Relapsed and Refractory Multiple Myeloma

What is Relapsed and Refractory Multiple Myeloma?

Multiple myeloma (MM) is a type of cancer that primarily affects a type of white blood cell called B cells. These abnormal cells, called monoclonal plasma cells, grow and multiply in the bone marrow and/or other parts of the body, making MM the second most common blood cancer. MM causes significant health problems and can lead to the failure of vital organs.

The good news is that, over the past few decades, the survival rates for MM have improved due to various advancements in treatment options. Targeted therapies and combination treatments have resulted in better outcomes. However, most individuals with MM will have the disease return at some point, even those who have previously achieved remission.

Patients whose disease does not show a significant response to initial treatment and who see their cancer progress while receiving treatment are said to have “primary refractory” MM. This term, established by the International Myeloma Working Group (IMWG), is used when MM continues to grow despite treatment, returns within 60 days of the most recent treatment, or if the patient doesn’t respond to treatment at all.

The IMWG also states that progressive MM occurs when certain protein levels in the blood or urine increase by at least 25% or new symptoms develop.

The term “double refractory” MM is used when the disease continues to progress despite treatment with two types of medication: a protease inhibitor and an immunomodulatory agent. If MM also resists treatment with a type of medication called monoclonal antibodies, it’s classified as “triple-class” refractory disease, which carries a poor prognosis.

During their treatment journey, most patients with MM will experience periods of remission and relapse, requiring several rounds of different combination treatments. This, along with varying patient characteristics, disease traits, and treatment-related factors, poses challenges in creating the most effective treatment strategies for individuals with MM.

What Causes Relapsed and Refractory Multiple Myeloma?

People with a type of cancer called multiple myeloma unfortunately will face a time when their treatment stops working or when their cancer comes back. The reasons behind this are still unclear. Knowing what increases the risk of this happening is important. This way, doctors can provide specific treatments and preventive steps, helping to manage the disease better and lessen the chances of the cancer returning.

There are many factors that could increase the likelihood of the cancer coming back or the treatment not working. These include: the cancer returning quickly after treatment, the cancer spreading or getting worse quickly, certain changes in the genes of the cancer cells, the treatment not working well earlier, a type of cancer called plasma cell leukemia, and problems with the immune system.

About one in five patients experience a severe return of their cancer, characterized by specific genetic changes in the cancer cells. If a patient has any two of these high-risk genetic changes, it’s called “double-hit myeloma”. If they have three or more, it’s called “triple-hit myeloma”. On the other hand, patients with other specific genetic changes are thought to have a standard risk of their cancer returning.

Also, if the patient is in poor health or experiences negative effects from the combination of therapies, their treatment may need to be delayed or stopped. This, unfortunately, could result in the cancer coming back sooner.

Risk Factors and Frequency for Relapsed and Refractory Multiple Myeloma

Multiple myeloma, a type of cancer, makes up 1.8% of all new cancer cases and 2.1% of all cancer deaths every year in the United States. It generally affects 4.5 to 6 out of every 100,000 people each year. Most people are diagnosed around the age of 70. The occurence of multiple myeloma has increased more than twice worldwide and by over 40% in the US since 1990. However, the increase varies across different countries, being highest in Australia, Western Europe, and North America.

On the brighter side, the death rate from this cancer has dropped by 14% in the US, although it had a worldwide increase of 94%. Thanks to new advanced treatments, the survival rate for five years or longer in the US has more than doubled in recent decades.

In 2016, a healthcare institute analyzed outcomes for 511 multiple myeloma patients who were treated with new therapies between 2006 and 2014. They found that 82 patients (16%) experienced relapses soon after, within eight months of starting treatment, compared to 429 patients( 84%), who relapsed after a year or responded to the treatment for the duration of the study. The survival rate was poorer in patients with an early relapse compared to those who had a later relapse. Survival rate for patients who underwent autologous stem cell transplantation and relapsed within 12 months was 23.1 months, compared to 122.2 months in other patients indicating that early relapse isn’t a good sign.

The more lines of therapy a patient undergoes, and the more often the cancer relapses, the lesser the chances of complete recovery and the shorter the time until the disease progresses. The percentage of patients achieving a complete response decreased from 32% with the first line of treatment to just 2% with the fifth line of treatment.

