugs. These antibodies are associated with higher rates of infusion reactions than Empliciti, but these usually only occur during the first infusion and uncommonly prevent ongoing administration of these treatments.

When used in combination with PIs or especially IMiDs, the antibodies show increased side effects especially low blood counts that may be associated with high rates of infection from low white blood cell counts and reduced normal protective antibody levels. In some cases, severe bleeding may occur in association with low platelet counts. Thus, patients’ blood counts need to be carefully monitored when receiving these antibodies and patients must be watched carefully for signs and symptoms of infection or bleeding.

Also, all of these drugs can complicate the interpretation of the tests used to monitor myeloma patients since they are monoclonal antibodies and can be seen as small M proteins when protein electrophoresis is performed that are not really coming from the myeloma tumor cells. In addition, blood typing can be more difficult among patients receiving either daratumumab or Sarclisa making transfusion of blood a harder task to accomplish.

More recently, the antibodies have been made in such a way that they not only target the myeloma cells but the immune cells as well which are known as “T-cells.” This so-called bispecific antibody brings the tumor cell next to the killer T-cell making it more convenient and effective as an immune treatment. Teclistamab targets B-cell maturation antigen (BCMA) which is present on only myeloma cells and CD3 which is on the T-cells. This treatment has shown effectiveness in heavily previously treated patients.

Possible Side Effects:

However, since BCMA is also present on normal plasma cells that produce antibodies that fend off infections, many patients develop severe, life threatening infections. Also, the immune response that occurs during treatment may become uncontrolled and lead to side effects known as cytokine release syndrome (CRS) early in the treatment that can be quite troublesome. These may sometimes be controlled with antibodies that target interleukin 6 such as tocilizumab.

Also, significant neurologic side effects may also develop in some patients. As a result, these side effects have led to the requirement for administration of these treatments initially to be done in the hospital.

The use of T-cells that target myeloma have led to the use of these treatments for late-stage myeloma. The treatments are called “CAR T-cells” and also target BCMA and include a construct in the cell that turns on the T-cell so that can elicit a strong immune response to eliminate the myeloma cells. Both Ide-cel and CARVYKTI are now used in the clinic. It takes a number of weeks to manufacture these types of T cells during which the patient’s myeloma must be controlled. These treatments can be quite effective but are also fraught with similar complications (CRS and neurologic) that have been observed with the bispecific antibodies. Thus, the treatments require administration and observation in a hospital setting. The availability of this treatment modality has been limited by manufacturing capabilities but hopefully that will improve soon.

So, what’s happening in myeloma today in terms of new agents? There is an explosion of new drugs that are now used to treat myeloma and ones in development.

• Selinexor or Xpovio is one of the new drugs that has become recently available. It is a pill that is taken weekly. The drug is in a new class of drugs that blocks proteins from getting out of the nucleus and into the rest of the cell called the cytoplasm. By keeping these proteins in the nucleus, myeloma cells cannot survive. Selinexor works with steroids, but its effectiveness is much improved when these two drugs are combined with other agents such as the PI Velcade. Promising results with other combinations have also been shown.
• Venetoclax or Venclexta is a pill that is taken daily and has been widely used to treat certain types of leukemia and lymphoma. It targets a cancer gene called Bcl-2. It turns out that about 20% of myeloma patients show a genetic abnormality known as an 11;14 translocation in which parts of these two chromosomes combine in an abnormal way. These patients’ myeloma tumor cells are very sensitive to treatment with this drug, and they show high response rates when treated with this drug alone. In the subgroup of patients with this genetic abnormality, venetoclax has also been effectively combined with other active myeloma drugs, including anti CD38 antibodies such as daratumumab and Sarclisa as well as PIs including Velcade and Kyprolis.
• There are so many other new agents in development. Antibodies targeting other proteins are being studied. Antibodies that are combined with drugs are also in early development.
• These new treatments can deliver the drug only to the cancer cell because only the cancer cell expresses the target of the antibody. Thus, the antibody binds the cancer cell with the drug attached. The drug can be released and get right into the cancer cell; and, furthermore, it also helps immune cells in the neighborhood of the tumor to be more effective to eliminate the myeloma cells without causing off target effects on other healthy cells in the body.
• Thus, we can potentially deliver therapy that is truly tumor-specific and leave the rest of the patient alone. Other targets for use as CAR T-cells are also in development.
• We also are finding ways to target other proteins on the surface of myeloma tumor cells and identifying other key pathways within the myeloma cell that may be blocked. These include the PI3 kinase inhibitors as well as the histone deacetylase inhibitors. These latter drugs do not seem particularly active alone, but they may help other drugs to work more effectively such as the PIs and IMiDs.
• Recently, a class of drugs called JAK inhibitors that are currently used to effectively treat auto immune diseases, skin disorders and certain blood diseases, have recently been shown to be effective for some heavily previously treated myeloma patients and can overcome resistance for patients who have failed IMiDs.

