Multiple myeloma (MM) is a cancer of mature plasma cells, which are a type of white blood cell that produces immunoglobulins (antibodies). Antibodies are normally produced to protect the body from microbes, such as bacteria. In multiple myeloma, the monoclonal plasma cells produce a monoclonal immunoglobulin (M-spike) that is dysfunctional, may inhibit the immune system, and can lead to damage to different organs. Advancing MM generally manifests some or all of a constellation of defining events referred to as the CRAB signs: high serum Calcium, Renal failure, Anemia, and Bone lesions and fractures. Myeloma also puts patients at an increased risk for serious infections.^1,2

Multiple myeloma is preceded by precursor conditions known as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). These three conditions together represent a continuum of disease. Determining which patients will progress from lower-risk precursor conditions to active MM is a challenge for physicians and comprises an active area of research. Most patients with MGUS and some with SMM never progress to active MM. Overall, MM and its precursor conditions have a variable clinical course, and treatment-related decisions must be tailored to each patient’s individual risk profile.³

Myeloma is the second-most-common blood cancer in the United States⁴: an estimated 32,000 patients are diagnosed with myeloma every year.⁵ Over a span of five years, there are approximately 230,000 cases worldwide.⁶ Myeloma is more commonly diagnosed in older patients, with a median age at diagnosis between 66 and 70 years.⁷ About 3% of the general population over age 50 is thought to have MGUS.^8,9 Of these individuals, about 1% per year progress to myeloma or a related cancer.³

Myeloma is considered incurable with current therapies. However, the number of available treatment options has expanded substantially since the mid-1900s. Recent advances in therapeutic strategies, including novel classes of drugs such as proteasome inhibitors, immunomodulatory drugs, immunotherapy, and broader application of autologous stem cell transplantation have all extended the typical survival of patients with myeloma. Today, the likelihood of surviving five years following a myeloma diagnosis is over 70%.¹⁰

Blood Cells and Genes

Blood largely consists of fluid (primarily water) and a combination of three different cell types: platelets that help form clots and control bleeding, red blood cells that deliver oxygen throughout the body, and white blood cells, which are part of the immune system.¹¹ Blood cells grow and develop within bone marrow, the spongy tissue inside bones. Immature blood cells are referred to as hematopoietic stem cells, which develop into young precursor blood cells that eventually mature into platelets, red blood cells, and white blood cells before leaving the bone marrow and entering the bloodstream.

The two types of white blood cells produced in the bone marrow are B cells and T cells. When an invading organism enters the body, B cells mature to plasma cells, which are cells that produce antibodies.¹² Antibodies (also referred to as immunoglobulins) are proteins that circulate in the bloodstream and neutralize invading organisms, such as bacteria and viruses. An antibody is made up of two different kinds of proteins that are named according to their relative size. The smaller protein is called the light chain and the larger protein is called the heavy chain. Each antibody is composed of two heavy chains and two light chains. The heavy chain defines the antibody subtype. There are five different subtypes of antibodies—IgM, IgG, IgA, IgE, and IgD. There are two types of light chains: kappa (κ) and lambda (λ), and either of them can be bound to any of the heavy chains, leading to 10 different types of immunoglobulins. In addition, light chains can be secreted independently of the heavy chain and can circulate as free light chains.¹³

All cells in the body contain genes, which are instructions for how cells function and build new cells.¹¹ Genes are stored in the form of deoxyribonucleic acid (DNA) and organized into long strands called chromosomes. Changes in DNA sequence, which are referred to as mutations, have the potential to turn normal cells into cancer cells. In addition to mutations, a variety of other changes can occur in the chromosomes, including loss, gain, and rearrangements, as well as changes in the way genes are expressed (epigenetic changes).

Basics of Myeloma

Myeloma pathobiology is complex, and many aspects of the development of the disease are poorly understood. In general, myeloma develops as a result of genetic alterations in plasma cells. Unlike healthy mature cells, myeloma cells continue to divide and produce more myeloma cells. This expansion of the cancer cell population occurs in the bone marrow microenvironment and can crowd out healthy cells, reducing the production of other blood cells. Phenomena such as genetic instability and the breakdown of immune surveillance contribute to the expansion of malignant plasma cell populations and progression of MM. Additionally, the expansion of myeloma cell populations inside the bone interferes with typical bone turnover through a variety of complex mechanisms, resulting in bone pain and pathologic fractures.³

Myeloma can inhibit healthy antibody production in the bone marrow microenvironment, thereby suppressing the part of the immune response that is mediated by antibodies.¹⁴ Because antibodies play an important role in protecting the body from bacteria and viruses, patients with myeloma are susceptible to these infections.^15,16

The production of myeloma cells causes an increase in monoclonal proteins in the body. Monoclonal proteins are antibodies that are identical because they were produced by identical (clonal) plasma cells. Another term for monoclonal proteins is M proteins. The majority of patients develop myeloma cells that produce the IgG and IgA subtype of M protein.¹⁷ The remaining subtypes are less common. In addition to the two heavy chains and two light chains required to make a functional antibody, myeloma cells may produce extra light chains unbound to heavy chains called free light chains.¹⁸ This type of myeloma is called light-chain myeloma. Clinicians may use the type of myeloma to monitor disease status and predict the response to treatment and overall course of disease.

Metabolic Processes

All cells in the body require energy to function and survive. Glucose and glutamine are two critical nutrients that provide this energy.¹⁹ Glycolysis is the process of breaking down glucose inside the cell into energy that is usable by the cell.²⁰ Glycolysis can occur under either aerobic (with oxygen) or anaerobic (without oxygen) conditions, although aerobic glycolysis is more efficient. Glutamine is also important for cellular function, as it maintains cellular metabolism and serves as a precursor in the synthesis of nucleic acids.²¹ Glutamine enters the cell and is metabolized by a process called glutaminolysis to produce glutamate, citrate, aspartate, and other amino acids.^22,23

Compared with healthy cells, cancer cells have greater metabolic requirements because they are constantly proliferating and avoiding cell death. They meet this increased demand by altering the metabolic processes related to glycolysis and glutaminolysis.²⁴ Anaerobic glycolysis is enhanced to provide additional energy to malignant cells, a phenomena known as the “Warburg effect.”²⁵ As a result, glycolysis no longer serves as a source of sufficient biosynthetic precursors. To compensate for this, cancer cells enhance the rates of glutaminolysis to increase the conversion of glutamine to α-ketoglutarate and other amino acids required for cellular function.²⁶

Myeloma cells are no exception to altered metabolic pathways present in other cancer cells.¹⁹ Hexokinase II (HKII) catalyzes the first step in glycolysis and has been shown to be upregulated in multiple myeloma cells.²⁷ Conversion of phosphoenolpyruvate into pyruvate and adenosine triphosphate (ATP) is the last step in glycolysis and is mediated by pyruvate kinase (PK). An isoform of PK, known as PKM2, is profuse in cancer cells and has increased expression in myeloma cells, further promoting increased energy production.²⁸ Myeloma cells also show signals of increased glutaminolysis. The myelocytomatosis oncogene (MYC) is often overexpressed in myeloma cells²⁹ and promotes enhanced cellular uptake of glutamine, resulting in increased tumor growth and protein synthesis.³⁰ Researchers are investigating different ways these metabolic alterations could be leveraged as drug targets.³¹

Symptoms

Anemia is present in almost all myeloma patients at some time during the course of disease^17,32 and can manifest as fatigue or generalized weakness. The cause of anemia is often related to bone marrow suppression or kidney damage, which results in reduced number of red blood cells. Myeloma can also reduce the number of platelets in the blood. Platelets stop bleeding when the body is injured, and reduced levels can result in increased bleeding or bruising.

Bone pain occurs in the majority of patients with myeloma and is commonly localized to the axial skeleton (spine, rib cage, and pelvis).¹⁷ This happens when myeloma cells crowd and damage healthy bone, making it more susceptible to fractures. Destruction of bone can result in high calcium blood levels, which may cause excessive thirst, nausea, confusion, and constipation.³³

Patients with MM are at increased risk of bacterial infections due to multifactorial immune deficiency related to the disease itself and to common treatment regimens.^34,35 Patients should monitor themselves for fever, since this is an early sign that the body is fighting an infection.

Around half of patients with MM will experience kidney dysfunction.³⁶ This damage can be caused by high levels of calcium in the blood or damage from the monoclonal proteins filtering through the kidneys into the urine (monoclonal proteins detected in the urine of MM patients are called Bence Jones proteins).³⁷ The use of non-steroidal anti-inflammatory drugs (NSAIDs), like ibuprofen or aspirin, should be avoided in patients with myeloma-induced kidney injury as these types of medications may worsen kidney function.

Neurological problems sometimes arise in MM due to breakdown of bone surrounding the spinal cord or nerve compression by a plasmacytoma, although these are relatively rare manifestations.³⁸

Age

Myeloma is most commonly diagnosed in older adults. The median age at diagnosis of active myeloma is 67‒70 years.³⁹ The incidence of the early-stage myeloma precursor condition, monoclonal gammopathy of undetermined significance (MGUS), increases more than 4-fold between the ages of 50 and 90 years in males.⁴⁰ The prevalence of MGUS was found in one U.S. county to be 5.3% in people over 70 years of age and 7.5% in people over 85 years.⁴¹

Ethnicity

The risk of MGUS is approximately twice as high in blacks compared with whites,^41-43 and the incidence of developing active myeloma in blacks is two to three times higher than in whites.⁴⁴ People of Asian descent may be at lower risk for developing myeloma.⁴⁵

Genetics

Genetic alterations play a role in the development and progression of myeloma and myeloma precursor conditions. While alterations in certain chromosomal regions and specific genes have been identified as playing key roles in the development of MM, research is ongoing to better define the genetic landscape of the disease and clarify potential therapeutic targets.^3,46

The acquisition of new mutations over time can shape how cases of MGUS, SMM, and MM evolve and progress. In some cases, mutations can contribute to the rapid progression from MGUS to SMM and MM. Myeloma cells sometimes acquire new mutations that make them more resistant to treatment. In fact, some evidence suggests that some treatments may select for resistant clones, which subsequently expand and contribute to relapse.^3,47

There is some evidence for heritability of myeloma risk. The risk of developing MGUS or myeloma is about 2- to 4-fold higher in those with a first-degree relative who has been diagnosed.^48-50 However, the number of cases of familial myeloma is believed to be small.

Environmental Exposures

A number of environmental factors are thought to contribute to myeloma, including exposure to certain pesticides and radiation.⁵¹ One study showed that radiologists with high exposure to radiation were at increased risk for developing myeloma.⁵² Another study showed that occupational exposure to some chemicals was also associated with increased risk.⁵³ Agricultural workers who come into contact with livestock or pesticides may be more likely to develop the disease; however, the evidence for these associations is relatively weak.^54-56

Modifiable Risk Factors

Adults with a higher body mass index (BMI) are more susceptible to developing cancer, including myeloma.^57-59 In one study, obesity, defined as a BMI of 30 kg/m² or greater, was associated with a 2.4-fold increased risk of myeloma in men, compared with non-obese males, after accounting for age and physical activity.⁶⁰ A more modest 1.6-fold increase was identified for women with BMIs over 30 kg/m². A strong association between tobacco use and myeloma has also been identified.⁶¹ This effect seems to be most pronounced in women and those smoking more than 20 cigarettes per day.⁶²

Diagnosis

MGUS, the precursor to myeloma, is an asymptomatic, non-cancerous condition where abnormal levels of M proteins are found in the blood.⁶⁸ Only a small number of patients with MGUS develop myeloma. There are two main stages of myeloma: smoldering (or asymptomatic) and symptomatic or active. The difference between smoldering myeloma and active myeloma is the presence of end-organ damage or certain biomarkers indicating high risk of development of end-organ damage. Rarely, active myeloma may progress to a terminal plasma cell dyscrasia known as secondary plasma cell leukemia, which is very aggressive and has a poor prognosis.⁶⁹ Table 1 summarizes typical diagnostic criteria for MGUS, smoldering myeloma, and active myeloma.

