Multiple Myeloma: Symptoms, Causes & Treatment Guide

What Is Multiple Myeloma?

Multiple myeloma is a blood cancer that develops from plasma cells—white blood cells that normally produce antibodies to fight infections. In myeloma, these plasma cells become malignant, multiply uncontrollably in the bone marrow, and produce abnormal proteins that can damage bones, kidneys, and the immune system. The condition accounts for approximately 1% of all cancers and 10% of blood cancers.

Understanding multiple myeloma requires knowledge of how plasma cells normally function in the body. Plasma cells are a specialized type of B lymphocyte (a white blood cell) that matures in the bone marrow and produces antibodies, also known as immunoglobulins. These antibodies are essential proteins that help the immune system recognize and fight bacteria, viruses, and other pathogens. Each plasma cell is programmed to produce one specific type of antibody.

In multiple myeloma, a single plasma cell undergoes genetic mutations that cause it to become cancerous. This malignant cell then multiplies rapidly, creating many identical copies of itself—hence the term "multiple" in the name. These abnormal plasma cells, called myeloma cells, crowd the bone marrow and interfere with the production of normal blood cells. They also secrete large amounts of a single type of antibody or antibody fragment, known as monoclonal protein or M-protein, which can accumulate in the blood and urine.

The "myeloma" part of the name refers to the bone marrow (myelo- meaning marrow), where the disease originates and primarily affects. Unlike some other blood cancers that may circulate freely in the bloodstream, myeloma cells tend to remain clustered in the bone marrow, though they can spread to multiple sites throughout the skeleton—leading to the characteristic bone problems associated with this condition.

How Does Multiple Myeloma Develop?

Multiple myeloma typically develops through a progressive series of stages. Nearly all cases of myeloma are preceded by a precursor condition called monoclonal gammopathy of undetermined significance (MGUS). MGUS is relatively common, affecting approximately 3% of people over age 50, and involves the presence of M-protein in the blood without the harmful effects of myeloma. Only about 1% of people with MGUS progress to myeloma each year.

Between MGUS and active myeloma lies an intermediate stage called smoldering multiple myeloma (SMM). In this stage, there are more plasma cells in the bone marrow and higher levels of M-protein than in MGUS, but still no organ damage or symptoms. Approximately 10% of people with smoldering myeloma progress to active myeloma each year for the first five years, with the rate decreasing afterward. Some high-risk smoldering myeloma patients may be offered early treatment in clinical trials.

The progression from MGUS to smoldering myeloma to active myeloma involves the accumulation of additional genetic mutations in the plasma cells. These mutations affect genes controlling cell growth, survival, and interaction with the bone marrow environment. Common genetic abnormalities in myeloma include translocations involving chromosome 14 (where the immunoglobulin genes are located), deletions of chromosome 17p, and gains of chromosome 1q. Understanding these genetic changes is important because they influence prognosis and treatment decisions.

What Are the Symptoms of Multiple Myeloma?

The main symptoms of multiple myeloma are summarized by the acronym CRAB: elevated Calcium (hypercalcemia), Renal (kidney) problems, Anemia, and Bone lesions or pain. Many patients first notice persistent back pain, fatigue, frequent infections, or unexplained weight loss. Some people have no symptoms initially and are diagnosed through abnormal blood test results.

The symptoms of multiple myeloma arise from the effects of malignant plasma cells on the bone marrow and other organs, as well as from the abnormal proteins they produce. These symptoms can develop gradually over months or years, or they may appear more suddenly if the disease progresses rapidly. Understanding these symptoms is crucial for early detection and prompt treatment.

Bone-related symptoms are among the most common in multiple myeloma, affecting up to 70% of patients at diagnosis. Myeloma cells produce substances that activate osteoclasts (cells that break down bone) while inhibiting osteoblasts (cells that build bone). This imbalance leads to bone destruction, particularly in the spine, pelvis, ribs, and skull. Patients often experience persistent back pain that may be worse at night or with movement. In severe cases, the weakened bones can fracture with minimal trauma—these are called pathological fractures.