Signs and Symptoms of Relapsed and Refractory Multiple Myeloma

People with relapsed or treatment-resistant multiple myeloma (MM), a type of blood cancer, are closely monitored by their healthcare team. The recurrence of the disease is generally detected through an increase in certain proteins (M-protein or free light chains), a condition known as biochemical progression.

During routine check-ups, or even after the cancer seems to have vanished entirely, patients might experience a variety of symptoms. These can range from mild ones like fatigue, to more severe instances such as wide-spread metastasis or cancer spread. As a result, regular assessments and careful management by clinicians are crucial. Unearthing a thorough medical history, performing regular physical examinations, and conducting specific tests for multiple myeloma are all critical steps to early diagnosis and effective treatment planning.

The most often seen symptoms include:

• Bone pain
• Fatigue
• Shortness of breath

In the early stages, individuals with multiple myeloma may look and feel perfectly healthy, while those with an advanced disease may appear visibly sick. They might have severe reductions in all types of blood cells (pancytopenia), suffer from bone fractures even with minor injuries, encounter high calcium levels in the blood (hypercalcemia), and experience frequent infections due to a weakened immune system.

Healthcare providers face challenges in managing the physical and mental health impacts of relapsed and treatment-resistant diseases. They therefore emphasize the need for ongoing care and regular check-ups with the multiple myeloma care team. This consistent and thorough approach helps in detecting and addressing any disease relapses or resistance to current treatments, promoting comprehensive care for multiple myeloma patients.

Testing for Relapsed and Refractory Multiple Myeloma

If a patient who has been in remission from multiple myeloma (MM, a type of blood cancer) shows certain signs, it might mean that the disease has come back or is resisting treatment. When the symptoms of MM get worse or new ones appear, doctors need to start treatment straight away or change the ongoing treatment. The International Myeloma Work Group (IMWG), a team of researchers that works on MM, updated a set of criteria in 2016. They use these to check how well a patient is responding to treatment for MM.

Even if the patient feels fine, if tests show an increase in certain chemicals in the body (biochemical relapse), it’s important to start or change treatment. Regular checks are essential to slow down the disease’s progress. For patients who have had very successful treatment – when there’s no evidence of disease (minimal residual disease status) – it’s useful to use whole body imaging. This technique can spot small changes in the patient’s body that could suggest the disease is reappearing. MRI scans are usually better for this than PET/CT scans, but both types of scan are commonly used.

Looking at these scans alongside the ones taken when the patient was first diagnosed can highlight any growth in the damage to the bones. These new injuries to the bones aren’t always proof that the disease is progressing; they could be a result of the state of the disease at an earlier time. Regular checks for minimal residual disease (MRD) are recommended because tests have shown that patients who test negative for MRD (in other words, no disease can be detected) tend to respond better to treatment and live longer.

To check for MRD in the bone marrow, doctors use a test that measures multiple characteristics of cells (multiparametric flow cytometry) as well as cutting-edge genetic testing techniques such as next-generation sequencing. For MM that’s outside the bone marrow, a type of scan known as fluorodeoxyglucose positron emission tomography (FDG-PET) is used to check for MRD. However, whether or not a patient tests positive for MRD isn’t necessarily used to determine treatment choices. This is still being studied, and for now, a patient testing positive for MRD doesn’t necessarily mean that their treatment plan needs to change.

The International Myeloma Work Group suggests starting or changing treatment if certain specific criteria are met. For example, obvious worsening of symptoms like high calcium level in blood, drop in hemoglobin level, rise in creatinine because of MM, blood having too many cells causing a clot or blockage, enlargement of tumor or bone damage and appearance of new soft-tissue tumors or bone lesions.

In case of patients who show biochemical signs of relapse without worsened symptoms, this could be doubling of a specific type of protein in the blood in two consecutive tests, increase in the levels of a particular protein or urine protein or increase in a type of light chain protein present in the blood.

Treatment Options for Relapsed and Refractory Multiple Myeloma

Most patients with MM, or multiple myeloma, initially respond well to treatment, but unfortunately, relapse is common as current treatments cannot totally cure the disease. Some patients may not respond to the first line of treatment at all. Subsequent treatments for relapsed or refractory multiple myeloma (RRMM) can be similar to the first line, depending on how effective they were and how long the patient stayed in remission. Doctors have to consider possible resistance to certain types of drugs within the same group, a phenomenon known as cross-resistance.