All of these new types of drugs are works in progress presently and we hope over the next few years we learn how to use these agents so we can attack the myeloma cell and leave the rest of the body alone. We also hope to determine how to use these drugs with other drugs that have already been effective to improve outcomes for myeloma patients.

So how do we know if the treatment is working or not working? Well, we cannot directly measure the amount of the tumor cells themselves because they are spread throughout the bone marrow, so we are unable to accurately measure their amount there.

So, instead we measure the product of the tumor cells which is the monoclonal antibody marker. Most patients have it in their blood but some patients (around 15%) have the protein as only part of the antibody known as the light chain (see below) which may be in the blood and urine.

Thus, the doctors will monitor your disease using several tests to measure the levels of these proteins to determine whether the treatment is working or not.

• They will watch for changes in the monoclonal protein levels in the blood and urine using a technique called protein electrophoresis which separates proteins in the blood and urine based on their size and charge.
• Another way to measure those same protein levels is by determining the amount of the type of antibody in the blood that makes up the monoclonal antibody – e.g., IgG levels if the patient has IgG myeloma, IgA levels if the patient has IgA myeloma, etc.
• A newer test to evaluate the monoclonal antibody measures only part of it called the light chains. Antibodies are made of two pairs of light and heavy chains. Light chains are often made in excess in the myeloma cells; and, thus, cannot pair with heavy chains. Sometimes, all of the patient’s myeloma tumor cells make only light chains. In either case, these so called “free” light chains can be measured in the blood. Changes in these levels correlate with changes in the amount of myeloma in the patient. Light chains can be kappa or lambda so that for each patient’s myeloma tumor cell, only one type of this chain is produced. Thus, one can track the myeloma through changes in these levels as well as determining the differences between the involved type and the other type of light chain - e.g., the difference between the lambda level for a lambda-producing myeloma and the levels of kappa. Also, sometimes the ratio between these two types of light chains is used to assess the patient’s disease.

When measuring the reduction in monoclonal protein levels, there are 3 different degrees of a response:

• Minimal Response: For example, if it’s 25% - 49% below where it was when you started a new treatment, it’s called a minimal response.
• Very Good Partial Response: Fifty to 89% is a partial response and greater than or equal to 90% but not all gone is considered a very good partial response.
• Complete Response: If the protein markers completely disappear, that is considered a complete response, but this must be confirmed with examination of the bone marrow (see below).

The urine tests used to determine responses are used a little differently to designate different types of response. A 24-hour urine collection is required.

• Minimal Response: At least a 50% but less than 90% reduction in the monoclonal protein level is considered a minimal response
• Partial Response: More than 90% but some protein remains is a partial response.

Most patients respond to their first treatment, and many achieve a complete response so that the monoclonal protein cannot be identified. However, the achievement of a complete response does not mean the patient is cured. It certainly can come back over time.

A new blood marker is also gaining interest called serum B-cell maturation antigen (sBCMA). This protein is found at high levels on the surface of myeloma tumor cells. It is shed into the blood and can be used to predict outcomes for myeloma patients and monitor their course of disease. sBCMA can also be used to predict the risk of MGUS or smoldering multiple myeloma to develop active myeloma requiring treatment. Since it is a different protein than the monoclonal antibody, this biomarker can also be used to track the disease course of those patients with nonsecretory myeloma who do not produce a conventional monoclonal antibody marker. It also appears that sBCMA can more quickly determine when a patient’s disease is worsening than conventional markers which will allow patients who are failing their current treatment to change to another therapy more quickly. This blood test is still considered a research tool.

