Understanding Relapsed vs. Refractory Multiple Myeloma

While there are many effective treatments for multiple myeloma, unfortunately, it is currently incurable. This means that even after successful treatment has provided a period of remission or stable disease, myeloma will return. When this happens, it’s called recurrent or relapsed. If it doesn’t respond to treatment or comes back within 60 days after your last therapy, it’s known as refractory.

Thankfully, for people who relapse or become refractory, secondary therapies may be successful in providing another remission. And while you can’t prevent or avoid relapse, you may be able to spot certain signs and symptoms earlier, which could lead to better care.

Doctors encourage patients to sleep on the bed.


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Relapsed Multiple Myeloma

Myeloma is a relapsing-remitting cancer, which means there are periods when myeloma is active and causing problems in the body and needs to be treated and times when it is not causing problems and does not need to be treated.

Myeloma Remission

Treatment aims to bring myeloma under control causing a period of remission, where myeloma does not cause symptoms and sometimes does not require treatment. Many patients are now continued on lower intensity "maintenance therapy" for very long periods of time. It may be months or years before myeloma becomes active again.

However, at some point after a period of treatment or remission, in the vast majority of cases, myeloma will become active again and further treatment is required. This is called a relapse. 

Refractory Multiple Myeloma

Refractory is another word for resistant. Refractory myeloma is cancer that develops resistance to treatment or does not respond to it at all. There are two types of refractory myeloma:

  • Relapsed and refractory myeloma: Myeloma that initially responds to treatment but then stops responding to it after a time or myeloma which progresses within 60 days of receiving the last dose of treatment. 
  • Primary refractory myeloma: Myeloma that has not yet responded to any treatment.

These definitions are quite technical and are primarily used by doctors and researchers to standardize the descriptions of people taking part in clinical trials. 

Signs and Symptoms

A relapse is diagnosed when—after a period of response to treatment—you begin to show signs and/or symptoms that myeloma is becoming active again. The regular tests you will have throughout the course of your myeloma, in addition to any new or increasing symptoms, can give a good indication as to whether the disease is becoming active again.

Symptoms of multiple myeloma include:

  • Bone pain, especially in the back or ribs
  • Bones that break easily
  • Fever for no known reason
  • Frequent infections
  • Easy bruising or bleeding
  • Trouble breathing
  • Weakness of the arms or legs
  • Feeling very tired

Relapse Symptoms

It is important that you report any new or increasing symptoms promptly to your doctor or nurse so that tests and investigations can be carried out to establish whether you have relapsed.

Diagnosis

The diagnosis of relapsed or refractory multiple myeloma depends on bone marrow tests and markers that can be detected in blood and sometimes in urine, all in addition to any signs and symptoms that may be present. Tests carried out include:

  • Specialized blood tests: These include immunoglobulin studies, complete blood count, and blood chemistry studies.
  • Urine tests: This is performed since the protein markers of interest in myeloma can sometimes pass to the urine.
  • Bone marrow aspiration and biopsy: If you have multiple myeloma, there will be an excess of plasma cells in your bone marrow.
  • Imaging studies: These include X-ray of the bones, MRI, CT scan, and/or PET scan to determine whether bones have been damaged by multiple myeloma.

How Long Does Remission Last?

When relapse will occur is impossible to predict with any accuracy, but there are characteristics of myeloma which are known—to some degree—to influence how quickly a relapse might occur. 

Response to Treatment 

The depth of response to initial treatment is an important factor in generating a longer remission and delaying relapse. For example, people who achieve a complete response following high-dose therapy and stem cell transplantation generally will have a longer period of remission before a relapse.

Age, Frailty and Comorbidities 

The median age of myeloma diagnosis is 69, with 35% of people diagnosed at 75 and older. Older, frailer people can experience a higher rate of side effects whilst on treatment and may also experience more symptoms and complications. This can then affect how they tolerate and respond to treatment and therefore how quickly they might relapse.

