Stage 4 Multiple Myeloma

What is stage 4 multiple myeloma?

Stage 4 multiple myeloma, also known as stage 4 myeloma, is an advanced stage blood cancer that has metastasized, i.e., spread throughout the body and is causing organ damage. [¹]

Note that there are only three stages for this type of cancer because multiple myeloma does not spread to lymph nodes. Therefore, the terms stage 3 multiple myeloma and stage 4 multiple myeloma are used interchangeably to define this late stage.

What are the subtypes of stage 4 multiple myeloma?

Multiple myeloma is caused by abnormal plasma cells, which are antibody-producing white blood cells in the bone marrow. These abnormal cells rapidly multiply and replace the healthy white and red blood cells in the bone marrow, significantly weakening the body. [²]

Furthermore, these abnormal plasma cells produce abnormal antibodies, known as monoclonal or M proteins, which cause more complications. There are two broad types of multiple myeloma, which are subdivided as follows: [³]

1. Smoldering Multiple Myeloma

Slow growing and mostly asymptomatic, with 10 – 59% of bone marrow consisting of abnormal plasma cells.

• Solitary plasmacytoma
• Multiple solitary plasmacytoma
• Extramedullary plasmacytoma

2. Active Multiple Myeloma

Aggressive and symptomatic, with 60% abnormal plasma cells

• Light chain multiple myeloma
• Non-secretory myeloma
• Immunoglobulin A myeloma
• Immunoglobulin D myeloma
• Immunoglobulin E myeloma
• Immunoglobulin G myeloma

Stage 4 multiple myeloma staging and diagnosis

Multiple myeloma staging

Given that multiple myeloma does not spread to the lymph nodes or always has a tumor growth, it is staged by blood counts and serum levels of certain proteins using the Revised International Stage System (RISS). The RISS is based on four factors: [⁴] [⁵]

• The level of albumin in the blood
• The level of beta-2-microglobulin in the blood
• The level of Lactate dehydrogenase (LDH) in the blood
• The gene abnormalities of cancer, i.e., high-risk chromosomes

Based on this system, the stages for late-stage multiple myeloma are given in the table below.

Table 1: Stages of active multiple myeloma [⁴] [⁵]

How common is stage 4 multiple myeloma?

Multiple myeloma is a relatively rare type of cancer in the US, with approximately 35,700 people diagnosed In 2023, accounting for 1.8% of new cases. Currently, an estimated 159,787 people in the US with multiple myeloma. [⁶]

Also, the following factors have been shown to increase the risk of multiple myeloma: [¹][⁶]

• Age – seen in patients over 60 with the median age of diagnosis at 69. Less than 3% of cases are seen in people under the age of 40
• Race - seen nearly twice as many in black people. Appearing more common in people of Mediterranean, North African, or Middle Eastern descent
• Exposure to carcinogens
• History of solitary plasmacytoma of the bone or monoclonal gammopathy of undetermined significance (MGUS)

How is stage 4 multiple myeloma diagnosed?

As multiple myeloma is generally asymptomatic in its early stages, over 90% of cases are diagnosed in later stages when the cancer has metastasized. [⁶]

Stage 4 multiple myeloma is diagnosed after a completed a battery of tests that include laboratory tests, biopsies, and imaging as described below: [⁷]

• Complete blood count (CBC) tests that measure the levels of normal blood cells. Too low, and they can indicate too many abnormal plasma cells in the blood.
• Blood antibody tests such as quantitative immunoglobulin tests and serum protein electrophoresis (SPEP) to identify any abnormal antibodies in the blood.
• Blood serum tests check the levels of creatinine, calcium, lactic dehydrogenase (LDH), albumin, and other electrolyte. In multiple myeloma, all these will be out of normal ranges.
• Beta-2 microglobulin tests measure the blood level of beta-2 microglobulin, another protein abnormal plasma cells produce.
• Urine sample tests to test for abnormal proteins
• Bone marrow biopsies to examine the plasma cells and identify any abnormalities. Furthermore, this is used to do a FISH test, a specialized diagnostic method that identifies genetic mutations on plasma cell chromosomes to determine if they are high-risk.
• Imaging tests such as bone X-rays, CT scans, and MRIs are used to determine the extent of bone damage caused by the myeloma and measure the spread of the disease.