Bone marrow examination can be used to assess the status of the myeloma. Because of the differences in the amount of marrow involvement, i.e., percentage of myeloma tumor cells, throughout the bone marrow, it is not often used to follow patients for routine monitoring. Its use is usually limited to patients showing low blood counts in which this evaluation may help differentiate whether this is from myeloma involvement or overtreatment with drugs. It is also used to confirm the absence of myeloma cells for patients whose monoclonal protein becomes undetectable and free light chain levels become normal. However, the differences throughout the bone marrow in myeloma cell involvement that occurs in most patients as mentioned above, limits its ability to truly define absence of myeloma cells in a patient.

Recently, development of more sensitive assays to determine whether minimal residual disease is present in the bone marrow have gained interest. These assays are much more sensitive to detect small amounts of myeloma in the bone marrow. They may rely on genetic- or flow-based assays of whole cells derived from bone marrow samples. The usefulness of these tests is limited by the marked differences in marrow involvement with myeloma in different parts of the marrow compartment and the specificity of these tests in identifying true myeloma tumor cells. Overall, these tests show that patients with so-called minimal residual disease negativity have improved outcomes.

Other ways to determine the status of the myeloma are to track changes in the kidney function although this may be problematic because there may be other causes for impaired function of the kidney that are unrelated to myeloma. Blood counts can be monitored and worsening of these may also often be from other causes. For example, treatments can lower the blood counts. Anemia may also be caused by low iron or B12 levels that have nothing to do with myeloma.

Certainly, radiologic imaging can be useful to find changes in the patient’s clinical status. However, routine use of these procedures including bone surveys, PET CT scans and MRIs are not recommended. Importantly, these tests may be necessary for cases where new symptoms related to bone disease develop.

The good news is today there are so many options so when it comes back when we say, “Okay, it’s progressing?” If the monoclonal protein marker goes up by 25% or more, we consider that the patient’s disease to be worsening or what we call progressing. In many cases, it is obvious that the treatment is not working even if the marker does not increase by 25%.

It is also important to not only consider whether the treatment is working but whether you are tolerating the treatment. In many cases, reduction in doses or schedule of the drugs can help the patient stay on a treatment that is effective.

“So, if I’m being treated, how long do I have to stay on the treatment?” The data is emerging that maintaining the remission with maintenance therapy is a key part of the treatment plan for your myeloma today.

Early studies we and others performed first showed that steroids were effective and more recently studies with lenalidomide (Revlimid) have shown an improvement in myeloma patient’s survival with their long-term use.

We also use other IMiDs long-term such as Pomalyst and PIs including Velcade, Kyprolis and Ninlaro. The long-term use of these drugs is relatively safe although their effectiveness as maintenance treatments has not been completely established.

The monoclonal antibodies are also gaining use as long-term treatments to control myeloma without signs of showing significant side effects.

When these drugs are used in the maintenance phase of treatment, lower doses are administered using longer dosing intervals. This adds to the convenience for drugs that must be administered in the clinic. However, that does not have to be the case with oral agents such as Revlimid and/or steroids.

Maintaining the remission is a key part of the treatment plan through maintenance therapy. During maintenance therapy, patients’ myeloma labs are generally monitored on a monthly basis to assure that they are continuing to respond without signs of their disease worsening or other side effects developing from the treatment.

If the patients have been on chemotherapy agents, such as anthracyclines, including doxorubicin and Doxil or alkylating agents such as melphalan, cyclophosphamide and bendamustine, these are discontinued when maintenance therapy begins. This avoids the known long-term negative effects of these drugs that may include permanent damage on bone marrow and heart problems for those receiving Doxil or doxorubicin.

You may be asked to participate in a clinical trial; and, thus, want to learn what clinical research is before you even decide that you want to participate.

In general, this involves the testing of drugs that we hope will help many patients, like you, with myeloma. So, we conduct many types of clinical trials to determine whether drugs either are safe or more effective than the presently available agents.

The clinical trials are done in phases ranging from phases 1 to 4.

• Phase 1: In phase 1, we don’t even know if the drug is safe so we’re just trying to evaluate safety and we hope to get a hint regarding whether the drug has clinical benefit for patients.
• Phase 2: In phase 2 trials, now that we know the proper dose that is safe and well tolerated, we evaluate them on more patients to establish more precisely their effectiveness.
• Phase 3: Next, we conduct a phase 3 trial in which we randomize patients to receive either the tried and-true gold standard treatment compared to the new treatment.
• Phase 4: Finally, in phase 4 trials, now that we know that the new treatment is better than the gold standard, other studies are conducted to adjust doses and schedule of the drug(s) and evaluate the treatment for specific types of patients. This helps better define the most effective ways to use the drug(s).