Creating a treatment plan for each RRMM patient involves careful customization. Various combinations and dosages of drugs may be tested to find the most effective treatment. In choosing treatment options, factors such as drug resistance, the patient’s age and overall health, and any remaining side effects from previous treatments should be taken into account. In the context of the current pandemic, patients should also be up-to-date with vaccinations. It’s worth noting that the patient’s response to vaccines might be affected by their myeloma treatment.

It’s vital to recognize any increase or spread of the multiple myeloma for appropriate treatment changes in order to reduce illness and risk of death. Regular check-ups are recommended and treatment or adjustments to the existing treatment plan should be made if a relapse or disease progression is noted. If a clinical relapse doesn’t present typical features, biochemical markers can be checked to monitor the disease progression. These biochemical markers could include elevated lactate dehydrogenase and M-protein levels associated with increasing cases of myeloma cells. In such cases, it’s important to begin or adjust treatment promptly as the RRMM may progress aggressively.

Therapy is chosen based on different factors such as:

1. Aspects related to the patient: Age, overall health, eligibility for transplant, and how well they respond to previous treatments.
2. Aspects related to the disease: The specific stage of the disease, severity of the current relapse, the presence of other diseases and abnormalities, etc.
3. Aspects related to the treatment: The multi-drug combination plan, cost, the risk of infections, and potential thrombotic events.

Various treatment options include stem cell transplantation, protease inhibitors (PIs), immunomodulatory drugs (IMiDs), targeted agents like monoclonal antibodies (mAbs), antibody-drug conjugates, chimeric antigen receptor T-cells (CAR-T-cells), selinexor, venetoclax, and more. These treatments help to control the growth of myeloma cells and manage the disease.

For patients who have relapsed, the kind of relapse determines the next step. If the patient progresses within two months of standard lenalidomide therapy, the patient is considered lenalidomide refractory. If the disease returns or develops after two months of lenalidomide treatment or if patients are currently only on maintenance lenalidomide, they are considered lenalidomide sensitive. Each state requires a different set of treatment strategies.

Typically, at the first relapse, standard therapeutic interventions include combinations of three or four drugs like lenalidomide, dexamethasone, Daratumumab, carfilzomib, pomalidomide, and bortezomib. These combinations help fight the relapse. Sometimes, autologous stem cell transplant (auto-SCT), in which the patient’s stem cells are infused back into their body after high-dose treatment, may be suggested. A second auto-SCT procedure can also aid relapsed MM patients who have previously undergone the procedure.

On subsequent relapses, similar treatments to those recommended for the first relapse can be tried. Additionally, other therapies such as BMCA-targeted therapy and alkylator-based combinations can also be helpful in managing the disease for patients who do not respond to standard treatments.

What else can Relapsed and Refractory Multiple Myeloma be?

The symptoms of Multiple Myeloma (MM), a type of blood cancer, can be similar to other diseases. Hence, it is necessary to conduct various tests, both invasive and noninvasive, for an accurate diagnosis. The following conditions should also be considered in the initial diagnosis process due to their unique characteristics that distinguish them from MM:

• Monoclonal Gammopathies of Undetermined Significance (MGUS):
  • Monoclonal protein spike of less than 3 g/dL
  • Less than 10% of the bone marrow containing clonal plasma cells
  • No signs of CRAB features (which stands for high Calcium levels, Renal failure, Anemia, and Bone lesions)
• Smoldering Multiple Myeloma:
  • Monoclonal protein spike of more than 3 g/dL
  • More than 10% of the bone marrow containing clonal plasma cells
  • No signs of CRAB features
• Waldenstrom Macroglobulinemia:
  • IgM (a type of antibody) monoclonal protein present in the serum
  • Appearance of lymphoplasmacytic lymphoma with lymphoid cells in the bone marrow
  • End-organ damage includes nerve damage, swelling of the lymph nodes and spleen, and high blood viscosity syndrome
  • Most common genetic variation: MYD88 L265P
• Solitary or Isolated Plasmacytoma:
  • Localized mass of monoclonal plasma cells in the bone or locations outside of the bone, in contrast to widespread infiltration in multiple myeloma
  • Absence of CRAB features
  • Bone marrow biopsy results are normal if performed outside of the lesion
• AL Amyloidosis:
  • Plasma cell clones in the bone marrow that release unstable monoclonal kappa and lambda light chains leading to the formation of amyloid fibrils
  • Deposition of a type of protein (monoclonal immunoglobulin) in different body organs like the heart, kidneys, and gastrointestinal tract)
  • Less than 20% plasma cell infiltration of the bone marrow
  • No bone destruction (lytic lesions)
  • Apple green coloration when stained with congo red observed in the affected tissue

Looking out for these conditions and their distinct features helps doctors to distinguish between these diseases and Multiple Myeloma, leading to a precise diagnosis.