Stage 4 multiple myeloma symptoms

Patients with stage 4 multiple myeloma experience a broad range of symptoms caused by the associated complications of this cancer as described below: [¹] [⁸]

1. Bone lesions and abnormalities that lead to pain, weakness, and frequent fractures

2. Low blood counts of red blood cells, platelets, and white blood cells lead to anemia, leukopenia, and thrombocytopenia.

3. Higher rate of infections due to a compromised immune response

4. Hypercalcemia, i.e., high levels of blood calcium, causes numerous problems, including:

• dehydration
• increased thirst
• kidney problems
• poor appetite
• muscle weakness
• constipation
• abdominal pain
• mental confusion

5. Nervous system damage that includes nerve damage, spinal compression, pain, weakness, and numbness

6. Blood thickening (hyperviscosity) from the large amounts of abnormal protein production caused by myeloma plasma cells leads to confusion and stroke-like symptoms.

Stage 4 multiple myeloma treatment

Treatment for Stage 4 multiple myeloma varies as it depends on several factors, including the health of the patient and the type of multiple myeloma.

First-line treatments are systemic treatments as by this late stage, the myeloma has spread, and localized treatments will not help. But this is conditional upon the patient's health and subtype of multiple myeloma.

Alternative treatments and supportive options may be recommended for patients who are not eligible candidates for drug therapy.

Stage 4 multiple myeloma first-line treatment

The first line treatment for stage 4 multiple myeloma is often a combination of drug therapies as explained below:[⁷] [⁹]

Chemotherapy: certain drugs that kill cancerous plasma cells but have significant side effects such as hair loss, nausea, and mouth sores.

Corticosteroids: decrease the side effects of chemotherapy, such as nausea and vomiting but further suppress the immune system

Proteasome inhibitors: stop certain enzymes from breaking down proteins that control cell division and have been shown to affect cancerous cells more than normal ones but have numerous side effects

Immunomodulating agents: slow the growth of plasma cells but increases the risk of serious blood clots

Monoclonal antibodies: synthetic antibodies that attack and kill abnormal plasma cells but can lower normal blood counts and lead to respiratory infections

Bispecific T cell engager (BiTE): an immunotherapy that strengthens an immune response by bringing healthy white blood cells closer to abnormal ones.

Nuclear export inhibitor: a drug that inhibits cell function and leads to cell death. However, it is aggressive and can affect normal body function. Generally, it is given when other drug treatments are non-responsive.

In recent years chemotherapy has taken a backseat in treating multiple myeloma. And while it may be used in some cases, it has become less important as more advanced targeted therapies have been developed. [¹⁰]

Furthermore, research has shown that drug therapy is more effective when combining two or three different kinds of drugs. Healthcare providers will closely monitor how cancer responds to these personalized treatments and make adjustments as necessary.

However, if a stem cell transplant is recommended, most healthcare providers will avoid using certain drugs as they can damage the bone marrow and hinder recovery.

Alternative treatments for stage 4 multiple myeloma

Alternate treatments are also available for stage 4 multiple myeloma which can be used alongside drug therapy or separately for patients who are not responsive or ineligible for drug interventions.

Stem cell transplant: Stem cell transplants can effectively slow down and even stop abnormal cell growth. First, the multiple myeloma patient is given a high dose of chemotherapy to kill the cells in the bone marrow. Then they receive healthy, blood-producing stem cells.

These healthy stem cells can be the patient's own, extracted from healthy bone marrow sites or peripheral blood (autologous transplant). Another option is from a donor (allogeneic transplant).