There also may be trials that are called “PK” or “PD trials.” So, what are these types of clinical studies? These are pharmacokinetic (PK) or pharmacodynamic (PD) trials which test not necessarily whether the drugs work but correlate the drug levels with their effectiveness. They also evaluate other measures of outcome that may help better define how they work besides just measuring the conventional ways to assess the status of the patient’s myeloma. All these types of trials help teach us in a way that will ultimately help many patients like yourself.

Is a clinical trial right for you?

For you to decide about whether you want to participate in trials, you have to consider if you want to be part of the extra effort required. Y

You may be asked to:

• Have additional blood draws.
• Come to clinic more often for those blood tests.
• Participate in other extra tests that are part of the trial.

You must weigh that against the possible benefit for you and help you are providing to many other patients like yourself over the long run.

Overall, clinical trials are a great thing to participate in for most patients. After all, treatments used today resulted from participation of many patients in clinical trials in the past. This has led to not only marked improvement in the length of lives for those with myeloma but just as important their quality of life as well.

Now that we’ve learned about what myeloma generally is and how to treat it, let’s discuss the specific clinical manifestations of the disease.

Bone Disease:

The most important and frequent clinical problems are related to bone disease. Patients with myeloma lose increased amounts of bone. That is because the “Pac man” cell in the bone called the “osteoclast” is stimulated by the myeloma tumor cells to actually get rid of bone. Our job is to stop the bone “gobbling up” osteoclast from activating and destroying bone. Fortunately, today we have drugs that help with this called bisphosphonates, and the monthly infusion of either Zometa or Aredia has been shown to dramatically reduce the risk of fractures and spinal cord compression as well as these patients’ requirements for radiation or surgery to bone.

Thus, the use of both radiation and surgery for bone problems related to myeloma has been greatly reduced today because of the effective use of these drugs. These drugs are very potent; they can have a negative impact on the kidney so it’s important that patients have monthly monitoring of the kidney function.

Today, we have another effective option for patients who have kidney problems or develop them from bisphosphonates or other drugs. Denosumab or Xgeva is administered on a monthly basis by subcutaneous injection and has similar benefits in reducing bone-related complications to the bisphosphonates.

Infrequently, patients may have jaw problems from all of these agents resulting often from surgical procedures especially the extraction of teeth or dental implantation procedures. These types of procedures should be avoided among patients receiving these drugs. Thus, maintaining excellent dental health is a key to making sure these drugs not only are effective but in order to reduce the risk of jaw problems that can occur with the use of these drugs.

Not only can we show effectiveness with drugs such as bisphosphonates for treating myeloma bone disease, but we also know that simply vitamin D and calcium can help. It’s important that vitamin D levels be measured in all myeloma patients since many of them are vitamin D deficient. So simply the usual amounts like 800 international units per day may not be sufficient for a myeloma patient who is vitamin D deficient. Frequently, myeloma patients may require increased amounts of vitamin D to achieve levels that are in the normal range.

In addition to medical management using treatments with drugs, vitamins, and calcium, we also may have you seen by an orthopedic or back surgeon. They can help assess your bone disease - do you need surgical intervention, or help from a physical therapist or rehabilitation physician? Remember the oncologists and hematologists are trained in diseases of the bone marrow and not the bone which requires the expert input of an orthopedic or back surgeon.

Staying active is very important, especially weight-bearing exercise which keeps your bones healthy and strong. Without use, more bone loss will occur putting you at higher risk of developing fractures. Overall, keeping your bones healthy and happy over the long run requires an integrative approach not only involving regular exercise and treatment with drugs like bisphosphonates or denosumab or vitamins like vitamin D or minerals like calcium but also often the involvement of an orthopedic or back surgeon, physical therapist, and rehabilitation medicine physician as well. Occasionally, patients may require radiation therapy to relieve bone pain or treat fractures, but this form of treatment is being used less these days with the effective use of bisphosphonates and denosumab and the surgical interventions that are now available through our orthopedic surgical colleagues.