Table 1: Definitions of MGUS, Smoldering Myeloma, and Symptomatic Myeloma*

Monoclonal Gammopathy of Undetermined Significance (MGUS)

Non-IgM monoclonal gammopathy of undetermined significance

Serum monoclonal protein (non-IgM type) <30 mg/dL (<30 g/L)

Clonal bone marrow plasma cells <10%

Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder

IgM monoclonal gammopathy of undetermined significance

Serum IgM monoclonal protein <30 mg/dL (<30 g/L)

Bone marrow lymphoplasmacytic infiltration <10%

No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, hepatosplenomegaly, or other end-organ damage that can be attributed to the underlying lymphoproliferative disorder

Light-chain monoclonal gammopathy of undetermined significance

Abnormal FLC ratio (<0.26 or >1.65)

Increased level of the appropriate involved light chain (increased κ FLC in patients with ratio >1.65 and increased λ FLC in patients with ratio <0.26)

No immunoglobulin heavy chain expression on immunofixation

Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder

Clonal bone marrow plasma cells <10%

Urinary monoclonal protein <500 mg/24 h

Smoldering (Asymptomatic) Myeloma

Serum monoclonal protein (IgG or IgA) ≥30 mg/dL (≥30 g/L) or urinary monoclonal protein ≥500 mg per 24 h and/or clonal bone marrow plasma cells 10–60%

Absence of myeloma defining events or amyloidosis

Active Myeloma

Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma** and any one or more of the following myeloma-defining events:

Myeloma defining events:

Evidence of end-organ damage that can be attributed tothe underlying plasma cell proliferative disorder (CRAB features), specifically:

Hypercalcemia: 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 min or serum creatinine >177 μmol/L (>2 mg/dL)

Anemia: hemoglobin value >2 g/dL (>20 g/L) below the lower limit of normal, or hemoglobin value <10 g/dL (<100 g/L)

Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT

Any one or more of the following biomarkers of malignancy:

Clonal bone marrow plasma cell percentage ≥60%

Involved:uninvolved serum free light chain ratio ≥100

>1 focal lesion on MRI studies

*To be interpreted with the help of a clinician skilled in the management of myeloma. Derived from National Comprehensive Cancer Network (NCCN) Guidelines and 2014 International Myeloma Working Group (IMWG) consensus criteria.70,71 **Clonality should be established by showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used.

Testing for Myeloma

Evaluation of a potential myeloma case should involve a complete medical history and physical exam, including a neurological exam. Examination should focus on any signs or symptoms related to bone pain and infections. On occasion, tests for myeloma will be conducted when a separate routine blood test identifies something unusual. If myeloma is suspected, tests should be conducted to examine the blood and bone marrow for evidence of myeloma.^72,73

Complete blood count with differential. A complete blood count (CBC) provides information on the amount of red blood cells, white blood cells, and platelets in the body.⁷⁴ Inclusion of a differential measures each type of white blood cell. These tests help determine the status of a patient’s immune system and can help diagnose anemia.

Blood chemistry panel. A blood chemistry panel can provide information on blood electrolytes and markers of kidney function. High levels of calcium may represent a marker for bone damage in myeloma.⁷⁵ Abnormalities in blood creatinine or urea nitrogen may be indicative of kidney damage.

Tests for serum protein. Serum quantitative immunoglobulin tests measure the amount and type of immunoglobulins in the blood. Typically IgG, IgM, and IgA subtypes are included.⁷⁶ Serum immunofixation electrophoresis shows the type of M proteins present in the blood, while serum protein electrophoresis (SPEP) measures the amount of M proteins in the blood.⁷⁷ Serum free light chain assay allows for estimating the amount of free light chain in the serum and is particularly useful in patients with light chain myeloma.

Tests for urine protein. Similar to tests for blood proteins, there are tests for urine proteins that measure the amount and types of M protein in the urine.⁷⁷

Bone marrow aspiration and biopsy. To confirm diagnosis of myeloma, a small piece of bone marrow and a small amount of bone marrow aspirate are sampled for testing, typically from the hip bone. These tests can determine the number of myeloma cells in the bone marrow and also allow for additional tests on the myeloma cells such as proliferation rate and presence of genetic abnormalities.^78,79

Imaging. X-rays may be used to check for bone damage or fractures resulting from myeloma; however, they are less accurate than other types of imaging. A low-dose computed tomography (CT) scan, which is a series of X-rays put together to assemble a single image,⁸⁰ is sometimes used in combination with a positron emission tomography (PET) scan. A PET scan uses a drug that is injected into the bloodstream to identify possible sites of cancer with high sensitivity.⁸¹ The use of magnetic resonance imaging (MRI), or pictures taken using a series of magnets, has also increased recently as it is more accurate than traditional imaging approaches in identifying abnormalities in both tissue and bone marrow.^82-85

Staging

After diagnosis of myeloma, staging is used to determine how much cancer is in the body. There are two main methods for staging myeloma. The International Staging System (ISS),⁸⁶ which is the more commonly used method, classifies patients into one of three stages based on the amount of beta-2 microglobulin and albumin in the blood. The ISS was revised to include prognostic information based on blood lactate dehydrogenase and genetic abnormalities.⁷ This system is known as the Revised ISS (R-ISS). The second staging system, known as Durie-Salmon Staging,⁸⁷ determines prognosis by classifying patients into one of three stages based on bone marrow tumor density and other markers of organ damage.

Table 2: Comparison of International Staging System and Revised International Staging System*

Method	Stage	Criteria
International Staging System (ISS)	1	Serum β2-microglobulin <3.5 mg/L, Serum albumin >3.5 g/dL
	2	Not meeting criteria for ISS Stage 1 or 3
	3	Serum β2-microglobulin >5.5 mg/L
Revised International Staging System (R-ISS)	1	Criteria for ISS Stage 1, and No high-risk chromosomal abnormality [(t4;14), t(14;16) del 17p], and Serum LDH at or under upper limit of normal
	2	Not meeting criteria for R-ISS Stage 1 or 3
	3	Criteria for ISS Stage 3, and High-risk chromosomal abnormality, or Serum LDH over upper limit of normal
*To be interpreted with the help of a clinician skilled in the management of myeloma. Derived from Palumbo et al.7 and National Comprehensive Cancer Network (NCCN) Guidelines.70 LDH, lactate dehydrogenase.

Prognostic Scoring and Risk Groups

Prognosis and risk stratification are important to help predict the course of disease and determine the likelihood that a patient progresses from MGUS to smoldering myeloma or from smoldering myeloma to active myeloma.⁸⁸ Risk of disease progression is most commonly determined using the amount of myeloma cells in the body, blood labs, and other tests that look at genetic abnormalities.⁸⁹ Additionally, risk stratification is used to guide myeloma treatment. In general, more aggressive treatment approaches are reserved for high-risk patients, while patients stratified into lower risk categories are usually considered for less aggressive treatments that limit exposure to side effects.⁹⁰ However, how to best stratify patients and determine which patients are likely to benefit from early treatment is a matter of ongoing debate and research.

Risk-based stratification for smoldering myeloma. Smoldering myeloma is defined by low levels of M proteins in the blood and lack of end-organ damage at time of diagnosis; however, disease severity and progression risk in patients with smoldering myeloma can vary greatly. Therefore, many attempts have been made to develop methods to accurately categorize patients according to progression risk.

Developing better methods of identifying patients at high risk of progressing from smoldering MM to active MM and stratifying patients according to progression risk are very active areas of MM research. The International Myeloma Working Group (IMWG) is one of the groups at the forefront of myeloma research and has played an influential role in helping establish currently accepted risk stratification classifications. At a presentation at the 2019 American Society of Clinical Oncology annual meeting, researchers associated with the IMWG presented their latest model for risk stratification.⁹¹ The model assigns one point for each of the following risk parameters:

• Free light chain ratio > 20,
• Serum M spike > 2 g/dL,
• Bone marrow plasma cell percentage >20%, and
• Presence of a high-risk genetic factor [t(4,14), t(14,16), 1q gain, or del13q]

After the points have been assigned appropriately, scores are tabulated and assigned to progression risk categories as shown in Table 3.

Table 3: Risk of Progressing from Smoldering Myeloma to Active Multiple Myeloma

Risk Stratification Group	Number of risk factors (points)	Risk of Progression at 2 years
Low risk	0	8%
Low-Intermediate risk	1	21%
Intermediate risk	2	37%
High risk	≥3	59%

New strategies for risk-stratifying that utilize, for example, genomic analyses are being investigated. Recent evidence suggests mutations in genes involved in certain cell-signaling pathways (eg, MAPK, APOBEC) may help identify patients at higher risk of progressing from SMM to MM.⁹² However, these kinds of analyses are not yet generally included in standard risk-stratification assessments because they may not be available in all facilities and more research is needed to validate their predictive value. Hopefully, these kinds of emerging techniques will improve risk-stratification algorithms in the not-too-distant future.

Risk-based stratification for active myeloma. Bone marrow cytogenetics and fluorescence in situ hybridization (FISH) are two tests that can be used to measure genetic abnormalities in patients with active myeloma to evaluate the aggressiveness of disease.⁹³ Abnormalities might occur when genetic material is lost from a chromosome, gained by a chromosome, or moves from one chromosome to another. The human body has 23 pairs of chromosomes. Examples of abnormalities that may put myeloma patients at higher risk for progression include translocation of genetic material between chromosomes 4 and 14 [abbreviated t(4;14)] or loss of genetic material from chromosome 17 [abbreviated del(17p)].⁸⁸ It is recommended that all patients undergo cytogenetic evaluation at the time of diagnosis.⁹⁰ Patients can be assigned to risk groups based on cytogenetic abnormalities as shown in Table 4.

Table 4: Risk-Based Stratification for Active Myeloma

Risk	Description
Standard	All other abnormalities, including t(11;14), t(6;14)
Intermediate	t(4;14), del(13), hypodiploidy, PCLI >3%
High	del(17p), t(14;16), t(14;20)
*To be interpreted with the help of a clinician skilled in the management of myeloma. Derived from Mikhael, et al.90 IgH, immunoglobulin heavy chain; t(), translocation; del(), deletion; PCLI, plasma cell labeling index.

Chemotherapy

Chemotherapy uses intravenous or oral drugs to kill abnormal cells or stop new ones from being made. Chemotherapeutics for treatment of myeloma are commonly used in combination with other drugs, such as steroids. These medications can also affect normal cells, so they are given in varying cycles of treatment days followed by rest. Chemotherapeutic agents may be used alone, prior to stem cell transplantation, or after stem cell transplantation for maintenance.