Genetic Abnormalities of Myeloma Cells 

A person's myeloma can be defined by the genetic abnormalities that occur within myeloma cells (also known as cytogenetics). The genetic abnormalities present in a person’s myeloma cells appear to influence how well a person responds to treatment and the speed of relapse.

Relapse Prevention

Unfortunately, there is nothing you can do to prevent myeloma from returning. Some patients do get "maintenance therapy" which won't prevent relapse but delays relapse. At the moment, the causes of myeloma remain uncertain, and there is no direct correlation between myeloma and lifestyle or diet.

Treatment

The aim of treatment for relapsed myeloma is to control and slow down the progression of myeloma, and give you the best quality of life, for as long as possible. 

The exact treatment combination you will receive at relapse will depend on many things, including:

  • The treatment you have had previously, and how you responded to it
  • The length of remission you achieved from your previous treatment
  • Any persistent side effects following your previous treatment
  • Whether you are known to be refractory to any treatment
  • Your general health, age, and any comorbidities, such as diabetes or heart disease

Following a relapse, you may be treated with some of the following drugs, which are approved for use in various combinations for multiple myeloma:

  • Lenalidomide 
  • Bortezomib (Velcade)
  • Carfilzomib (Kyprolis) 
  • Cyclophosphamide
  • Daratumumab (Darzalex) 
  • Elotuzumab (Empliciti)
  • Isatuximab (Sarclisa)
  • Ixazomib (Ninlaro) 
  • Panobinostat (Farydak) 
  • Pomalidomide (Pomalyst) 
  • Selinexor (Xpovio)
  • Other chemotherapy-based combination such as DT-PACE (a combination of six drugs) or ESHAP (a combination of four drugs)
  • A different drug/combination via a clinical trial

Available Medications

Generally speaking, the same drugs and combinations available for relapsed people are also available to people with refractory myeloma.

The treatment approach for refractory myeloma might be a little different than for relapsed myeloma due to the treatment resistance that has been identified. 

Being refractory to a particular drug does not necessarily mean you will be refractory to all others; finding the right drug or combination may take a little time but is achievable for the majority of people.

Supportive Care 

Due to the cumulative effects of myeloma on the body and the ongoing exposure to the effects of treatment, treating relapsed myeloma involves much more than anti-myeloma treatment.

Equal priority should be given to relieving and managing symptoms and complications with supportive treatments. For example, there may be a role for the following supportive treatments in your ongoing care at relapse:

  • Radiotherapy: Can be used to kill myeloma cells and to relieve pain in areas where there is damage caused by myeloma bone disease. 
  • Bisphosphonate treatment: Bisphosphonates are drugs that slow down or prevent bone damage. Bisphosphonate treatment is recommended for all people with symptomatic or active myeloma.
  • Painkillers: You may be prescribed painkillers to try to control any new or increasing pain at relapse. There are many types of painkillers available to treat different types and levels of pain, and a trial and error approach may be needed to find a suitable one to manage your pain.

Outlook

Relapsed myeloma can respond very well to treatment and go into another period of remission. Your doctor should be able to tell you about average remission periods for the particular treatment combination you are on.

This will be based upon evidence from clinical trials and their own experiences of using the treatment. However, each individual is different and you may respond better or worse than the average.

Eventually, however, relapses will occur with increasing frequency and unfortunately, myeloma will become increasingly refractory to treatment.

Becoming Refractory to Treatments

Most people with myeloma will eventually become refractory to all treatments. This may take many years or may take less time than this—this is very difficult, if not impossible, to predict.

Coping

Many strong emotions can surface when you are told your cancer has returned or is resistant to treatment—fear, sadness, anxiety, and helplessness, to name only a few. You will have your own ways of adjusting and coping, but here are a few things to consider and keep in mind: 

You are not alone. Relapsing and becoming refractory to treatment are realities of living with myeloma and more and more people are living longer than ever before with relapsed and/or refractory myeloma. Find a local or online support group for people living with multiple myeloma.

There are many effective treatment options for relapsed and refractory myeloma. Many treatment options exist already, and new drugs are being developed and tested every day.

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Article Sources
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