However, this treatment is not without its side effects and is often more severe than drug therapy. Furthermore, in the case of an allogeneic transplant, the donor’s stem cells may attack the patient's body, leading to a life-threatening condition known as graft-versus-host disease. [¹¹]

CAR T-cell therapy: CAR T-cell therapy is a type of immunotherapy that uses cell-based gene therapy to alter the genes inside immune cells. This makes them more capable of attacking cancerous cells. This treatment involves: [¹²]

• Filtering and freezing the patient’s T-cells
• Genetically modifying and multiplying them in a lab to have specific receptors on their surface.
• Giving the patient a course of chemotherapy to prepare their body
• Infusing the modified T-cell back into their bloodstream

While effective, this is an intensive process with serious life-threatening side effects. Therefore, it may not be suitable for every multiple myeloma patient.

Supportive treatments: These therapies aim to relieve and reduce the effects of symptoms instead of curing the cancer. The main purpose is to improve the quality and comfort of a patient's life as they deal with stage 4 multiple myeloma complications.

Also referred to as palliative care or symptom management, it can be given during any stage. It includes antibody transfusions, treatments for anemia, plasmapheresis to remove abnormal proteins in the blood, and pain management.

Can stage 4 multiple myeloma be cured?

Multiple myeloma is considered a manageable disease in its early stage but is generally incurable. Once it has progressed to stage 4, it becomes more challenging to control the growth as a patient's health deteriorates.

Stage 4 multiple myeloma prognosis

As with treatment, the prognosis for stage 4 multiple myeloma highly depends on the patient's health and the cancer's specifics. For example, lower albumin and higher LDH levels indicate a poorer prognosis.

Moreover, prognosis usually deals with two separate metrics: survival and quality of life (QOL).

• Survival is usually reflected by the five-year survival rate, which indicates the percentage of patients alive five years after their diagnosis.
• Quality of life is concerned with the ability of the patient to continue to live a healthy and enjoyable life, considering the status of their health condition and the characteristics of medical interventions they are going through.

With advances in treatment and therapies, the prognosis for stage 4 multiple myeloma has improved.[⁷]

Stage 4 multiple myeloma survival rate

The five-year survival rate for stage 4 multiple myeloma is 57%, with the median survival at 29 months. Yet, this is just an estimation, and trend analysis has shown a significant increase in survival rate in the last two decades, increasing from 34% in 2000. [⁶] [⁷]

Furthermore, if multiple myeloma is diagnosed early, survival rates drastically improve to 79% with early intervention. [⁷]

Stage 4 multiple myeloma recurrence rate

Most patients with stage 4 multiple myeloma experience relapse at some point with this disease, with research showing an average recurrence time of 26.9 months following first-line treatment. Furthermore, a relapse of less than 12 months suggested a poorer prognosis. [¹³]

Stage 4 multiple myeloma growth rate

How fast does multiple myeloma spread? This depends on the type. Generally, active multiple myelomas are aggressive, with abnormal plasma cells that multiply quickly and rapidly spread within a year of an early-stage diagnosis. If left untreated, survival rates drastically fall, as mentioned above.

Lifestyle changes for preventing and managing multiple myeloma

Those with a higher risk of multiple myeloma or survivors currently in remission can make some lifestyle changes to prevent cancer from growing or coming back. This includes: [¹⁴]

• Exercising regularly and following a nutritious diet to support the immune system
• Maintaining a healthy weight
• Not smoking or drinking
• Regular screening and bones to check blood levels and the presence of lesions

Conclusion

Takeaway

Stage 4 multiple myeloma is an aggressive, advanced-stage blood cancer with life-threatening complications. However, with early detection, the growth of abnormal cells can be controlled, and patients can go into remission.

While stage 4 multiple myeloma is incurable, researchers continue to study new medical interventions and treatment protocols that can improve survival rates and long-term prognosis.