Proteasome inhibitors, one class of commonly used drugs, work by disrupting mechanisms that cancer cells use to avoid normal cell death.⁹⁴ Bortezomib (Velcade) is one example of a commonly used proteasome inhibitor.^95-98 It is used with lenalidomide (Revlimid), another anti-cancer agent, and dexamethasone, a steroid medication, for first-line treatment of myeloma.^70,99-101 Bortezomib is given as four doses spread over a 21- or 28-day cycle. Side effects observed with this class of medications are similar to other chemotherapeutic agents and include numbness in the hands and feet, nausea, fatigue, constipation, and headache. It should be administered subcutaneously to reduce the risk of peripheral neuropathy.¹⁰²

Immunomodulators

Immunomodulatory drugs (IMiDs) work against cancer through several mechanisms. They boost the immune system to allow the body to fight cancer. They can also slow cancer growth directly by cutting off the blood supply to the tumor and leveraging inflammatory pathways, though it is unclear how much these mechanisms contribute to the efficacy of IMiDs in myeloma.^117,118

Thalidomide (Thalomid) was the first of this class of drug to be tested in myeloma, but its use has waned recently given its considerable severe side effect profile. At the time of this writing, lenalidomide, a more potent immunomodulator that has greater tolerability, is a mainstay of myeloma therapy.^119,120 It can be used in combination with other drugs for the initial treatment of myeloma, or by itself for long-term maintenance therapy.⁷⁰ Lenalidomide is given by mouth once daily for 21 days out of a 28-day cycle. Side effects of lenalidomide include low red blood cell, white blood cell, and platelet counts, diarrhea, and fatigue. Lenalidomide is extremely toxic to unborn children and can cause birth deformities. Women of child-bearing potential, as well as their partners, must use contraception when taking lenalidomide.¹²¹ Pomalidomide (Pomalyst) is another IMiD used in myeloma that has relapsed after prior treatment.

Glucocorticoids

Glucocorticoids are a type of steroid known to modulate gene expression and induce cancer cell death through various mechanisms.¹²² They are an important part of myeloma treatment.¹²³

The most commonly used glucocorticoid is dexamethasone, which is used in combination with chemotherapeutic agents, immunosuppressants, and targeted therapies, such as bortezomib, lenalidomide, cyclophosphamide (Cytoxan), and daratumumab (Darzalex).^124,125 Dexamethasone is part of most recommended drug regimens for both first-line and relapsed treatment of myeloma. Side effects of glucocorticoids include weight gain, fluid retention, increased blood sugar, weakened bones, and increased risk of infections.^126,127 Due to these side effects, long-term use of glucocorticoids is not recommended.

Targeted Therapies

Targeted therapies are drugs that target specific mechanisms of myeloma. Unlike chemotherapy, these drugs are generally directed towards cancer cells and have less of an effect on healthy cells; therefore, they have fewer side effects.¹²⁸

One example of a targeted therapy is daratumumab. Daratumumab is a therapeutic antibody that binds to proteins on myeloma cells and induces cell death.^129,130 It is most commonly used in combination with other drugs and is part of a preferred regimen for patients who are not eligible to undergo a hematopoietic stem cell transplant (SCT).⁷⁰ It can be administered weekly, every two weeks, or monthly, depending on how long the patient has been receiving it.¹³¹ Side effects of daratumumab may include fatigue, nausea, low blood cell counts, and infusion-site reactions when the medication is administered.¹³² Patients should receive other medications before taking daratumumab to reduce the risk of experiencing a skin reaction.

Stem Cell Transplant

Stem cell transplant (SCT) is a transplantation of hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood of a donor to a recipient whose bone marrow was destroyed with high-dose chemotherapy prior to SCT. The goal of SCT is to fight the cancer by using high doses of chemotherapy to wipe out bone marrow cells, both cancerous and normal, while allowing healthy blood stem cells to grow from the infused stem cells and form new blood cells. This process, called engraftment, takes about 2 to 4 weeks.^133-137 These new cells grow into healthy bone marrow and can produce non-cancerous blood cells.

There are two types of stem cell transplants—autologous and allogeneic. “Autologous” means the patient’s own stem cells are transplanted back into his or her body. “Allogeneic” means the stem cells of another person with similar characteristics are transplanted into the patient. Allogeneic transplantation is much riskier and patients receiving allogeneic transplants typically have more side effects than those receiving autologous transplants.¹³⁸ It can also be difficult to find an appropriate donor. For these reasons, autologous transplants are considered the standard of care in patients with myeloma.⁷⁰

Autologous SCT is an important part of myeloma treatment and should be considered in all eligible patients; however, it is an intensive procedure that not everyone can tolerate.^70,139-141 Patients take medication before the procedure to wipe out the existing cancerous cells and prepare their body for transplantation, and again after the procedure to maintain control of the tumor.^70,138 Whether SCT should take place early in the disease course or upon relapse is a matter of some debate. As of late 2020, evidence suggests early SCT results in deeper responses, but may not improve overall survival. Thus, the decision to undergo transplantation is an individualized choice and must be based upon several factors taken into consideration by the treating oncology team and the patient.¹⁴²

After transplantation, response is typically measured by assessing serum or urinary monoclonal M-protein levels. Free light chain measurements can be used in patients with undetectable M-protein levels in their serum or urine. Bone marrow immunohistochemistry or immunofluorescence may be utilized as well. An approach taken by some experts is to assess patients 100 days after SCT, then reassess every three to four months thereafter if the patient is doing well. The degree of response following therapy may be predictive of survival, but this is controversial in the myeloma research community (see section titled “Evaluating Response” below).¹⁴²

Serious side effects (eg, nausea, vomiting, weakened immune system) may result from medication. Eligibility for transplant depends on patients’ age, fitness, and other disease-related factors, but the decision to have a transplant should involve a discussion between the patient and his or her doctor.

Radiation

Radiation therapy uses strong beams of energy to kill cancer cells or stop their growth. The most commonly used radiation therapy in myeloma is external beam radiation therapy. It is predominantly used where there is a single, localized mass of myeloma cells called a plasmacytoma.^70,143,144 Radiation therapy can also damage healthy cells and cause side effects. Common side effects of radiation-based therapies include pain or other changes to the skin at the site of radiation. Patients may also develop fatigue and nausea over time in response to radiation.

Supportive Care

Myeloma can cause damage to several organs, including the kidneys. It is important to stay hydrated and avoid nephrotoxic medications, such as NSAIDs, if a patient is experiencing kidney injury.¹⁴⁵ Because myeloma reduces production of red blood cells, patients with low red blood cell numbers may develop anemia. Doctors may suggest treatment with erythropoietin (EPO) to help regenerate red blood cells.^146,147 Myeloma also puts patients at increased risk for infection by suppressing the immune system. Vaccines and prophylactic antibiotics may be administered to reduce the risk of infection.^148-150

Addressing Bone Health

Bone disease affects almost all myeloma patients. Approximately 60% of patients present with bone pain (particularly in the back or chest) at the time of diagnosis,^17,38 and approximately 20‒25% present with pathologic fractures, compression fractures, or osteoporosis at diagnosis.¹⁷ These bone-related events represent a huge burden to myeloma patients, decreasing survival rates, increasing treatment costs, and reducing quality of life.^38,151,152

Bone remodeling is an important part of maintaining healthy bone in all individuals. It is achieved through a delicate balance of the resorption of old bone (by cells called osteoclasts) and formation of new bone (by cells called osteoblasts).¹⁵³ Increased expression of cytokines in myeloma patients contribute to an imbalance in bone turnover, characterized by increased osteoclast and reduced osteoblast activity.^154,155 This means bone is being resorbed but not being replaced by new bone,¹⁵⁶ which manifests as osteolytic bone lesions, weakened bone, and increased calcium release into the blood.

Due to the morbidity and mortality associated with myeloma bone disease, most experts recommend that MM patients with lytic bone lesions and/or osteopenia or osteoporosis be treated with an osteoclast inhibitor. However, the potential for benefit is less clear for patients with no apparent bone lesions or osteopenia/osteoporosis, so experts disagree on the best approach. Some recommend osteoclast inhibitors to all patients with MM requiring treatment regardless of whether they have bone disease, while others avoid these drugs in patients without bone disease. The decision to use an osteoclast inhibitor should be made on a case-by-case basis.⁷⁰

Pamidronate and zoledronic acid (Reclast) are two bisphosphonates that work by reducing bone resorption and have both demonstrated a similar reduction of skeletal-related events in myeloma.^157-161 Denosumab, a therapeutic antibody that also works by reducing bone resorption, has similar bone health benefits to bisphosphonates but is preferred in patients with kidney dysfunction.¹⁶² All subjects receiving either bisphosphonates or denosumab should receive calcium, vitamin D, and have regular dental monitoring for osteonecrosis of the jaw.⁷⁰

Treatment of Solitary Plasmacytoma

A solitary plasmacytoma is a single mass of plasma cells that has not yet developed into myeloma. This is a rare condition. Since this mass is isolated, it can be treated with radiation therapy and/or surgery, which may have curative potential. There are two types of solitary plasmacytomas: those originating in bone (osseous) and those involving soft tissue (extraosseous).^70,174 Treatment of both types of solitary plasmacytomas with radiation and surgery (if needed) has resulted in favorable outcomes and disease control.^175,176 Patients are closely watched after treatment to monitor for disease recurrence.

Treatment of Smoldering Myeloma

In general, progression from smoldering myeloma to active myeloma occurs in about 60% of patients within 10 years.¹⁷⁷ However, the risk of progression varies greatly between patients, with some very high-risk patients having an 80‒90% likelihood of progression within two years. Treatment decisions depend on the likelihood that the patient will progress. Patients determined to be at low risk of progression may not require treatment and will instead be closely monitored at regular time intervals. On the other hand, those deemed to be at high risk of progression may undergo treatment with some of the same drugs used to treat active myeloma. There is much ongoing research attempting to clarify the best ways to identify which SMM patients are at high risk of progression as well as determine the ideal treatment regimen.¹⁷⁸

The National Comprehensive Cancer Network (NCCN) guidelines⁷⁰ recommend all patients with smoldering myeloma be monitored at three to six month intervals; however, the Mayo Clinic provides recommendations¹⁷⁹ to determine the frequency of monitoring based on risk of disease progression. According to these recommendations, patients with low-risk disease may be monitored every six months to test for disease progression. Intermediate-risk patients can be re-tested for disease progression every three to four months. Patients with high-risk smoldering myeloma should be monitored every two to three months and should also be considered for enrollment in clinical trials to prevent or delay progression.

Some emerging evidence suggests early treatment can delay progression to active myeloma and extend overall survival, although this is very controversial as of late 2020 and more trials are needed to clarify overall benefits.⁷⁰ One study on 119 patients with high-risk smoldering myeloma showed treatment with a combination of dexamethasone and lenalidomide prolonged the time to progression to active myeloma and extended overall survival at three years, compared with observation only. A subsequent analysis at a median of about six years showed lenalidomide continued to provide benefit in terms of time to progression: the treatment group had not yet reached their median time to progression, while the observation-only group had a median time to progression of 23 months. Eighty-six percent of participants in the observation-only group progressed to active myeloma, compared with only 39% of those in the lenalidomide plus dexamethasone group.^180,181 A more recent study, published in 2020, showed lenalidomide alone delayed progression to symptomatic disease and lengthened progression-free survival among 182 patients with high-risk smoldering multiple myeloma. Half of the participants in the lenalidomide group exhibited a treatment response, and one-, two-, and three-year survival in the lenalidomide group was 98%, 93%, and 91%, compared with 89%, 76%, and 66% in the observation-only group. Subgroup analysis showed that the progression-free survival benefit was clear in high-risk patients, but not as apparent in those with intermediate-risk disease. Serious adverse events occurred in 41% of participants in the lenalidomide group.¹⁸²

Based on promising results from these studies, some experts now recommend either lenalidomide plus dexamethasone or lenalidomide alone, rather than observation, for patients with high-risk smoldering multiple myeloma. It should be noted that the criteria used to identify patients at high risk for progression to active myeloma was not uniformly defined in these studies, and many experts continue to recommend that more intensive treatment for lower-risk SMM patients should be reserved for the clinical trial setting as opposed to routine practice.⁷⁰ Importantly, this is a very active area of research and is a matter of much debate in the myeloma research community. Decisions to initiate early treatment must be made on a case-by-case basis and must involve careful consideration of risks and benefits by physicians experienced in treating myeloma.