Anemia:

It’s likely that sometime during the course of your myeloma that you will become anemic. So, what is anemia? It means your red blood cell count is low. What does that do to you if your red blood cell count is low? Red blood cells carry oxygen, so if you don’t have enough oxygen, you will feel weak and tired and may become short of breath. We will do everything we can to prevent this from happening. It turns out there may be a lot of reasons why anemia may develop in a myeloma patient. It may be the myeloma itself is causing it, so you are unable to make red blood cells in your bone marrow and they are no longer available to go out into the blood. After all, the red blood cells are made there, and the myeloma tumor cells are lurking there. They may shut off your ability to make red blood cells by producing substances that stop their production. Anemia could also be due to the treatments such as chemotherapy, other myeloma drugs or radiation therapy. It also may be that your kidneys are not working well from myeloma or other causes. Because of this, you are not making the red blood cell growth protein called erythropoietin or EPO which is produced in the kidney. Without EPO, you’re going to become anemic.

How do we monitor for anemia? We simply measure the number of red blood cells in your blood. We measure it using three assessments - amounts of blood levels of hemoglobin, hematocrit, and number of red blood cells. If the count is very low, we’re going to want to either transfuse you or give you some supplements to help improve your red blood cell count. The most effective growth factor we have right now is called EPO itself. This is commonly administered in several forms today, Aranesp, Retacrit or Procrit. All of these can boost the level of red blood cells in the blood. But we have also learned over the last several years many patients with myeloma are iron deficient from causes that have nothing to do with myeloma. In fact, simply giving EPO isn’t enough to improve red blood cell counts in that case. They need iron as well, especially intravenously administered iron. Often, these patients are found to have a source of bleeding, especially in the gastrointestinal tract. Other patients may be vitamin B12 deficient and taking this vitamin may reverse anemia in those cases. Sometimes, patients may have a destructive process causing their anemia called hemolysis. Steroids and antibody treatments can help reverse this process.

If patients have received many transfusions of red blood cells, they may become iron overloaded. This can cause serious problems in the heart, liver, and other major organs. We have drugs to help with that problem including Exjade.

Proper monitoring of your red blood cell counts is key to the long-term success of your myeloma treatment. Recently, there’s concern that the use of EPO for patients with myeloma and other types of cancer is actually speeding up the cancers’ growth and shortening the survival of these patients. There are ongoing studies currently evaluating this. Some have shown that this is the case, and some have not. For that reason, you don’t want to go overboard with the use of EPO drugs like Procrit, Retacrit or Aranesp. Your doctor will work with you to make sure you’re only receiving it when you absolutely need to. We want to make sure that you have proper levels of circulating red blood cells, so that you have good energy levels. We don’t want to overdo it, however. So, make sure your doctors are measuring your hemoglobin level on a regular basis and treating you with either drugs like Procrit or Aranesp or, if necessary, transfusions so you have good energy.

Infections:

Myeloma patients are at higher risk of developing infections because of their impaired immune system. The reasons for this are multiple. Patients with myeloma show reduced levels of antibodies that protect them from infections. This results from the disease itself as well as treatments especially the monoclonal antibodies that target both the plasma cell that is cancerous but also the noncancerous plasma cells; the latter normally produce the protective antibodies that prevent and fight off infections. In addition, functions of other immune cells such as T-cells and natural killer cells are impaired putting patients at higher risk of developing many types of infections. Sometimes, the bone marrow is filled with myeloma tumor cells that reduce the production of a protective type of white blood cell called a neutrophil. Many treatments can also frequently result in a reduction in the amounts of these cell types. When the levels of these types of cells are low, patients are at high risk of developing many types of serious infections. Use of growth factors such as G-CSF can help increase levels of these cells in the blood and prevent these infections from occurring. Use of intravenous immunoglobulin for patients with low normal antibody levels may be helpful for some patients who have frequent infections. Also, some groups use antibiotics to prevent these infections but studies to show their effectiveness for reducing the occurrence in this clinical setting are lacking. The viral infection shingles from reactivation of the herpes zoster virus that causes chicken pox occurs more frequently among myeloma patients who receive treatment with many of the different myeloma drugs, including PIs and monoclonal antibodies. As a result, patients taking these drugs are often given low doses of antiviral medications including acyclovir, Valtrex or Famvir while receiving these drugs which markedly reduce the occurrence of this type of viral infection. Patients with myeloma are at higher risk to develop serious complications and death from infection with COVID 19. They show impaired immune responses to vaccination as well. Use of antiviral drugs such as Paxlovid has shown effectiveness for treating patients infected with COVID-19.

