GeneHealth - Your precision medicine

Multiple Myeloma

Disease Details

Family Health Simplified

Buy Membership

Description: Multiple myeloma is a type of blood cancer that originates in the plasma cells of the bone marrow, leading to bone damage, kidney dysfunction, and compromised immune function.
Type: Multiple myeloma is a type of blood cancer that affects plasma cells in the bone marrow. It is generally not considered to have a straightforward or predictable pattern of genetic transmission like some hereditary diseases. While there may be an increased risk if a person has a family history of multiple myeloma, the disease is usually thought to result from a combination of genetic mutations and environmental factors rather than from inheritance of specific genes.
Signs And Symptoms: Because many organs can be affected by myeloma, the symptoms and signs vary greatly. Fatigue and bone pain are the most common symptoms at presentation. The CRAB criteria were formerly the benchmark used to establish presence of active multiple myeloma (as opposed to an earlier, generally asymptomatic, "smoldering" form of the disease). The CRAB criteria are:
Calcium: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >1.77 mol/L (>2 mg/dL)
Anemia: hemoglobin value of >2g/dL below the lowest limit of normal, or a hemoglobin value <10g/dL
Bone lesions: osteolytic lesions on skeletal radiography, CT, or PET/CTAs of 2014 the diagnostic criteria were expanded and updated by the IMWG (International Myeloma Working Group) to add three myeloma defining events, any one of which indicates presence of active multiple myeloma. Each of these three events may occur before any of the CRAB criteria appears, thereby making more people eligible for treatment with myeloma drugs earlier.
Prognosis: Overall the 5-year survival rate is around 54% in the United States. With high-dose therapy followed by ASCT, the median survival has been estimated in 2003 to be about 4.5 years, compared to a median around 3.5 years with "standard" therapy.The international staging system can help to predict survival, with a median survival (in 2005) of 62 months for stage-1 disease, 45 months for stage-2 disease, and 29 months for stage-3 disease. The median age at diagnosis is 69 years.
Onset: The onset of multiple myeloma is often gradual and can be asymptomatic in its early stages. Symptoms, when they do appear, may include bone pain, fractures, fatigue, frequent infections, and anemia. Typically, multiple myeloma is diagnosed in older adults, with the median age at diagnosis being around 65 to 70 years.
Prevalence: Multiple myeloma is a relatively rare cancer, accounting for about 1% of all cancers and approximately 10% of all hematologic malignancies. In the United States, the annual incidence is estimated to be around 4 to 5 per 100,000 people. It is more common in older adults, with a median age at diagnosis of around 69 years. Additionally, it is slightly more prevalent in men than in women and more common in African Americans compared to other racial groups.
Epidemiology: Globally, multiple myeloma affected 488,000 people and resulted in 101,100 deaths in 2015. This is up from 49,000 in 1990.
Intractability: Multiple myeloma is generally considered intractable, meaning it is challenging to cure. While treatments can manage symptoms and improve quality of life, the disease often relapses and becomes more difficult to treat over time. Advances in medical therapies have extended survival rates, but a definitive cure remains elusive.
Disease Severity: Multiple myeloma is a type of blood cancer that affects plasma cells in the bone marrow. The disease severity can vary depending on several factors, including the stage at diagnosis, the extent of organ damage, and response to treatment. It is generally classified into three stages using the Revised International Staging System (R-ISS), which considers factors like levels of serum albumin, beta-2 microglobulin, lactate dehydrogenase (LDH), and certain genetic abnormalities. Treatment aims to control the disease, alleviate symptoms, and improve quality of life, as it is usually considered a chronic condition that can be managed but not cured.
Healthcare Professionals: Disease Ontology ID - DOID:9538
Pathophysiology: B lymphocytes start in the bone marrow and move to the lymph nodes. As they progress, they mature and display different proteins on their cell surfaces (cell surface antigens). When they are activated to secrete antibodies, they are known as plasma cells.Multiple myeloma develops in B lymphocytes after they have left the part of the lymph node known as the germinal center. The normal cell type most closely associated with MM cells is generally taken to be either an activated memory B cell or the precursor to plasma cells, the plasmablast.The immune system keeps the proliferation of B cells and the secretion of antibodies under tight control. When chromosomes and genes are damaged, often through rearrangement, this control is lost. Often, a promoter gene moves (or translocates) to a chromosome, where it stimulates an antibody gene to overproduction.A chromosomal translocation between the immunoglobulin heavy chain gene (on chromosome 14, locus q32) and an oncogene (often 11q13, 4p16.3, 6p21, 16q23 and 20q11) is frequently observed in people with multiple myeloma. This mutation results in dysregulation of the oncogene which is thought to be an important initiating event in the pathogenesis of myeloma. The result is a proliferation of a plasma cell clone and genomic instability that leads to further mutations and translocations. The chromosome 14 abnormality is observed in about 50% of all cases of myeloma. Deletion of (parts of) chromosome 13 is also observed in about 50% of cases.
Production of cytokines (especially IL-6) by the plasma cells causes much of their localized damage, such as osteoporosis, and creates a microenvironment in which the malignant cells thrive. Angiogenesis (the generation of new blood vessels) is increased.The produced antibodies are deposited in various organs, leading to kidney failure, polyneuropathy, and various other myeloma-associated symptoms.
Carrier Status: Multiple myeloma is a type of blood cancer that originates in plasma cells, a type of white blood cell found in bone marrow. It is not an infectious disease, so the concept of a carrier status does not apply. It is also not inherited in a straightforward Mendelian fashion, though genetic factors may contribute to an individual's risk of developing the disease.
Mechanism: Multiple myeloma is a type of blood cancer that affects plasma cells in the bone marrow. The mechanisms and molecular mechanisms of multiple myeloma involve several complex processes:

1. **Clonal Proliferation**: The disease begins with the clonal proliferation of a single plasma cell that has acquired genetic mutations. These mutations can lead to the uncontrolled growth of plasma cells.

2. **Genetic Mutations and Chromosomal Abnormalities**: Multiple myeloma is associated with various genetic mutations and chromosomal abnormalities, including translocations (e.g., t(11;14), t(4;14)), deletions (e.g., del(17p)), and amplifications. These genetic alterations often involve genes that regulate cell cycle, apoptosis, and DNA repair mechanisms.

3. **Bone Marrow Microenvironment**: The bone marrow microenvironment plays a crucial role in disease progression. Interactions between myeloma cells and the bone marrow stroma enhance cell survival and proliferation. Growth factors, cytokines, and chemokines produced in the bone marrow contribute to this supportive environment.

4. **Signaling Pathways**: Aberrant activation of multiple signaling pathways is common in multiple myeloma. Key pathways include:
- **MAPK/ERK Pathway**: Promotes cell growth and survival.
- **PI3K/AKT Pathway**: Involved in cell survival and resistance to apoptosis.
- **NF-κB Pathway**: Plays a significant role in inflammation, cell growth, and survival.
- **JAK/STAT Pathway**: Contributes to cell proliferation and drug resistance.

5. **Immune Evasion**: Myeloma cells develop mechanisms to evade the immune response, including the suppression of T-cell activity and reduced antigen presentation. This helps them to survive and proliferate unchecked.

6. **Bone Disease**: The interaction between myeloma cells and osteoclasts (cells that break down bone) leads to bone destruction and the release of growth factors that further fuel myeloma cell growth.