Treatment of Symptomatic Myeloma

Patients with newly diagnosed symptomatic myeloma should receive treatment with a combination of medicines. Initial treatment depends on whether the patient is eligible for autologous SCT. Preferred drug regimens based on NCCN guidelines for patients that are eligible and those that are ineligible to receive a transplant are listed below. Patients should also receive a medication for bone health and other supportive care based on symptoms.

Table 5: Preferred Initial Treatment Regimens for Myeloma Based on NCCN Guidelines*

Myeloma Treatment for SCT-Eligible Patients

Bortezomib, lenalidomide, dexamethasone

Bortezomib, cyclophosphamide, dexamethasone

Myeloma Treatment for SCT-Ineligible Patients

Bortezomib, lenalidomide, dexamethasone

Daratumumab, lenalidomide, dexamethasone

Lenalidomide, dexamethasone (low dose)

Bortezomib, cyclophosphamide, dexamethasone

*To be interpreted with the help of a clinician skilled in the management of myeloma. Derived from NCCN Guidelines70 SCT, stem cell transplant.

A risk-based treatment algorithm for patients eligible for autologous SCT is provided below. Initial treatment consists of three to four cycles of induction therapy using bortezomib, lenalidomide, and dexamethasone (VRd) in standard-risk and intermediate-risk patients or carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd) in high-risk patients. All initial treatment regimens should include low-dose dexamethasone (40 mg once weekly) as it has been associated with higher overall survival and lower rates of toxicity compared with high-dose dexamethasone.¹⁸³ Induction therapy is then followed by either early or delayed transplantation. Maintenance therapy with either lenalidomide or a proteasome inhibitor is provided after transplantation to reduce the risk of disease progression.⁷⁰ Maintenance therapy can prolong progression-free survival and may improve overall survival. The selection of drug(s) used during maintenance therapy will depend on risk stratification and other patient-specific characteristics. Maintenance therapy is generally recommended for at least two years. Research is ongoing to determine if longer maintenance therapy provides benefits that outweigh drug toxicity risks.¹⁴²

Table 6: Risk-Based Treatment Algorithm for SCT-Eligible Patients*

	Standard Risk	Intermediate Risk	High Risk
Initial Treatment	VRd x3 to 4 cycles	VRd x3 to 4 cycles	VRd or KRd x3 to 4 cycles
Transplantation#	Early or Delayed ASCT	Early ASCT	Early ASCT
Maintenance Therapy	Lenalidomide	Bortezomib-based	Carfilzomib or bortezomib-based
*To be interpreted with the help of a clinician skilled in the management of myeloma. Derived from Rajkumar, et al.88 and NCCN Guidelines70 #The decision to initiate ASCT early or delay the procedure until first signs of progression must be made on an individual basis. Whether early transplantation is superior to delayed transplantation is somewhat controversial, although early ASCT is considered standard of care by most institutions. More research is needed. Abbreviations: VRd, bortezomib, lenalidomide, dexamethasone; KRd, carfilzomib, lenalidomide, dexamethasone; ASCT autologous stem cell transplantation.

Patients diagnosed with myeloma may be ineligible for SCT due to frailty or age. High-risk patients that are ineligible for SCT may receive primary treatment with bortezomib, lenalidomide, dexamethasone (VRd) followed by maintenance therapy with bortezomib or a bortezomib-based regimen. It is recommended that patients categorized as standard-risk receive daratumumab, lenalidomide, and dexamethasone (DRd) or bortezomib, lenalidomide, dexamethasone (VRd) followed by maintenance therapy with either lenalidomide and daratumumab or lenalidomide alone. Frail patients or patients over age 75 may receive lenalidomide and dexamethasone until disease progression.⁷⁰

Table 7: Risk-Based Treatment Algorithm for SCT-Ineligible Patients*

	Standard Risk	Intermediate Risk	High Risk
Initial Treatment	VRd or DRd x8 to 12 cycles**	VRd x8 to 12 cycles
Maintenance Therapy	Lenalidomide or lenalidomide-daratumumab	Bortezomib or bortezomib-based
*To be interpreted with the help of a clinician skilled in the management of myeloma. **If patient is frail, treat with Rd until progression. Derived from Rajkumar, et al.88 and NCCN Guidelines70 VRd, bortezomib, lenalidomide, dexamethasone; Rd, lenalidomide, dexamethasone.

Due to high rates of organ damage associated with active myeloma, all patients initially diagnosed with myeloma should be considered for appropriate supportive care. Patients receiving treatment for myeloma may also be prescribed medication to manage potential side effects. For example, patients receiving immunomodulatory agents (eg, lenalidomide), particularly in combination with high-dose glucocorticoids, are at significantly greater risk of thrombotic complications and should receive preventative aspirin therapy. Similarly, those receiving treatment with proteasome inhibitors should receive preventative antiviral therapy to prevent viral infectious diseases common in MM patients, such as shingles.⁷⁰

Evaluating Response

After treatment, the doctor will evaluate how well the patient has responded based on symptoms and how many myeloma cells remain in the body. Response to treatment is generally categorized as complete, partial, minimal, or progressive, as defined below. Relapse is defined as an initial positive response to treatment followed by worsening of disease.

Table 8: International Myeloma Working Group Myeloma Response Criteria*

Category	Definition
Complete Response	No M proteins in the blood or urine, and Under 5% plasma cells in the bone marrow No evidence of plasmacytoma, if previously present
Partial Response	50% or greater reduction in M proteins in the blood , and 90% or greater reduction in 24-hour urinary M proteins, and 50% or greater reduction in plasma cells in the bone marrow, and 50% or greater reduction in the size of solitary plasmacytoma, if previously present
Minimal Response	25% to less than 50% reduction in M proteins in the blood, and 50% to less than 89% reduction in M proteins in the urine, and 25% to less than 50% reduction in size of plasmacytoma, if previously present
Progressive Disease	25% or greater increase in M proteins in the blood (at least 0.5 g/dL), or 25% or greater increase in M proteins in the urine (at least 200 mg/24 hours), or 50% or greater increase the number of plasma cells in the blood, or 10% or greater increase in the percentage of plasma cells in the bone marrow, or 50% or greater increase in the size of existing lesion or presence of new lesions.
*To be interpreted with the help of a clinician skilled in the management of myeloma. Derived from Kumar, et al.184 and NCCN Guidelines70

Treatment of Relapsed Myeloma

The majority of myeloma patients will relapse at some point during the course of their disease.¹⁸⁵ Treatment for relapsed disease should consider previous treatments, time to relapse, and disease severity. Patients that underwent successful autologous SCT for initial therapy and had a durable response can be considered for a second transplant.⁷⁰ Preferred treatments for patients experiencing their first relapse include three-drug regimens containing either a proteasome inhibitor (eg, bortezomib, carfilzomib)¹⁸⁶ or monoclonal antibody (eg, daratumumab, elotuzumab [Empliciti]).^187,188 Treatment of subsequent relapses should focus on therapeutics not previously used to treat the initial relapse.

This section outlines several clinical developments in the myeloma treatment pipeline. None of the therapeutics described in this section are approved for first-line myeloma treatment as of mid-2020, though some are approved for use in patients who have undergone prior therapies. These clinical developments represent some important advancements in myeloma research, but more research is required to translate these developments into routine clinical care.

Second-Generation Proteasome Inhibitors

First-generation proteasome inhibitors, such as bortezomib, are associated with serious adverse effects, such as numbness in the extremities. They are also associated with high rates of relapse. Second-generation proteasome inhibitors work the same way as first-generation therapies, but boast higher response rates, new routes of administration, and lower incidence of side effects.¹⁸⁹ Carfilzomib is an approved second-generation proteasome inhibitor that is administered by intravenous (IV) infusion as part of combination therapy in patients previously treated for myeloma.^70,190 Ixazomib (Ninlaro), an oral proteasome inhibitor administered weekly, is approved for treatment of myeloma.¹⁹¹ Oprozomib, an analog of carfilzomib that can be administered orally, is currently under investigation¹⁹²; the FDA has designated it an orphan drug for the treatment of Waldenström’s macroglobulinemia. Oral medications for myeloma are becoming increasingly important as clinical advancements are made and patients live longer on therapies. Marizomib is another novel second-generation proteasome inhibitor that has shown promising results in patients with relapsed/refractory multiple myeloma.^193,194

Monoclonal Antibodies

Daratumumab is a monoclonal antibody approved as monotherapy for multiple myeloma as of the time of this writing. Another monoclonal antibody, elotuzumab, is approved as part of combination therapy for relapsed or refractory MM. Several additional monoclonal antibodies are in various stages of clinical development. Because monoclonal antibodies can target many different parts of cancer cells, there are numerous possibilities for the development of effective therapies. For example, GSK2857916 (belantamab) is an antibody that targets the BCMA receptor on myeloma cells. It has been studied in a Phase I study and found to be well tolerated and efficacious in patients with relapsed/refractory myeloma.^195,196 In August 2020, The FDA granted belantamab accelerated approval for use in relapsed MM patients who have undergone a minimum of four prior therapies.¹⁹⁷

Interim analysis of a phase III clinical study (IKEMA) indicated the combination of a monoclonal antibody, isatuximab (Sarclisa), with carfilzomib and dexamethasone (known as Isa-Kd) increased progression-free survival in patients with relapsed or refractory MM compared with carfilzomib and dexamethasone without isatuximab (Kd) after a median follow-up of 20.7 months. In the Isa-Kd arm, nearly 30% of patients were negative for minimal residual disease (a measure of whether myeloma cells are still detectable in the body after treatment), while only 13% in the Kd arm were negative. The researchers concluded that Isa-Kd “represents a possible new standard of care in patients with relapsed MM.”¹⁹⁸

One of the major research challenges that currently faces monoclonal antibody-based therapies is identifying adjuvants or combination therapies that effectively enhance response while maintaining a reasonable safety profile.¹⁹⁶ Many clinical trials of monoclonal antibodies are recruiting or are in the pre-recruiting phase as of the time of this writing. More information about these trials is available at ClinicalTrials.gov.