Fatigue is one of the earliest and most common symptoms, affecting the vast majority of myeloma patients. This fatigue has multiple causes: anemia from crowding of normal blood-forming cells in the bone marrow, the metabolic burden of the cancer itself, and the effects of elevated calcium or kidney dysfunction. The fatigue in myeloma is often described as profound and not relieved by rest, significantly impacting quality of life and daily activities.

The CRAB Criteria

Medical professionals use the CRAB criteria to identify organ damage from myeloma that indicates the need for treatment:

Infection Susceptibility

Patients with multiple myeloma are significantly more prone to infections, particularly bacterial infections like pneumonia. This increased susceptibility occurs because the malignant plasma cells crowd out the normal immune cells, and the abnormal M-protein produced by myeloma cells does not function properly as an antibody. Additionally, myeloma and its treatments can suppress the normal immune response. Recurrent infections, especially respiratory infections, may be one of the first signs that leads to a myeloma diagnosis.

Neurological Symptoms

Neurological problems can occur in multiple myeloma through several mechanisms. Spinal cord compression from vertebral collapse or direct tumor spread is a medical emergency that can cause back pain, leg weakness, numbness, and loss of bladder or bowel control. Peripheral neuropathy—numbness, tingling, or pain in the hands and feet—can result from the disease itself or as a side effect of certain treatments. Hyperviscosity syndrome, where the blood becomes too thick from excess M-protein, can cause headaches, vision changes, confusion, and stroke-like symptoms.

What Causes Multiple Myeloma?

The exact cause of multiple myeloma is unknown, but it develops when genetic mutations accumulate in plasma cells, causing them to grow uncontrollably. Risk factors include age over 65, male gender, African ancestry, family history of myeloma or MGUS, obesity, and history of MGUS. Environmental exposures like radiation and certain chemicals may increase risk.

Multiple myeloma, like most cancers, develops through a complex interplay of genetic mutations and environmental factors. While researchers have identified several genetic abnormalities common in myeloma cells, the exact trigger that initiates the malignant transformation remains unclear. What is known is that the disease involves a stepwise accumulation of genetic changes over time, typically over many years.

The genetic mutations in myeloma affect various cellular processes. Primary genetic events, which occur early in disease development, often involve translocations (exchanges of genetic material) affecting chromosome 14, where the immunoglobulin heavy chain gene is located. These translocations bring oncogenes (cancer-promoting genes) under the control of the highly active immunoglobulin promoter, leading to overexpression. Other primary events include hyperdiploidy, where cells gain extra chromosomes. Secondary genetic events, which occur as the disease progresses, include deletions of chromosome 17p (which contains the tumor suppressor gene TP53), gains of chromosome 1q, and various other mutations.

Risk Factors for Multiple Myeloma

Several factors have been associated with an increased risk of developing multiple myeloma:

• Age: The risk increases significantly with age. Multiple myeloma is rare before age 40, with fewer than 2% of cases occurring in people under 40. The median age at diagnosis is 69 years, and the incidence continues to rise with advancing age.
• Gender: Men are approximately 1.4 times more likely to develop myeloma than women. The reasons for this difference are not fully understood.
• Race and ethnicity: African Americans have about twice the risk of developing multiple myeloma compared to white Americans. The incidence is also higher in people of African descent globally. This disparity appears to be due to both genetic factors and higher rates of MGUS in this population.
• Family history: Having a first-degree relative (parent, sibling, or child) with multiple myeloma, MGUS, or other B-cell cancers increases risk approximately 2-4 fold. This suggests that inherited genetic factors play a role.
• MGUS: Monoclonal gammopathy of undetermined significance is the primary precursor to myeloma. People with MGUS have about a 1% per year risk of progressing to myeloma or a related condition.
• Obesity: Higher body mass index (BMI) is associated with increased risk of myeloma. Studies suggest that for every 5 kg/m² increase in BMI, the risk increases by about 12%.

Environmental and Occupational Exposures

Certain environmental and occupational exposures have been linked to increased myeloma risk, though the evidence is not as strong as for the factors listed above:

Radiation exposure, particularly in survivors of atomic bomb blasts and those receiving high-dose radiation therapy, has been associated with increased myeloma risk. However, routine diagnostic X-rays are not considered a significant risk factor.