Understanding these mechanisms is crucial for developing targeted therapies to treat multiple myeloma effectively.
Treatment: Most drug therapies employ multiple agents, e.g., so-called "triplet" or "quadruplet" therapies. Many such groupings include one or more of a monoclonal antibody (e.g., isatuximab or daratumumab), an immunomodulatory agent (e.g., lenalidomide or pomalidomide), and a proteasome inhibitor (e.g., or bortezomib, carfilzomib or ixazomib), in combination with a steroid (e.g., dexamethasone).While triplet therapies were the standard of care for many years, current practice more commonly applies quadruplets of drugs. Such combination therapies are commonly referenced by initials, employing upper-case letters for drug brandnames and lower-case letters for generic drug names, e.g., VRd for Velcade (brandname for bortezomib), Revlimid (brandname for lenalidomide) and dexamethasone. Similarly with DKRd, with the D representing Darzalex (brandname for daratumumab), and K representing Kyprolis (brandname for carfilzomib). (Emerging practice is not to call such drugs "chemotherapy" because they are not the traditional non-specific intracellular poisons that operate in the classic "chemo" fashion of inhibiting mitosis or inducing DNA damage.)
Commonly, the efficacy of each drug diminishes over time, as the cancer develops drug resistance mechanisms, such as by clonal evolution or genetic mutations. In part for this reason, multiple myeloma has not historically been treated when in its "smoldering" stage, since the drug(s) utilized may then be of diminished efficacy if the disease progresses to a symptomatic stage. Thus, the standard of care was "watchful waiting" while the disease smoldered. Increasingly, however, efforts are underway to study whether drug therapies applied during the smoldering stage might prevent the disease from ever advancing to the active stage. Exemplary are the GEM-CESAR, ASCENT and Immuno-PRISM clinical trials.
After drug therapy has reduced a patient's cancer burden, some patients undergo a bone marrow transplant (more properly termed a autologous hematopoietic stem cell transplant, or ASCT) to further suppress the disease. However, this procedure is not available for frail patients, as it essentially resets aspects of the immune system and requires redevelopment of natural defenses, such as by administering childhood vaccines.Increasingly, precision medicine therapies are being explored, with research indicating that certain variants and genetic sub-types of the disease respond more favorably to some drug therapies than others. For example, some research indicates that patients with the t(11,14) genetic translocation (present in about 15-20% of multiple myeloma patients) may particularly benefit from Venetoclax therapy (which is FDA approved for other blood cancers but not yet available for multiple myeloma patients except through clinical trials).While drug therapies commonly entail months or years of treatment, CAR-T therapy offers the alternative of a single treatment (albeit involving a prolonged hospital stay). Moreover, CAR-T treatment seems to provide a deeper, longer lasting disease remission than existing drugs. Presently, however, such therapy is FDA-approved only for patients in later stages of the disease, and is available only at certain medical centers.An upcoming therapy that also leverages T-cell immune response is the class of drugs termed bispecific T-cell engagers (BITE), or sometimes simply bispecific antibodies. The first drug in this class approved for multiple myeloma is Teclistamab, but again its use is presently reserved for patients in later stages of the disease. Another BITE drug,Talquetamab, is under study; others are in the pipeline. (Ongoing clinical trials are investigating BITE therapy for smoldering and newly diagnosed patients.)
Some patients seek out clinical drug trials, as these provide a degree of medical oversight not present in most other clinical settings – not to mention access to new drugs that seem to hold promise over existing therapies. Some patients temporarily relocate to urban areas where such trials are available.
The major cancer research institutes offer the most clinical trials, but some trials (particularly later-stage, Phase 3, trials) are available at satellite networks that extend to hundreds of hospitals. The U.S. National Institutes of Health maintains a directory of clinical trials. In the U.S., cities such as New York, Boston, Houston and Rochester host leading multiple myeloma research efforts; globally, other top-tier myeloma research programs are found at the University of Salamanca, Spain, and at Vrije Universiteit Brussels, amongst others.
Medical information soon becomes outdated in fast-moving medical arenas, such as therapies for multiple myeloma, so oncologists at smaller medical centers may not be able to stay up-to-date with the literature in all relevant disciplines. This has given rise to organizations that work to educate patients on latest developments in the disease, e.g., by offering webinars featuring prominent researchers and practitioners who focus on multiple myeloma; examples of such organisations are the International Myeloma Foundation and the Multiple Myeloma Research Foundation. Some patients interested in following latest developments review proceedings from major hematologic cancer conferences, such as the American Society of Hematologists (ASH) Conference, the American Society of Clinical Oncology (ASCO) Conference, the IMF IMWG Summit, and the European Hematology Association (EHA) Annual Conference.Treatment is indicated in myeloma with symptoms. If there are no symptoms, but a paraprotein typical of myeloma and diagnostic bone marrow is present without end-organ damage, treatment is usually deferred or restricted to clinical trials. Treatment for multiple myeloma is focused on decreasing the clonal plasma cell population and consequently decrease the symptoms of disease.
Compassionate Use Treatment: Compassionate use treatment and off-label or experimental treatments for multiple myeloma are options for patients who do not respond to standard therapies or have limited treatment options. These treatments may include:

1. **Compassionate Use Treatment**:
- **Selinexor**: Recently approved for multiple myeloma, it may be available under compassionate use protocols in certain cases.
- **BCMA-Targeted Therapies**: Agents targeting B-cell maturation antigen (BCMA), such as certain CAR T-cell therapies and bispecific antibodies, may be available through compassionate use.

2. **Off-Label Treatments**:
- **Pomalidomide (Pomalyst)**: Used to treat patients who have previously been treated with other medications and whose disease has progressed.
- **Panobinostat (Farydak)**: A histone deacetylase inhibitor, sometimes used in combination with other drugs for multiple myeloma.

3. **Experimental Treatments**:
- **Immunotherapies**: Including CAR T-cell therapy targeting BCMA and bispecific T-cell engagers (BiTEs).
- **Venetoclax**: Often used for specific subtypes of multiple myeloma, particularly those with certain genetic abnormalities such as the t(11;14) translocation.
- **Checkpoint Inhibitors**: Such as pembrolizumab, being evaluated in combination with other standard therapies.

These options are typically considered when a patient has exhausted standard treatment options and are often accessible through clinical trials or special access programs.
Lifestyle Recommendations: For multiple myeloma, lifestyle recommendations include:

1. **Balanced Diet**: Focus on a nutritious diet with plenty of fruits, vegetables, whole grains, lean proteins, and healthy fats to help maintain your strength and energy levels.

2. **Hydration**: Drink plenty of fluids to stay hydrated, which is especially important if you're undergoing treatment that can be dehydrating.

3. **Regular Exercise**: Engage in moderate physical activities like walking, swimming, or yoga to improve your strength and overall well-being. Always consult your healthcare provider before starting any exercise regimen.

4. **Avoid Infections**: Practice good hygiene, avoid large crowds, and stay away from people who are sick, as your immune system may be compromised.