CAR-T Therapies

Chimeric antigen receptor T-cell (CAR-T) therapy is a technique that removes immune cells from the body and modifies them to recognize cancer cells. The immune cells are then put back in the body to fight cancer. CAR-T treatments have been recently approved for other cancers and have the potential for long-term disease control, but are still under investigation for myeloma.^199-201 The results from a Phase I trial investigating bb2121, a CAR-T therapy that targets B-cell maturation antigen (BCMA), were recently published.²⁰² Myeloma patients with refractory disease responded well to the treatment; however, a large number of subjects experienced side effects, including neurotoxicity. A clinical trial is underway to compare bb2121 to standard triplet therapy in a Phase III study of patients with relapsed and refractory myeloma.²⁰³

Vaccines

Studies are currently investigating vaccines that target proteins highly expressed by myeloma cells. Vaccines are generally well-tolerated with fewer side effects compared with conventional therapies. One promising vaccine candidate (ImMucin) under development was recently studied in a Phase I/II clinical trial²⁰⁴ that included MM patients with disease that progressed following autologous SCT. Of the 15 patients in the trial that received the vaccine, 11 either demonstrated improvement or had disease that remained stable through the follow-up period of 41 months.

Histone Deacetylase Inhibitors (HDACis): Panobinostat

Due to the propensity of multiple myeloma to relapse and progress to refractory disease, many anti-cancer drugs typically used in other cancers have been tested specifically in the setting of relapsed or refractory myeloma in hopes of mitigating treatment failure and relapse. Histone deacetylase inhibitors (HDACis) are one class of drug that has shown promise in this setting, with panobinostat (Farydak) in particular demonstrating evidence of efficacy and tolerability. Panobinostat received accelerated FDA approval in 2015 for use in MM patients who have already received at least two prior treatment regimens, including bortezomib and an IMiD.²⁰⁵ A 2019 meta-analysis of data from 19 trials and nearly 2,200 patients found that panobinostat led to a more robust overall response rate (0.64) than two other HDACis, vorinostat (Zolinza) and ricolinostat (ORRs 0.51 and 0.38, respectively). The ORR was 0.36 for patients whose myeloma was refractory to bortezomib and 0.43 for those whose myeloma was refractory to lenalidomide. The researchers concluded panobinostat-containing regimens were effective and tolerable for patients with relapsed, refractory MM.²⁰⁶ More trials are needed to further validate the superiority of panobinostat over other HDACis in the setting of refractory MM.

As research progresses, the molecular biology of MGUS, SMM, and MM is continually being elucidated, and targeted approaches have helped improve treatment of MM, particularly over the past decade. Some of the pathways involved in the perpetuation and progression of MGUS/SMM/MM may also be targeted by natural agents or repurposed drugs. Below are some pathways that are appealing as potential intervention targets with natural agents or repurposed drugs.

Nuclear Factor-Kappa B (NF-κB)

Nuclear factor-kappa B (NF-κB) regulates the transcription of numerous genes involved in proliferation, angiogenesis, survival, and apoptosis, making NF-κB an attractive target for control of the disease.³²⁶ Some drugs currently approved to treat MM suppress NF-κB, including thalidomide and bortezomib.³²⁷

Constantly activated NF-κB in myeloma results in higher levels of inflammatory mediators [eg, insulin-like growth factor, interleukin-6, vascular endothelial growth factor, and macrophage inflammatory protein-1alpha (MIP-1α)] in the microenvironment of the bone marrow.³²⁸ The net effect of these mediators is increased bone degradation and proliferation of myeloma cells.

NF-κB is involved in the production of osteoclasts (osteoclastogenesis) through the action of cytokine receptor activator of NF-κB ligand (RANKL). Denosumab, a monoclonal antibody, is used to control bone loss in MM patients through the inhibition of RANKL binding to the receptor activator of NF-κB (RANK), which normally stimulates osteoclast-driven bone loss. Inhibition of NF-κB may result in interference of RANK/RANKL osteoclastic bone loss as well.

There is emerging information that suggests there is a positive feedback loop between osteoclasts and myeloma cells, creating a vicious cycle of proliferation and activation of both cell types.³²⁹ NF-κB is an integral part of this cycle. Thus, suppressing NF-κB has the potential to simultaneously disrupt osteoclast generation and myeloma cell proliferation/activity.

Among the numerous natural agents that suppress NF-κB,curcumin is one of the most well studied.^330,331 Additional natural suppressors of NF-κB activation include resveratrol, ursolic acid,capsaicin, silibinin,silymarin, guggulsterone, and plumbagin.^332-334 Quercetin has evidence of interfering with NF-κB activation in addition to simultaneously increasing the action of osteoblasts.³³⁵ Honokiol, a polyphenolic compound from Magnolia officinalis, has demonstrated a dual action of both being anabolic as well as anti-catabolic on bone through the disruption of NF-κB mediated bone loss.^336-338 Glycyrrhetinic acid, a compound found in licorice root, also inhibits RANKL-induced osteoclastogenesis through suppression of NF-κB.^339,340

MAPK Pathway

Mitogen-activated protein kinase (MAPK) pathways play critical roles in cellular proliferation and differentiation.³⁴¹ Mutations in genes involved the MAPK pathway are among the most common in MM, present in up to half of newly diagnosed MM patients.^342,343 MAPKs are grouped into three families: ERKs, JNKs, and p38. One of the most frequent ways the MAPK pathway is overactivated is via mutations in RAS proteins, which regulate cell growth, proliferation, and differentiation.³⁴⁴ Recent studies using next-generation sequencing (NGS) have shown that the RAS protein family mutations accumulate during myeloma progression. NRAS and BRAF mutations that result in their constitutive activation are found in both MGUS and MM cells.³⁴⁵ Thus, the dysregulated MAPK pathway represents an appealing target through which novel therapies might disrupt the progression from MGUS to MM.

Interestingly, statin drugs have piqued the interest of cancer researchers due to evidence suggesting they can inhibit some processes that activate the MAPK pathway. Statins appear to inhibit prenylation of small GTPases such as Ras and Rho, which activate the mitogen-activated protein (MAP) kinase MEK/ERK cascade regulating proliferation, survival, and apoptosis.^346-349 In bone and prostate cancer cells, statins have been shown to decrease proliferation and induce apoptosis through inhibition of the ERK/Bcl-2 pathway.^350-352 Observational evidence suggested statin use may be associated with lower MM incidence as well as better outcomes in MM patients.^{224,226,227,353} Some preliminary interventional evidence suggests statins may be helpful in the context of MM,^228,229 but more rigorous research is needed to clarify whether statin use meaningfully affects the clinical course of MM or its precursor conditions.

PI3K/AKT/mTOR Signaling Pathway

The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is aberrantly activated in MM cells, and its inhibition induces apoptosis.^354,355 Because it plays a critical role in regulating proliferation, growth, survival, and migration of malignant plasma cells, the PI3K/AKT/mTOR pathway is central in MM pathophysiology and disease progression. As such, the mTOR pathway has become an emerging therapeutic target in MM.^354,356-358

Metformin, a first-line diabetes drug with many potentially beneficial off-target effects, has emerged as a potentially viable therapeutic agent in some cancers.^359-365 Because metformin targets multiple signaling pathways in cancer cells, many questions remain unanswered concerning relevant mechanisms of action.^363,366 However, two potential accepted anti-cancer mechanisms of metformin have been proposed. First, metformin activates AMP-activated protein kinase (AMPK) resulting in inhibition of downstream AKT/mTOR signaling and consequent suppression of cell proliferation.^367-369 Consistent with this postulate, metformin was shown to induce cell cycle arrest without apoptosis by activating AMPK and inhibiting mTORC1 and mTORC2 and downstream pro-survival signaling pathways including AKT in human MM cell lines.³⁷⁰ Metformin was also shown to inhibit IL-6 signaling and increase cell death via AMPK activation and mTOR inhibition in human MM primary cells and cell lines.²³⁰ Second, metformin’s anti-cancer effects appear to also be driven by reduced circulating levels of growth factors insulin and insulin-like growth factor 1 (IGF-1), which prevents activation of AKT/mTOR downstream signaling to inhibit cell proliferation and induce apoptosis.^371,372 Indeed, metformin has been shown to inhibit proliferation and induce apoptosis of MM cells by inhibiting the PI3K/AKT/mTOR downstream signaling pathway.³⁷³

Angiogenesis

Angiogenesis is the growth of new blood vessels. These blood vessels provide blood and nutrients for tumor growth.³⁷⁴ Angiogenesis is needed to create a conducive microenvironment for the perpetuation of MM in the bone marrow.³⁷⁵ Studies suggest an increase in angiogenesis (ie, the angiogenic switch) is an essential step in the progression from plasmacytoma or MGUS to MM.³⁷⁶ Angiogenic mediators arising from clonal plasma cells as well as resident osteoclasts and stromal cells in the bone marrow are associated with increased aggressivity and worse prognosis. Several drugs used to treat MM are primarily anti-angiogenic agents (eg, thalidomide),³⁷⁷ suggesting this may be a valuable therapeutic tactic in the control of MM.

Natural compounds with anti-angiogenic effects deserve to be investigated for those with MGUS or SMM, where the intent is not necessarily to treat but to prevent progression to MM. The types of naturally occurring compounds that have antiangiogenic effects include polyphenols, alkaloids, phytohormones, and terpenes that can be found in fruits, vegetables, herbs, and spices.³⁷⁸ Some of the best researched antiangiogenics from nature include ellagic acid from berries,genestein from soy, resveratrol, silymarin, and epigallocatechin 3-galate (EGCG).³⁷⁷

Immune-related Targets

In addition to aberrant signaling, malignant cells exploit a wide range of immune escape mechanisms, including induction of an immunosuppressive tumor microenvironment to evade immune destruction. Myeloid-derived suppressor cells (MDSCs), a diverse population of immature myeloid cells that expand during cancer and have potent immunosuppressive activity, play a key role in the pathophysiology of MGUS and MM.^379,380 The metabolism of the non-essential amino acid L-arginine was the first identified mechanism for MDSC immunosuppression.^236,381 Specifically, L-arginine serves as a substrate for inducible nitric oxide synthase (iNOs, generating NO) and arginase 1 (Arg-1). The upregulation of both enzymes in MDSCs leads to a shortage of L-arginine in the tumor microenvironment, and consequently to the impairment of T-cell function.³⁸⁰ Furthermore, the increased NO production leads to suppression of T-cell function through the inhibition of the IL-2 downstream pathway.^382,383

From a systemic perspective, there are many natural agents that support immune function and may lessen the risk of infection. General immune support to prevent infection should begin with ensuring the nutrients supportive of immune function (eg, vitamin D, zinc) are replete.³⁸⁴ Then, extracts from plants or mushrooms that have been used traditionally for immune support as well as validated with current research may be considered. A few of the most well-known immune supportive natural agents include echinacea, elderberry, reishi, and maitake.³⁸⁵ In a study of mice with plasmacytoma, echinacea added to their chow led to an increase in natural killer (NK) cells in the bone marrow and spleen, partly negating the immunosuppression caused by the plasmacytoma cells without affecting either T- or B-cell immune lineages (ie, humoral immunity).³⁸⁶

Interleukin-6 (IL-6) is an immune cytokine that perpetuates clonal populations of plasma cells in an autocrine and paracrine fashion.³⁸⁷ IL-6 is a key messenger in the microenvironment of the bone in MM and inhibition of its signaling has recently been revived as a potential therapy for MM.³⁸⁸ While direct inhibition of IL-6 through monoclonal antibody binding has not led to benefit, targeting nearby stromal cell (eg, adipocyte) production of IL-6 may offer a more effective strategy.³⁸⁹ IL-6 may be inhibited by natural agents such as gossypol, parthenolide, and curcumin.³⁹⁰

There have been two case reports of complete remission, and as is the case with most spontaneous remissions, it appears they were immune-mediated. The first case is from 1955, in which a male with hepatitis had resolution of his underlying multiple myeloma after his illness.³⁹¹ The second case was of a woman who began using a Chinese medicine combination, Huangqi Guizhi Wuwu Tang (HGWT), a formula with a large amount of astragalus.³⁹² Astragalus is an immune tonic commonly used in Asian medicine. The patient had stable disease until the published report in 2017. During the course of her 18 years with stable disease, she did have progression at one point. Her dose of astragalus was quadrupled at that time from 30 grams to 120 grams daily, and stabilization resumed.