Occupational exposures to various chemicals and substances have been studied. Farmers and agricultural workers have shown slightly elevated risk, possibly related to pesticide exposure. Workers in the petroleum industry, rubber manufacturing, and leather processing have also shown some increased risk in epidemiological studies. Exposure to benzene, a known carcinogen, has been suggested as a possible risk factor.

Immune system factors may also play a role. Conditions that chronically stimulate the immune system or cause ongoing inflammation may increase risk. Additionally, certain autoimmune conditions and HIV infection have been associated with slightly elevated myeloma risk.

How Is Multiple Myeloma Diagnosed?

Multiple myeloma is diagnosed through blood tests (showing M-protein via serum protein electrophoresis, and abnormal free light chains), urine tests (detecting Bence Jones protein), bone marrow biopsy (showing ≥10% plasma cells), and imaging (X-rays, CT, MRI, or PET-CT to detect bone lesions). The IMWG criteria require specific findings to confirm diagnosis.

Diagnosing multiple myeloma involves a comprehensive evaluation including blood tests, urine tests, bone marrow examination, and imaging studies. The diagnostic process aims to confirm the presence of myeloma, assess the extent of disease, and identify characteristics that will guide treatment decisions. Because the symptoms of myeloma can be vague and overlap with other conditions, diagnosis may sometimes be delayed.

The journey to diagnosis often begins when a patient reports symptoms such as persistent back pain, fatigue, or recurrent infections, or when routine blood work reveals abnormalities such as elevated protein levels, anemia, or kidney dysfunction. Sometimes myeloma is discovered incidentally during workup for other conditions.

Blood and Urine Tests

Several blood and urine tests are essential for diagnosing and monitoring multiple myeloma:

Serum protein electrophoresis (SPEP) separates proteins in the blood by electrical charge and size. In myeloma, this test typically reveals a distinctive spike (M-spike) representing the monoclonal protein produced by the myeloma cells. This test can quantify the amount of M-protein present.

Immunofixation electrophoresis (IFE) identifies the specific type of M-protein—which immunoglobulin type (IgG, IgA, IgM, IgD, or IgE) and which light chain type (kappa or lambda). This is more sensitive than SPEP and helps characterize the disease.

Serum free light chain (FLC) assay measures the levels of kappa and lambda light chains circulating freely in the blood. An abnormal ratio between these light chains is highly suggestive of a plasma cell disorder. This test is particularly important in cases where the myeloma produces only light chains and no complete antibody.

Complete blood count (CBC) often reveals anemia (low red blood cells), and may show low platelets or white blood cells if the bone marrow is heavily infiltrated with myeloma cells.

Comprehensive metabolic panel assesses kidney function (creatinine, BUN), calcium levels, and other parameters that may be affected by myeloma.

24-hour urine collection for urine protein electrophoresis (UPEP) and immunofixation can detect Bence Jones protein (monoclonal light chains in urine), which occurs when excess light chains are filtered by the kidneys.

Bone Marrow Biopsy

A bone marrow biopsy is essential for confirming the diagnosis of multiple myeloma. This procedure, typically performed on the hip bone under local anesthesia, obtains samples of both liquid marrow (aspirate) and solid marrow tissue (core biopsy). These samples are examined to determine the percentage of plasma cells present and their appearance.

For a diagnosis of multiple myeloma, the bone marrow must contain at least 10% clonal plasma cells (plasma cells that are genetically identical) or a biopsy-proven plasmacytoma (a tumor of plasma cells outside the bone marrow). In addition to cell counting, the bone marrow sample undergoes several specialized tests including flow cytometry (to identify cell surface markers) and genetic testing to identify chromosomal abnormalities that affect prognosis and treatment.

Imaging Studies

Imaging is crucial for detecting bone involvement and assessing disease extent:

• Whole-body low-dose CT: The preferred initial imaging modality, detecting bone lesions more sensitively than standard X-rays
• MRI: Particularly useful for evaluating the spine and detecting bone marrow involvement before lytic lesions develop
• PET-CT: Helps identify active disease sites and is increasingly used for staging and assessing treatment response
• Skeletal survey (X-rays): Traditional method, now largely replaced by CT but still used in some settings

Diagnostic Criteria

The International Myeloma Working Group (IMWG) updated criteria for diagnosing multiple myeloma require:

Clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma, PLUS one or more of the following myeloma-defining events:

• Evidence of end-organ damage (CRAB criteria): hypercalcemia, renal insufficiency, anemia, or bone lesions
• OR any of the following biomarkers of malignancy:
  • Bone marrow plasma cells ≥60%
  • Serum free light chain ratio ≥100 (with involved light chain ≥100 mg/L)
  • More than one focal lesion on MRI (each ≥5mm)

What Are the Stages of Multiple Myeloma?