Surgical Treatment of Relapsed and Refractory Multiple Myeloma

Multiple Myeloma (MM) is a type of cancer that causes damaging holes, also known as osteolytic lesions, in the bone. This makes the bones fragile and can lead to painful fractures. Many people with MM experience bone pain due to these lesions. Serious issues can occur when these lesions affect the nerves or risk causing a bone fracture. To improve the patient’s quality of life and reduce the risk of further bone complications, surgical intervention may be needed. In simpler terms, sometimes doctors need to perform a surgery to reduce the pain and other risks associated with these lesions.

What to expect with Relapsed and Refractory Multiple Myeloma

While we’ve achieved fantastic progress in treating multiple myeloma, a form of cancer that forms in a type of white blood cell, relapse and resistance to treatment remain big hurdles. These challenges often result in a poor outlook or prognosis, meaning the likely course or outcome of the disease. Because every patient and every disease is unique, it’s crucial to consider both individual and disease-related factors. Understanding these factors can help estimate the prognosis and guide the best course of treatment.

Several factors influence how long a multiple myeloma patient might live, including tumor burden (which relates to the cancer’s stage), patient’s characteristics, genetic abnormalities in the cancer cells, and how well they respond to treatment. A tool called the R-ISS uses information such as tumor burden, specific protein levels in the blood (like beta-2-microglobulin), and risk assessment of genetic abnormalities to determine a patient’s prognosis.

Certain factors can imply a poorer prognosis:

1. Genetic abnormalities: Having more than one genetic abnormality, including specific types of gene rearrangements and other changes in the DNA of the cancer cells.
2. Tumor burden: More advanced cancer stages, kidney insufficiency, increased levels of a specific enzyme (LDH), cancer spread beyond the bone marrow, or a high level of a specific protein (beta-2-microglobulin).
3. Response to treatment: Relapse within a year of getting a type of transplant (autologous stem cell transplantation) or resistance to first-line therapy.
4. Having received multiple previous treatments.

However, survival rates after a relapse of multiple myeloma have improved in the past two decades. From 2000 onward, the average survival rate has increased from 12 months to 24 thanks to the availability of advanced treatments like protease inhibitors, immunomodulatory drugs, and autologous hematopoietic cell transplantation (auto-HCT).

Possible Complications When Diagnosed with Relapsed and Refractory Multiple Myeloma

If multiple myeloma, a type of cancer that forms in a type of white blood cell, progresses or comes back after treatment, it can lead to various complications. Such complications can include, kidney problems, weakened immune system, low red blood cell count (anemia), and issues related to the skeletal system such as, bone pain and fractures that occur for no apparent reason. Additionally, long-term use of various drugs can make these complications even more complex and numerous.

The Potential Complications Include:

• Kidney problems
• Weakened immune system
• Anemia (low red blood cell count)
• Bone pain
• Fractures that occur for no clear reason
• Increased complexities due to long-term drug use

Recovery from Relapsed and Refractory Multiple Myeloma

Setting goals based on your functionality and acknowledging the necessity for professional therapy services are vital for patients dealing with advanced multiple myeloma. ‘Multiple myeloma’ is a type of cancer that forms in a type of white blood cell called a plasma cell. If you have recurrent (having come back after initial treatment) or refractory (not responding to treatment) multiple myeloma, self-management workshops and group sessions could be beneficial. They can help you manage the negative impacts on your physical and mental well-being.

Preventing Relapsed and Refractory Multiple Myeloma

Getting a cancer diagnosis can be very distressing, particularly when it is treatable but not completely curable. During the initial visits and ones that follow, enough time should be set aside to address all questions and concerns raised by the patient and their family members involved in their care. This ensures that they fully understand the condition and the care process.