Dietary Considerations

A number of studies have evaluated associations between certain dietary habits and risk of developing multiple myeloma. A study published in 2007 found that greater consumption of specific foods was associated with reduced risk of multiple myeloma among women in Connecticut. These foods included cooked tomatoes, cruciferous vegetables, fresh fish, and food-derived vitamin A. On the other hand, this same study found that greater consumption of cream-based soups, jello, ice cream, and pudding was associated with increased multiple myeloma risk. This study also showed trends suggesting that increased carbohydrate consumption may be associated with increased risk, whereas consuming more vitamin D and calcium may be associated with reduced risk.³⁹³

A 2001 study examined dietary patterns among 539 people with multiple myeloma and 1,989 control subjects. The researchers found that greater consumption of fish and cruciferous vegetables was associated with reduced risk of multiple myeloma. Interestingly, this study also found that use of vitamin C supplements was associated with lower myeloma risk.³⁹⁴

In 2016, researchers in Italy published a study in which they examined the associations between various foods of animal origin and risk of non-Hodgkin lymphoma and multiple myeloma. They included data from 33 independent studies representing over 16,000 people with non-Hodgkin lymphoma and over 3,600 people with multiple myeloma. The analysis showed that greater consumption of fish and seafood was associated with lower multiple myeloma risk, while increased red meat and dairy consumption was associated with increased non-Hodgkin lymphoma risk. The researchers concluded that “Foods of animal origin likely play a role in the aetiology of non-Hodgkin lymphoma and multiple myeloma, with red meat and dairy tending to increase the risk, and fish that tends to decrease it. Our findings reinforce the recommendations to reduce the consumption of red meat by replacing it with vegetables, legumes and fish.”³⁹⁵

A remarkable study published in February 2020 by a collaborative group of researchers from prestigious universities and hospitals across the United States found that diet may not only influence the risk of developing myeloma, but also survival after diagnosis. This study included prospective survival analyses of 423 cases of MM from the Nurses’ Health Study and the Health Professionals Follow-Up Study. The researchers examined how closely the subjects adhered to healthy eating indices prior to diagnosis and their subsequent survival and cause of death. They found that for each standard deviation increase in adherence to a healthy eating index, death specifically related to MM was reduced by 15‒24%. Conversely, MM-specific death was 16‒24% more common for each standard deviation increase in adherence to an unhealthy dietary pattern. The researchers remarked, “… our consistent findings for multiple dietary patterns provide the first evidence that MM patients with healthier pre-diagnosis dietary habits may have longer survival than those with less healthy diets.”³⁹⁶

The study described in the previous paragraph was a follow-up to a 2019 study conducted by the same research group in which they evaluated dietary patterns and myeloma risk. In this study, the scientists found that proinflammatory dietary patterns and dietary patterns associated with insulin resistance were linked with increased myeloma risk among men. Specifically, adherence to an inflammatory dietary pattern was associated with a 16% increased multiple myeloma risk. Suggestive (though not statistically significant) positive associations were also observed between myeloma risk and greater adherence to dietary patterns linked to insulin resistance. For the inflammatory dietary pattern, adherence was determined by assessing frequency of consumption of foods predictive of three inflammatory markers: IL-6, CRP, and TNF-α. Foods associated with increases in these inflammatory biomarkers included processed red meat, refined grains, and high-sugar beverages. Conversely, foods associated with lower levels of these inflammatory biomarkers included green leafy vegetables and coffee.³⁹⁷

Other evidence suggests greater fruit intake may be associated with lower risk of progressing from MGUS to MM. In a study published in 2018, researchers analyzed data on over 5,700 participants who had submitted food frequency questionnaires as part of a population-based study in Iceland. The analysis showed people with MGUS who ate fruit at least three times per week during late life were much less likely to progress from MGUS to MM than those who ate fruit less frequently.³⁹⁸

Mental Health

Myeloma is a disease that suppresses the body’s ability to fight infections. Mental health is an important part of maintaining a healthy immune system.³⁹⁹ Patients should focus on reducing stress and getting enough sleep to support immune health. A myeloma diagnosis can be overwhelming. There are support groups available that can help patients better understand their condition and help them through this difficult time.

Stop Smoking

There is a strong association between smoking and the development of myeloma, especially in women and heavy smokers.^60,61 For patients with myeloma who smoke, it is imperative to stop. Various tobacco cessation programs are available through nonprofit organizations that offer helpful tips and resources.^149,160 The Centers for Disease Control and Prevention (CDC) also provides resources to aid in quitting tobacco smoking.

Body Mass and Physical Activity

Studies have shown that people who are obese (defined as a BMI of 30 kg/m² or greater)⁴⁰⁰ are at increased risk for myeloma.⁶⁰ Eating healthy to maintain an appropriate weight is an important lifestyle modification not only in the context of multiple myeloma, but in general. Exercise is also effective for helping maintain a healthy BMI.⁶⁰ It is important to note that bone disease from myeloma puts patients at increased risk of fracture when exercising. Patients should have a discussion with their physician about the risks and benefits of physical activity before initiating exercise regimens.

Table 10: Body Mass Index (BMI) Calculations*

Measurement Units	Formula and Calculation	Example
Kilograms and meters	weight (kg) = BMI kg/m2 [height (m)]2 The formula for BMI is weight in kilograms divided by height in meters squared. If height has been measured in centimeters, divide by 100 to convert this to meters.	81 kg = 25 kg/m2 1.8 m2
Pounds and inches	703 x weight (lbs) = BMI kg/m2 [height (in)]2 When using American measurements, pounds should be divided by inches squared. This should then be multiplied by 703 to convert from lbs/inches2 to kg/m2.	703 x 180 lbs = 25 kg/m2 71 in2
*To be interpreted with the help of a skilled clinician.

The integrative interventions described below may complement conventional myeloma treatments. Although these interventions have been shown to positively influence certain disease-related parameters or modify biological pathways involved in myeloma pathobiology, patients should always consult clinicians skilled in the management of myeloma before starting a new regimen with any agent.

Note that some of the interventions described here have sound biological plausibility to be supportive in the context of MM or its precursor conditions but have not necessarily been validated in rigorous clinical trials. The natural agents discussed in this section are covered in detail due to at least some research indicating their usefulness for MGUS/SMM/MM specifically. Most of the data on the agents is preliminary and trials, when available, are small. Regardless, the following natural agents may have potential benefits in those with MGUS/SMM/MM.

Agaricus Mushroom

Agaricus blazei Murill (AbM) is traditionally used as both an edible and medicinal mushroom. AbM has immunomodulating properties that may benefit those with MGUS/MM.⁴⁰¹ Mushrooms generally contain immune-supportive polysaccharides, and AbM possesses potent anti-angiogenic effects that are attributable to several compounds.⁴⁰² AbM is rich in beta-glucans, which are known to modulate the immune system by activating the complement system.^403,404 AbM also contains unique compounds such as agaritine, which was shown to induce death of leukemia and myeloma cells in culture.³²⁷ The mushroom’s antitumor properties have been demonstrated in mouse models of several different cancers.⁴⁰⁵

In addition to the well-characterized immune effects, AbM has anticlastogenic action, meaning it protects against the occurrence of chromosomal damage.^406,407 This may be particularly relevant for MM given that genetic translocations and deletions are integral to the progressive pathogenesis from MGUS to MM to refractory MM.

The potential use of AbM for MGUS/MM is based on a small study that needs verification through larger clinical trials.³³¹ In the study, 40 patients were randomized to receive placebo or a product with three mushroom extracts called AndoSan, (82.4% AbM, 14.7 % Hericium erinaceus, and 2.9% Grifola frondosa) in combination with chemotherapy and SCT. Patients receiving AndoSan (n=19) had enhanced immune responses based on lab findings. However, there was no difference in clinical outcomes between the treatment and placebo groups. Given the preliminary data that indicates it may be useful for those with MM, AbM is an intriguing option for immune support. Further research may elucidate the form, dose, and patient populations that may derive the most benefit from its use.⁴⁰⁸

Arabinoxylan

Arabinoxylan, a hemicellulose (ie, a class of compounds found in plant cell walls) derived from the nutrient-rich hard outer layer of rice, has been shown to stimulate the immune system. Biobran, or MGN-3, is a patented product containing arabinoxylan that uses enzymes from shitake mushroom (Lentinus edodes mycelia) to break down a particular hemicellulose compound (hemicellulose B) and render a unique immunomodulatory product. MGN-3 has demonstrated immunomodulatory effects both in lab tests and in humans.^332,333,409 Several animal cancer models showed arabinoxylan has antitumor and chemopreventive properties—effects possibly attributable to immune modulation and induction of cancer cell apoptosis.^410-412

Preclinical studies have shown arabinoxylan can stimulate macrophage phagocytotic activity, enhance NK cell activity, and promote production of IL-2 (a cytokine involved in modulating white blood cells).^410,413-416 MGN-3 was also shown to boost NK cell activity in a small clinical trial that enrolled older participants.⁴¹⁷ In addition, a clinical study in 80 healthy participants demonstrated that arabinoxylan supplementation increased production of interferon (IFN)-γ, a cytokine essential for innate and adaptive immunity.⁴¹⁸ These results are intriguing because immune suppression is a hallmark of MGUS/SMM and myeloma.

In a 2018 review of 11 clinical studies with cancer patients (including myeloma), the researchers concluded that MGN-3 can “complement the conventional cancer treatment through upregulating the patient’s immune system, especially in boosting the NK cell activity… It may be used as a complementary immune therapy to reduce side effects, improve treatment outcomes, and enhance long-term survival rate.”⁴¹⁹ One study found supplementation with MGN-3 improved survival in patients with various malignancies. The investigators noted that most of the studies included were small and of short duration.

MGN-3 has been tested specifically in myeloma. An in vitro study using a cell line of human multiple myeloma (U266) cells found inhibition of MM proliferation when either MGN-3 or curcumin was added to the cells’ medium. When the two were combined (100 µg/mL MGN-3 plus 10 µM curcumin) there was a synergistic effect that resulted in an 87% decrease in U266 myeloma cell count and 2.6-fold increase in apoptosis.⁴²⁰ A small pilot study assessed the use of curcumin (6 grams/day of 95% curcuminoids) and MGN-3 (2 grams/day) on the complete blood counts of 10 MGUS/MM patients and 10 patients with stage 0/1 chronic lymphocytic leukemia (CLL) over a six-month period.⁴²¹ Half of the MGUS/MM patients were neutropenic at baseline. The intervention increased neutrophil counts in eight of the 10 participants with MGUS/MM. In addition, four of the 10 MGUS/MM patients experienced a reduction in erythrocyte sedimentation rate (ESR), indicating lower systemic inflammation. Additionally, in a small randomized study of 48 myeloma patients (32 receiving 2 grams MGN-3 daily and 16 receiving placebo), MGN-3 increased the activity of the innate immune system, including increasing NK cell activity, myeloid dendritic cell level, and Th1-related cytokine activation, all of which target imbalances inherent to MM.³³² Further studies on the use of MGN-3 in those with MGUS/MM are warranted.