5. **Rest and Sleep**: Ensure you get adequate rest and sleep to help your body recover and manage fatigue.

6. **Quit Smoking and Limit Alcohol**: Avoid smoking and limit alcohol consumption, as these can interfere with your treatment and overall health.

7. **Stress Management**: Techniques like mindfulness, meditation, and counseling can help manage the emotional and psychological impact of the disease.

8. **Regular Medical Check-ups**: Maintain regular appointments with your healthcare team to monitor your condition and adjust treatments as necessary.

These lifestyle adjustments can support your treatment and improve quality of life.
Medication: In the treatment of multiple myeloma, various medications are used. Common categories include:

1. **Immunomodulatory Drugs**: Examples include lenalidomide (Revlimid) and pomalidomide (Pomalyst).
2. **Proteasome Inhibitors**: Examples include bortezomib (Velcade) and carfilzomib (Kyprolis).
3. **Monoclonal Antibodies**: Examples include daratumumab (Darzalex) and elotuzumab (Empliciti).
4. **Chemotherapy**: Examples include melphalan and cyclophosphamide.
5. **Steroids**: Examples include dexamethasone and prednisone.

These medications can be used in combination depending on the patient's specific condition and response to treatment.
Repurposable Drugs: Repurposable drugs for multiple myeloma include:
- Thalidomide: Originally developed as a sedative, it is now used for its immunomodulatory effects.
- Lenalidomide: A derivative of thalidomide, it also has immunomodulatory and anti-angiogenic properties.
- Bortezomib: Initially developed for other malignancies, it inhibits proteasomes and is used in multiple myeloma treatment.
Metabolites: In the context of multiple myeloma, metabolites refer to the small molecules that are produced or altered during metabolism which can be influenced by the cancer's presence. These can include abnormal proteins like monoclonal immunoglobulins or light chains, elevated levels of calcium, and increased levels of markers such as beta-2 microglobulin. Monitoring these metabolites helps in diagnosing and tracking the progression of the disease.
Nutraceuticals: The role of nutraceuticals (food-derived products with potential health benefits) in multiple myeloma is an area of ongoing research. Some commonly studied nutraceuticals include:

- **Curcumin:** Found in turmeric, curcumin has shown anti-inflammatory and anti-cancer properties in some studies. It may inhibit the growth of myeloma cells and enhance the effectiveness of certain chemotherapy drugs.

- **Resveratrol:** Present in red grapes and berries, resveratrol has antioxidant and anti-cancer characteristics. Laboratory studies have suggested that it might induce cell death in myeloma cells and inhibit their proliferation.

- **Green Tea Polyphenols (EGCG):** Epigallocatechin gallate (EGCG), a major component of green tea, has been found to have multiple anti-cancer effects, including inducing apoptosis (programmed cell death) and inhibiting cell growth in myeloma.

It's important to remember that while these nutraceuticals show promise in laboratory studies, their effectiveness in humans with multiple myeloma is still under investigation. Always consult a healthcare professional before starting any new supplement regimen.

Nanotechnology (nan): In the context of multiple myeloma, nanotechnology is being explored for its potential to improve diagnosis and treatment. Some applications include:

- **Targeted Drug Delivery:** Nanoparticles can be engineered to deliver chemotherapy drugs directly to myeloma cells, minimizing damage to healthy cells and reducing side effects.

- **Imaging:** Nanoparticles can enhance imaging techniques like MRI and CT scans, helping to detect multiple myeloma at earlier stages or monitor disease progression more effectively.

- **Therapeutics:** Nanotechnology can also support the development of new therapeutic approaches, such as using nanoparticles to deliver gene therapy or immunotherapy specifically to myeloma cells.

While these nanotechnology solutions are promising, many are still in the experimental or clinical trial stages. Further research is needed to establish their safety and effectiveness for routine clinical use in multiple myeloma patients.
Peptides: In the context of multiple myeloma, peptides and nanoparticles (nan) represent emerging areas of research and therapy.

1. **Peptides:**
- Peptides are small chains of amino acids that can be used in multiple myeloma for diagnostic and therapeutic purposes.
- Therapeutic peptides can target specific pathways involved in the proliferation of myeloma cells, potentially inhibiting their growth.
- Peptide-based vaccines are being explored to stimulate the immune system to recognize and attack myeloma cells.

2. **Nanoparticles:**
- Nanoparticles can be designed to deliver drugs directly to myeloma cells, enhancing the efficacy and reducing the side effects of chemotherapy.
- They can also be used for imaging purposes, improving the detection and monitoring of the disease.
- Research is ongoing to develop multifunctional nanoparticles that combine diagnostic and therapeutic functions (theranostics) for more personalized treatment approaches.

These innovations hold promise for improving the management and outcomes of multiple myeloma.