Multiple myeloma is staged using the Revised International Staging System (R-ISS), which classifies patients into Stage I, II, or III based on serum albumin, beta-2 microglobulin, LDH levels, and high-risk genetic abnormalities. Higher stages indicate more advanced disease and generally predict shorter survival, though individual outcomes vary greatly with modern treatments.

Staging in multiple myeloma serves to estimate prognosis and guide treatment intensity rather than describe anatomical spread as in solid tumors. Because myeloma is a blood cancer that inherently involves multiple sites in the bone marrow, traditional cancer staging based on tumor location and spread is not applicable. Instead, staging systems use laboratory values and genetic markers that reflect tumor burden and biological aggressiveness.

The Revised International Staging System (R-ISS), introduced in 2015, is the current standard for staging newly diagnosed multiple myeloma. It builds upon the original International Staging System (ISS) by incorporating information about cytogenetic (chromosomal) abnormalities and serum lactate dehydrogenase (LDH), which provide additional prognostic information.

R-ISS Staging Criteria

High-Risk Genetic Features

Certain chromosomal abnormalities in myeloma cells are associated with more aggressive disease and shorter survival. These high-risk features include:

• Deletion 17p (del(17p)): Loss of part of chromosome 17 containing the tumor suppressor gene TP53; associated with the poorest prognosis
• Translocation t(4;14): Exchange between chromosomes 4 and 14; responds well initially but tends to relapse
• Translocation t(14;16) and t(14;20): Less common but also high-risk
• Gain of chromosome 1q (gain 1q): Extra copies associated with worse outcomes

Patients with multiple high-risk genetic features (so-called "double-hit" or "triple-hit" myeloma) have particularly challenging disease that may require more intensive treatment approaches and clinical trial participation.

How Is Multiple Myeloma Treated?

Multiple myeloma treatment combines several approaches: induction therapy with drug combinations (typically including a proteasome inhibitor, immunomodulatory drug, and steroid), followed by stem cell transplantation for eligible patients, then maintenance therapy. Novel agents include monoclonal antibodies (daratumumab), CAR-T cell therapy, and bispecific antibodies for relapsed disease. Supportive care addresses bone health, infection prevention, and symptom management.

The treatment of multiple myeloma has advanced dramatically over the past two decades, transforming it from a rapidly fatal disease to a chronic condition that many patients live with for years or even decades. Treatment strategy depends on several factors including the patient's age and fitness level, disease stage and risk features, and personal preferences. The goals of treatment are to control the disease, relieve symptoms, preserve quality of life, and extend survival.

Treatment for newly diagnosed myeloma typically follows a sequential approach: induction therapy to rapidly reduce disease burden, consolidation with high-dose chemotherapy and autologous stem cell transplant (for eligible patients), and maintenance therapy to prolong remission. Patients who are not candidates for transplant receive extended induction therapy followed by maintenance.

Induction Therapy

Induction therapy uses combinations of drugs to quickly reduce myeloma cells and M-protein levels. Modern regimens typically include three or four drugs from different classes working together:

Proteasome inhibitors (bortezomib, carfilzomib, ixazomib) block the cellular machinery that breaks down proteins, causing myeloma cells to accumulate toxic proteins and die. Bortezomib has been a backbone of myeloma treatment for over 15 years.

Immunomodulatory drugs (IMiDs) (lenalidomide, pomalidomide, thalidomide) work through multiple mechanisms including direct toxicity to myeloma cells, stimulating the immune system, and disrupting the bone marrow environment that supports myeloma growth.

Corticosteroids (dexamethasone, prednisone) directly kill myeloma cells and enhance the effects of other drugs. They are included in almost all myeloma treatment regimens.