Curcumin

“Curcumin” is a term often used loosely to refer to turmeric root (Curcuma longa) extracts containing naturally occurring curcuminoids (eg, curcumin, desmethoxycurcumin and bisdesmethoxycurcumin). Studies on curcumin are generally done using a highly concentrated extract from the turmeric root containing >90% curcumin rather than the whole turmeric root, which contains only 3‒5% curcumin. This is an essential consideration since studies suggesting curcumin’s benefit in MGUS/MM have resulted from very high doses of curcumin.

Studies of curcumin in potentially modulating MGUS/MM have shown possible mechanisms including suppressing proliferation, inducing apoptosis, and inhibiting osteoclast formation.^384,422,423

The anti-MM effects of curcumin are intriguing enough to elicit ongoing research into curcumin analogs (drugs) in the search for a novel multi-targeted anti-myeloma agent.^424-426 Many of the well-established pathways of myeloma growth and progression, including STAT3, MAPK, IL-6, NF-κB, and RANKL are affected by curcumin either directly or indirectly.

The transcription factor NF-κB is often involved in myeloma, and its liberation from the cytosol to the nucleus is suppressed by curcumin.³²⁶ Specific to MM, the addition of curcumin (as diferuloylmethane) reestablished apoptosis through suppression of NF-κB.⁴²⁷ Myeloma is one of many cancer types in which the pro-apoptotic effect of curcumin has been demonstrated.⁴²⁸

STAT3 must be phosphorylated to be activated, a process that can be induced by IL-6, a cytokine often high in those with MM. A cell study showed curcumin rapidly and reversibly blocked the activation of STAT3 by IL-6 at doses that can be achieved in humans (10 μM).⁴²⁹

Two small studies evaluated high doses of curcumin in people with MGUS/MM. In one study of participants with MGUS (n=26), daily supplementation with curcumin (4 grams/day) led to favorable effects, including a reduction in M protein for those with the highest levels (>20 grams/L) and a reduction in markers of bone resorption (urinary N-telopeptide of type 1 collagen) in 27% of patients.⁴³⁰

In the second study, patients with MGUS and SMM were randomized to receive either 4 grams curcumin per day or placebo.⁴³¹ The study groups crossed-over after three months, switching from the initial group to which they were randomized to the other group. So, subjects who started the study taking curcumin crossed over to taking placebo at three months. After the completion of the six-month crossover study, participants were given the option of continuing in a open-label study using higher-dose curcumin (8 grams daily). Curcumin supplementation led to improved markers of disease progression and bone turnover. The authors concluded that “… curcumin might have the potential to slow the disease process in patients with MGUS and SMM.”

In a dose-ranging study (2, 4, 6, 8, 10, and 12 grams/day) of 12 weeks duration, a minimum of six patients with MM were recruited to each dose either with or without 10 mg/d of Bioperine.⁴³² Patients with at least stable disease at 12 weeks were allowed to continue in the trial up to one year. While there were no objective responses (n=29 participants), 12 patients continued treatment for more than 12 weeks and five were stable at one year. There were significant reductions in constitutively active NF-κB, STAT3, and COX-2 at each monthly time point for most of the participants. The authors proposed that curcumin should be “further investigated either alone or as a modulator of chemo-resistance in combination with other active agents.”

There is a published case of stabilization of disease with the use of high-dose curcumin as a single agent.⁴³³ A 57-year-old female who had been diagnosed with ISS stage III MM and treated with two prior lines of standard therapy was given 8 grams/night of curcumin. All objective indicators of MM disease (M protein, bone imaging) stabilized, and the patient had no further disease progression at the time of the publication, which was five years.

Multi-drug resistance is a major hurdle in the control of MM, with eventual clonal expansion of drug resistant populations for every targeted drug currently used for the disease. In addition to direct anti-MM effects of curcumin, there is preliminary data on its role in sensitizing MM cells to anti-MM drugs. For example, curcumin enhanced the cytotoxicity of carfilzomib on MM cells (U266 cells) through multiple mechanisms, including NF-κB and induction of cell cycle arrest.⁴³⁴ In a mouse model of MM, curcumin prevented chemoresistance of bortezomib and thalidomide, potentiating their cytotoxic effects through NF-κB‒mediated mechanisms and increased apoptosis.⁴³⁵ Clinical trials using curcumin alongside targeted agents for MM should be considered to ensure the combination is safe and determine an optimal dose for this application.

Sea Cucumber

Sea cucumbers belong to the phylum Echinodermata (which also include starfish and sand dollars). Various species of sea cucumber have been valued for centuries as a traditional medicine and functional food with various bioactivities. These organisms contain a multitude of compounds with therapeutic properties, including triterpene glycosides, carotenoids, chondroitin sulfates, and collagen, as well as many vitamins, minerals, and more.⁴³⁶ One sea cucumber formulation, TBL-12, has already undergone phase II clinical trials for asymptomatic multiple myeloma.⁴³⁷

Various sea cucumber extracts have demonstrated properties that may be useful for patients with MGUS/SMM or active myeloma. Preclinical in vitro and animal studies have shown sea cucumber extracts have potent antitumor effects.^438,439 The extracts appear to exert their effects through many mechanisms that are important in the context of myeloma, including inhibiting angiogenic factors,^440,441 activating immune NK cells,^442,443 and stimulating macrophages via the NF-κB and MAPK signaling pathways.^444,445 The immune-enhancing effects may be helpful to slow down the progression of MGUS/SMM to active myeloma, while the antitumor effects may be beneficial for active disease. Sea cucumber extracts have also demonstrated anti-inflammatory activity in preclinical studies. This is important, as inflammation is a critical driver in the pathogenesis of MGUS/SMM and myeloma.⁴⁴⁶ In immune-suppressed rats, a sea cucumber extract reduced serum levels of inflammatory factors like IL-6 and TNF-α.⁴⁴⁷ Similar results were seen in insulin-resistant mice.⁴⁴⁸ Additionally, sea cucumber extracts appear to have some benefits for bone as well: in vitro studies indicate they can inhibit the development of osteoclasts which break down bone, and promote differentiation of bone marrow-derived stem cells into bone-building cells.^449,450 These effects may be helpful both in slowing the progression from MGUS/SMM to active myeloma and managing bone lesions associated with active myeloma.

In an open-label clinical trial of TBL-12, 20 patients with asymptomatic multiple myeloma were given a total of 80 mL daily of the sea cucumber extract. The patients were all at high or intermediate risk of disease progression. After follow-up of up to 72 months, the treatment was well-tolerated, and median progression-free survival rates compared favorably to expected outcomes.⁴³⁷ Further clinical trials are necessary to determine whether early intervention, and sea cucumber extracts, may offer overall survival and health benefits for patients with MGUS/SMM or active myeloma.

Omega-3 Fatty Acids (EPA and DHA)

Omega-3 polyunsaturated fatty acids (PUFAs) play a critical role in cell structure and function, including cell signaling and resolution of inflammation, and they have more direct anti-inflammatory effects as well. Notably, they inhibit the inflammatory regulator and transcriptional factor NF-κB. Omega-3 PUFAs have been studied extensively, clinically and preclinically, in the context of cancer complications.⁴⁵¹ Intake of omega-3 PUFAs has been shown in human studies to improve survival of cancer patients.^451,452 The omega-3 PUFA docosahexaenoic acid (DHA), primarily derived from marine sources such as fish, has been reported in preclinical studies to increase sensitivity of cancer cells to anti-neoplastic agents in drug-resistant cell lines when combined with anti-cancer agents.⁴⁵³

Exposure of human MM cells to eicosapentaenoic acid (EPA) and DHA in vitro inhibited constitutive NF-κB activity and induced cell apoptosis through mitochondrial perturbation and caspase-3 activation. EPA and DHA also increased sensitivity of human MM cells to the proteasome inhibitor bortezomib.⁴⁵⁴ Stimulation of human U266 MM cells with EPA and DHA in the presence of dexamethasone increased MM cell apoptosis indicating omega‐3 fatty acids increased the sensitivity of MM cells to dexamethasone.⁴⁵⁴ The increase in sensitivity of MM cells to dexamethasone correlated with the increased expression of tumor suppressor p53 and miR-34a and reduced expression of Bcl-2. Thus, EPA and DHA increase sensitivity of MM cells to dexamethasone through the NF-κB-dependent p53/miR-34a/Bcl-2 axis.⁴⁵⁵

As of mid-2020, no clinical studies have investigated the effects of omega‐3 PUFAs in MGUS or SMM patients. However, a few clinical studies have been conducted to study the effects of EPA and DHA on hematological malignancies and side effects of treatment.

A prospective, randomized, single-center, open-label clinical trial including 12 acute lymphoblastic leukemia and six acute myeloid leukemia patients investigated the effects of EPA as part of an energy- and protein-dense supplement. At the end of the trial, alleviation of cancer-induced weight loss and improvement of the overall conditions of pediatric patients was observed. Decrease in levels of acute phase proteins were attributed to the beneficial effects of EPA.⁴⁵⁶

A randomized clinical trial investigated the effects of EPA and DHA supplementation on inflammatory markers and long-term survival of 22 patients with acute and chronic leukemia and lymphomas (Hodgkin and non-Hodgkin) receiving chemotherapy. The study found that consumption of 2 grams/day fish oil (containing EPA and DHA) for nine weeks resulted in greater reduction in C-reactive protein (CRP) and CRP/albumin ratio in patients receiving the supplement and chemotherapy compared with those receiving chemotherapy only. The overall long-term survival time of patients receiving fish oil was also greater (465 days after the start of chemotherapy) relative to controls. These findings indicate an improved nutritional‐inflammatory risk and suggest potential for long‐term survival in patients with hematological malignancies receiving chemotherapy who also supplement with fish oil.⁴⁵⁷

A multi-institutional phase II cooperative group study to examine the potential of fish oil supplements administered at high doses to slow weight loss and improve quality of life in patients with malignancy‐related cachexia was conducted in 43 patients diagnosed with advanced hematological malignancies including leukemia, lymphoma, and MM. Patients were supplemented with high‐dose omega‐3 PUFA capsules containing 4.7 grams EPA and 2.8 grams DHA per day for about 1.2 months. Study data show 24 patients had weight stabilization, six gained > 5% of their body weight, and six lost ≥ 5% of their body weight. Quality of life scores were superior for patients who gained weight. Thus, supplementation with high-dose omega‐3 PUFAs supported weight stabilization or weight gain in a subset of patients, which resulted in improved quality of life in this group.⁴⁵⁸

Genistein

Genistein, an isoflavone found predominantly in soybeans, has been shown to exert a wide range of bioactivities, including anti-cancer activities.⁴⁵⁹ In MM cells, genistein (40 mM) increased the expression of miR-29b and suppressed NF-κB. The suppression of NF-κB resulted in reduced cellular proliferation, increased caspase-3 activity, and apoptosis.⁴⁶⁰

Bone marrow stromal cells (BMSCs) are critical for promoting myeloma cell survival and proliferation. Genistein was shown to downregulate NF-κB in BMSCs, which decreased the expansion of MM cells when these two cell types were co-cultured.⁴⁶¹ Furthermore, genistein inhibited cellular proteasome activity,⁴⁶² which could be beneficial for MM patients as proteasome inhibitors are a standard drug therapy for MM. In clinical settings, genistein was shown to strengthen NK cell activity.⁴⁶³