Overall, careful monitoring of blood counts is important for myeloma patients and attention to symptoms related to infection should be part of the routine care of myeloma patients.

Kidney Disease:

Another frequent problem with your myeloma involves its effects on the kidney. Your kidneys may be negatively impacted directly by the myeloma cells, the myeloma’s monoclonal antibody or its light chains that are produced by the tumor cells or its breakdown products called amyloid. Also, sometimes patients may develop dangerously high calcium levels from the release of calcium from their bones which can damage the kidney. There may be drugs you are receiving for the myeloma that impair the function of your kidneys. Drugs like the bisphosphonates, antibiotics, or other treatments for the myeloma may have negative effects on kidney function. Frequently, myeloma patients may also have other diseases that cause kidney problems such as diabetes mellitus or hypertension. It is important to make sure those diseases are under optimal control, so you are not negatively impacting your kidney function further from these other diseases’ impact on your kidneys.

To reduce the impact of kidney disease most effectively, it is important that you see a kidney specialist if you have significantly reduced function of this organ. They help a lot with management of your fluids and acid, potassium, and phosphate levels as well as other minerals that may be impacted by impaired kidney function. We want to prevent irreversible kidney function that results in chronic dialysis for the patient. Keeping yourself well hydrated is always important.

So, kidney disease commonly occurs in myeloma patients and reducing its negative impact on the patient first and foremost involves rapid and effective treatment of the myeloma. In some cases, plasmapheresis has been used to reduce the levels of the kidney toxic antibodies in the blood. However, its ability to improve outcomes for myeloma patients with severe kidney problems has not been clearly shown. You also will need to take proper doses of drugs adjusted for your kidney function when it is not normal. This may require reduction of not only drugs to treat your myeloma but some of your other medications as well. It also may require avoidance of drugs that may be associated with kidney problems such as bisphosphonates or NSAIDs like ibuprofen or Naprosyn.

Nerve Problems:

Nervous system problems commonly occur among myeloma patients. They may involve the central nervous system, in other words your brain, from drugs we use to treat the myeloma. For example, IMiDs such as thalidomide may make you sleepy and tired. More frequently, these types of nerve problems involve your peripheral nervous system which include the nerves in your hands, feet, arms, and legs. Patients often develop peripheral neuropathies which are manifest as numbness, tingling, and less often pain in their hands and feet. Sometimes, patients may develop muscle weakness. This complication may be from the antibodies themselves that can coat the nerves and cause them not to function properly. Sometimes, removal of the antibody is attempted using plasmapheresis in which the antibody that is causing the problem is removed from the blood.

Today, peripheral neuropathy is most frequent from the medications we use to treat myeloma. Velcade and thalidomide often cause nerve damage resulting in peripheral neuropathy. Velcade-induced peripheral neuropathy is more often reversible whereas IMiD-induced problems are generally irreversible even following discontinuation of the drug.

Treatment of this problem may include drugs such as Neurontin or Lyrica. Other drugs used involve Cymbalta and doxepin. In addition, over-the-counter medications may help. For patients who receive IMiDs or the PI Velcade, alpha lipoic acid is continued during treatment with these agents to reduce the risk of neuropathy developing and its severity.

In addition to drug-induced neuropathies, infections can cause nerve problems. Specifically, shingles or herpes zoster is the most often cause of viral-induced nerve problems in myeloma patients. This develops because of reactivation of the chicken pox virus. Prevention of this infection can be accomplished with use of low doses of antiviral drugs such as acyclovir, Valtrex and Famvir.

It is very important to let your doctor know if you are experiencing any problems with your nerves especially if you are on drugs that may be causing this complication. Lower doses and less frequent dosing may improve these symptoms. Sometimes discontinuation of the offending drug will be required and substitution of another agent without these side effects can be used. For example, those with severe symptoms from Velcade peripheral neuropathy may be treated effectively with another PI such as Kyprolis without experiencing this complication. So, communication with your healthcare professional is the key which will lead to optimal long-term benefits from the drugs you’re receiving for myeloma while at the same time minimizing their side effects.