Monoclonal antibodies (daratumumab, isatuximab, elotuzumab) target specific proteins on myeloma cells. Daratumumab, which targets CD38, has become standard in first-line treatment and is often added to make "quadruplet" regimens.

Common induction regimens include VRd (bortezomib-lenalidomide-dexamethasone), often with the addition of daratumumab (D-VRd or Dara-VRd) for transplant-eligible patients. Treatment typically lasts 3-6 cycles before transplant or 8-12 cycles for non-transplant patients.

Stem Cell Transplantation

Autologous stem cell transplantation remains a standard component of treatment for eligible patients, typically those under age 70 with adequate organ function. In this procedure, the patient's own stem cells are collected from the blood after mobilization with growth factors, stored, and then reinfused after high-dose chemotherapy (usually melphalan) that kills remaining myeloma cells. The transplant allows the bone marrow to recover from this intensive treatment.

Studies show that transplant in the current era of effective drug therapy continues to provide benefits in terms of depth and duration of response. However, the question of optimal timing (early vs. delayed transplant) and whether all patients need transplant with newer drugs is being actively studied.

Maintenance Therapy

After achieving remission from induction therapy (with or without transplant), most patients receive ongoing maintenance therapy to prevent or delay relapse. Lenalidomide is the most commonly used maintenance drug, though other options include bortezomib (particularly for high-risk patients) or ixazomib. Maintenance continues until disease progression or intolerable side effects.

Treatment for Relapsed/Refractory Myeloma

Despite effective initial treatment, multiple myeloma eventually relapses in most patients, often with resistance to previously used drugs. Treatment at relapse typically involves combinations of agents from different classes than those used previously. Several newer therapies have transformed outcomes for relapsed myeloma:

CAR-T cell therapy (idecabtagene vicleucel, ciltacabtagene autoleucel) involves genetically engineering a patient's own T cells to recognize and attack myeloma cells expressing BCMA protein. These treatments can produce deep remissions in heavily pretreated patients.

Bispecific antibodies (teclistamab, elranatamab, talquetamab) are newer "off-the-shelf" immunotherapies that bring T cells into contact with myeloma cells to kill them. They offer CAR-T-like efficacy without the need for complex manufacturing.

Additional drugs used at relapse include selinexor (XPO1 inhibitor), belantamab mafodotin (antibody-drug conjugate), and venetoclax (for patients with t(11;14) translocation).

Supportive Care

Supportive care is essential throughout the myeloma journey:

• Bone protection: Bisphosphonates (zoledronic acid) or denosumab to reduce bone complications
• Infection prevention: Vaccinations, sometimes prophylactic antibiotics or antivirals, immunoglobulin replacement if needed
• Blood support: Transfusions, growth factors for anemia
• Kidney protection: Hydration, avoiding nephrotoxic drugs, treating underlying myeloma
• Pain management: Appropriate analgesics, radiation for painful bone lesions
• Blood clot prevention: Aspirin or anticoagulants during certain treatments

What Is Life Like Living with Multiple Myeloma?

Living with multiple myeloma means adapting to a chronic condition requiring ongoing treatment and monitoring. Most patients achieve periods of remission with good quality of life, though side effects and treatment burden vary. Regular blood tests monitor disease activity, and attention to bone health, infection prevention, and emotional wellbeing are important aspects of daily life.

A diagnosis of multiple myeloma marks the beginning of a journey that requires significant adjustment—physically, emotionally, and practically. However, with modern treatments, many patients live active lives for years or decades. Understanding what to expect can help patients and families prepare and cope effectively.

Treatment for myeloma is typically ongoing rather than curative. After initial intensive treatment, most patients enter a phase of maintenance therapy that may continue for years. This means regular clinic visits, ongoing medication with potential side effects, and periodic testing to monitor disease status. Finding a sustainable routine that integrates treatment into daily life is an important part of adaptation.

Managing Treatment Side Effects

Different myeloma treatments cause different side effects, and managing these is crucial for quality of life:

Peripheral neuropathy (numbness, tingling, pain in hands and feet) is common with proteasome inhibitors and some other drugs. Dose adjustments, supportive medications, and physical therapy can help manage this.

Fatigue remains one of the most challenging symptoms, whether from the disease, treatment, or anemia. Energy conservation strategies, appropriate exercise, and treatment of contributing factors (anemia, thyroid dysfunction) can help.

Gastrointestinal issues including nausea, diarrhea, and constipation often occur with treatment and can usually be managed with appropriate medications and dietary adjustments.

Immune suppression increases infection risk, requiring attention to hand hygiene, avoiding sick contacts, staying current with vaccinations, and prompt attention to signs of infection.

Monitoring and Follow-up

Regular monitoring is essential throughout the myeloma journey. During active treatment, this typically means clinic visits every 1-4 weeks with blood tests to check blood counts, kidney function, and M-protein levels. During maintenance or remission, visits may be less frequent (every 1-3 months) but continue indefinitely.

Key tests for monitoring include serum protein electrophoresis and free light chain assay to track M-protein, complete blood count, and metabolic panel. Periodic imaging may be performed to assess bone status or evaluate for relapse. Understanding your test results and what changes might signal problems helps you participate actively in your care.

Emotional and Psychological Wellbeing

Living with a chronic cancer brings emotional challenges including fear of progression or relapse, anxiety about treatment and side effects, and grief over life changes. Depression and anxiety are common and treatable. Resources that can help include:

• Support groups for myeloma patients (in-person or online)
• Counseling or therapy with professionals experienced in cancer care
• Patient advocacy organizations that provide education and community
• Mindfulness, stress reduction, and coping skills programs
• Open communication with healthcare team about emotional concerns

Practical Considerations

Practical aspects of life may need attention including work adjustments, financial planning (treatment costs, disability if needed), insurance navigation, and family communication. Social workers and patient navigators at treatment centers can help address these needs. Many patients continue working during treatment, though flexibility may be needed for appointments and side effect management.

What Is the Prognosis for Multiple Myeloma?

The prognosis for multiple myeloma has improved dramatically with modern treatments. Overall 5-year survival is approximately 55-60%, but ranges from 40% for high-risk disease to over 80% for standard-risk disease. Many patients now live 10-15+ years. Prognosis depends on disease stage, genetic risk features, response to treatment, age, and overall health.

Discussing prognosis in multiple myeloma requires acknowledging both the realistic challenges of this incurable cancer and the remarkable progress in treatment that has transformed outcomes. Statistics provide general guidance but cannot predict any individual's outcome, and new treatments continue to improve survival for all patients.

The median overall survival for multiple myeloma has more than doubled over the past two decades. In the 1990s, median survival was approximately 3-4 years. Today, with modern three- and four-drug combinations, stem cell transplantation, and effective therapies at relapse, median survival exceeds 7-10 years, and many patients live significantly longer.

Factors Affecting Prognosis

Several factors influence individual prognosis:

Genetic risk features: This is the most important prognostic factor. Patients with standard-risk genetics have median survival often exceeding 10 years. High-risk features like del(17p), t(4;14), t(14;16), and 1q gain are associated with shorter survival and earlier relapse, though new treatments are improving these outcomes.

R-ISS stage: Higher stage disease (more tumor burden, higher β2-microglobulin) is associated with shorter survival, though this gap is narrowing with modern treatment.

Response to treatment: Achieving deep responses, particularly minimal residual disease (MRD) negativity (no detectable disease by sensitive tests), is associated with longer remission and survival.

Age and fitness: Younger, fitter patients who can tolerate more intensive therapy including transplant generally have better outcomes. However, older patients also benefit substantially from age-appropriate treatment.

Kidney function: Patients presenting with significant kidney impairment may have somewhat worse outcomes, though kidney function often improves with effective myeloma treatment.

The Meaning of "Incurable"

Multiple myeloma is generally described as incurable because even with the best treatments, most patients eventually experience relapse. However, this designation may change as treatments improve. Some patients achieve very long remissions lasting decades, raising hope that a fraction may indeed be cured. Ongoing research into CAR-T therapy, bispecific antibodies, and combination immunotherapies may eventually lead to cure for more patients.

Even without cure, the goal of making myeloma a chronic, manageable condition has largely been achieved for many patients. Like other chronic diseases such as diabetes or heart disease, myeloma requires ongoing attention and treatment, but many patients maintain good quality of life for years.