An epidemiological study of 220 patients with MM compared with 220 matched controls suggested dietary soy intake was associated with a reduced risk of developing MM.⁴⁶⁴ Genistein (60 mg daily for seven days every two weeks) was tested in 13 patients with metastatic colorectal cancer undergoing chemotherapy and found to be safe and tolerable, with potential positive impacts on efficacy that include increased NK cell activity.⁴⁶³ In 16 patients with pancreatic cancer, a novel crystalline form of genistein administered at doses up to 1600 mg/day in combination with standard treatment resulted in maximum serum genistein concentrations of 1 µM.⁴⁶⁵ As genistein appears to follow a linear dose-response curve,⁴⁶⁶ these results suggest that clinically relevant doses of genistein up to 800 mg/day should not lead to serum levels exceeding 0.5 mM. At this dose genistein may help promote NK cell-mediated antitumor response in cancer patients. However, MM patients may wish to avoid genistein doses greater than 800 mg/day as genistein concentrations above 0.5 mM have been shown to adversely affect NK cell function in vitro.⁴⁶⁷

Green Tea Extract (EGCG)

Green tea’s (Camellia sinensis) main chemical components are tea polyphenols, which have been shown to exhibit various therapeutic effects against several human pathologies, including cancer. Tea polyphenols in green tea are comprised of catechins including epicatechin (EC), epicatechin-3-gallate (ECG), epigallocatechin (EGC), and epigallocatechin-3-gallate (EGCG). Among these components, EGCG is the most abundant tea polyphenol.^468,469

Effects of EGCG on cell death mechanisms via the induction of apoptosis, necrosis, and autophagy are well-documented in in vitro studies and several preclinical models.^470-472 The anti-cancer effects of EGCG have been demonstrated in MM cells as well.⁴⁷³

A phase I trial found that a concentrated green tea preparation containing EGCG, known as polyphenon E, was well tolerated at doses up to 2,000 mg twice daily in CLL patients and led to some positive clinical effects.^474,475

Note: Green tea may interact with bortezomib. See the sidebar titled “Potential Bortezomib Interactions with Natural Substances” for more information.

Icaritin

Icaritin is a flavonoid (prenylflavonoid) extracted from a traditional Chinese herb, Epimedium grandiflorum, also known as horny goat weed. Its cytotoxic effects are thought to induce tumor cell killing and inhibit the spread of several types of cancer cells through various mechanisms, including inhibiting proliferation, blocking the cell cycle, and inducing apoptosis.³³⁸ Studies into icaritin for control of MM have largely focused on its ability to inhibit signal transduction pathways, leading to improved apoptosis of MM cells.^340,476

Icaritin has been shown to reverse drug resistance exhibited by some myeloma cells.³³⁹ There is also potential for icaritin to regenerate bone in those with MM by increasing bone formation through increasing bone morphogenic proteins (BMPs) among other osteogenic mechanisms.⁴⁷⁷ Clinical trials are needed to further explore the potential of icaritin in patients with MM.

Parthenolide

Parthenolide, a sesquiterpene lactone naturally occurring in the feverfew (Tanacetum parthenium) plant, is known to have multiple anti-cancer effects.⁴⁷⁸ In an experiment using a 3D tissue culture that mimics the microenvironment of bone marrow, myeloma stem cells were cultured. Both parthenolide and andrographolide (from the plant Andrographis paniculata) inhibited the growth of the myeloma stem cells.⁴⁷⁹ However, once cells found in bone marrow stroma were added, only parthenolide maintained its cytotoxic effect.

In addition to the effect of parthenolide on myeloma stem cells, it also suppresses activation of NF-κB by binding TRAF6 in myeloma cells, effectively suppressing proliferation and inducing apoptosis.⁴⁸⁰

Parthenolide induced apoptosis in four separate myeloma cell lines while not harming normal lymphocytes.⁴⁸¹ In this cell experiment, apoptosis was completely stopped by the addition of N-acetyl cysteine, indicating the effect is mediated by reactive oxygen species (ROS). This was confirmation of an earlier cell study that showed parthenolide induced apoptosis through ROS generation.⁴⁸²

Proteolytic Enzymes

Enzymes have been used extensively alongside conventional cancer treatments worldwide.⁴⁸³ The most commonly used preparations for add-on therapy to cancer regimens are proteolytic or pancreatic enzymes. Research on the benefits of enzymes in cancer is fairly scant, but the predominant benefit reported in the available literature has been in the reduction in side effects from chemotherapy and radiation.⁴⁸⁴

One small study suggested better outcomes with proteolytic enzymes for MM patients undergoing chemotherapy. In this trial, oral enzyme tablets consisting of 100 mg papain, 40 mg trypsin, and 40 mg chymotrypsin were studied in 265 myeloma patients (stages I‒III). Patients received either standard chemotherapy alone or standard chemotherapy with two oral enzyme tablets three times daily.⁴⁸⁵ Dosing began on the first day of chemotherapy and was reduced to one tablet three times daily after 12 months. Across all stages of disease, the number of patients that achieved either remission or stable disease was significantly higher in the enzyme plus chemotherapy group versus chemotherapy alone. Participants with stage III myeloma (n=54) that received enzyme supplements plus chemotherapy survived longer compared with chemotherapy alone (83 months vs. 47 months; p= 0.0014). While this small trial was intriguing, placebo-controlled studies are needed before any recommendation regarding enzymes can be made.

Intravenous Vitamin C (Ascorbate)

Vitamin C insufficiency may be present in those with MM. One study of 50 patients with MM (ISS stage II) found higher oxidative stress (per malondialdehyde levels) as well as lower status of both enzymatic (glutathione peroxidase, superoxide dismutase, and catalase) and nonenzymatic (vitamins C and E) antioxidants in MM patients versus control subjects.⁴⁸⁶

Intravenous vitamin C, sometimes called pharmacologic ascorbate, has been studied extensively in cancer, including hematologic cancers, and in preclinical settings against multiple myeloma.⁴⁸⁷ Pharmacologic ascorbate’s anti-cancer activity has a different mechanism of action than oral antioxidant vitamin C, which has not been shown to be effective at killing cancer cells or tumors.^488,489 Multiple clinical trials of pharmacologic ascorbate are planned, underway, or completed. Most such trials have combined intravenous vitamin C with chemotherapy, and several of them have reported encouraging results.^487,490

Safety note: Some in vivo data suggests vitamin C may interfere with the efficacy of boronic-acid-based proteasome inhibitors such as bortezomib.¹¹⁰ Therefore, MM patients on bortezomib should talk with their oncologist before taking vitamin C in supplemental form (see sidebar titled “Potential Bortezomib Interactions with Natural Agents”).

Vitamin D

Vitamin D is a steroidal compound that is made in the skin as a result of direct exposure to sunshine. Vitamin D receptors are found in cells throughout the body. Given this widespread distribution, it is not surprising that vitamin D is involved in physiological homeostasis of nearly every system in the body.⁴⁹¹ Some foods (eg, fatty fish, mushrooms) contain small amounts of vitamin D, but repletion of circulating levels usually requires oral supplementation or intramuscular injection.

Clinical consideration of vitamin D use in those with MGUS/MM should be approached cautiously given its effect on calcium homeostasis. One of the classic presenting symptoms of MM is hypercalcemia, and the normal physiological role of vitamin D in preserving calcium by optimizing intestinal absorption and reducing renal clearance of calcium must be taken into consideration. In contrast, vitamin D deficiency portends poorer outcomes in MM patients. Given that vitamin D deficiency and hypercalcemia are each a risk for the patient, the prudent approach may be to monitor both circulating vitamin D and calcium on a routine basis in those with MGUS/MM.

Recent studies suggest low vitamin D status is associated with a higher risk and poorer prognosis of a variety of cancers, including MM.^492,493

Vitamin D deficiency has been associated with MM, even in tropical climates with ample sunshine.⁴⁹⁴ In a single-institution study that assessed vitamin D levels of incoming patients with bone metastasis or multiple myeloma, vitamin D deficiency was “alarmingly common” according to the authors.⁴⁹⁵ In the MM cohort, average vitamin D level was just under 15 ng/mL, a value low enough that bone loss is expected even in healthy individuals.

There is some controversy regarding optimal levels of circulating vitamin D (as 25-hydroxycholicalciferol). However, there is consensus that levels below 20 ng/mL represent a gross deficiency that results in bone loss.^496,497

In a study that assessed 83 myeloma patients and vitamin D levels, deficiency (<10 ng/mL) was associated with higher levels of plasma cells in the bone marrow.⁴⁹⁸ Furthermore, supplementation with vitamin D led to significant increases in hemoglobin, leukocyte, and RBC levels, and improvement in platelets.

Vitamin D deficiency (serum levels <50 nmol/L or 20 ng/mL) is associated with more inflammation (as measured by CRP levels), lower serum albumin, and higher creatinine when compared with MM subjects without vitamin D deficiency.⁴⁹⁹ In a small single clinic study of 31 MM patients (12 female, 19 male), the median level of circulating vitamin D was just below 12 ng/mL with 93.5% of patients deficient at the time of diagnosis.⁵⁰⁰ The clinic also reported that vitamin D levels were lower after each chemotherapy session.

While there is no clinical data to determine whether adequate vitamin D status is preventative of the progression from MGUS to MM, it is plausible to expect that the effects of vitamin D on preventing bone resorption, regulating immune function, and acting as a pro-differentiating agent may result in reduction of transformation from benign MGUS to MM.⁵⁰¹

A study of 158 patients scheduled to receive their first autologous stem cell transplant found pre-transplant vitamin D levels below 23 ng/mL were associated with inferior survival time after autologous stem cell transplant (25 months vs. 32 months; p=0.03).⁵⁰² They also found lower vitamin D levels were significantly associated with younger age at diagnosis of MM.

In one report of 108 MM patients followed for one year, lower vitamin D levels were associated with myeloma activity (paraprotein concentration), higher markers of bone turnover (urine deoxypyridinoline), and worse bone mineral density (dual-energy X-ray absorptiometry, or DEXA).⁵⁰³

Vitamin D repletion may benefit those taking bortezomib. Bortezomib has been shown to improve bone health through a mechanism that involves vitamin D and its receptor (VDR).⁵⁰⁴ One mechanism of bone loss in myeloma is disruption of vitamin D dependent differentiation of osteoblasts, a process that is inhibited by bortezomib. While bortezomib alone partially overcomes this, the addition of vitamin D had an additive effect, allowing for improved maturation of osteoblasts co-cultured with myeloma cells. As of this writing, there are no clinical trials published on the bone effects of repletion of vitamin D in those taking bortezomib.

Vitamin D may complement some MM drugs known to induce peripheral neuropathy. Vitamin D deficiency is associated with neuropathy induced by drugs used to treat MM such as bortezomib and thalidomide.⁵⁰⁵ Given the possible benefits to those taking such drugs, vitamin D should be closely monitored and supplemented as needed.

It appears that correcting vitamin D deficiency could improve outcomes in those with MGUS/MM. This simple intervention is important, since vitamin D levels are frequently low and infrequently assessed in MM patients.⁵⁰⁶

Vitamin K

Vitamin K is required to maintain homeostasis of osteoblasts and osteoclasts in normal bone turnover. While human data on the outcome of supplemental vitamin K in MGUS/MM is lacking, many of the mechanisms of bone degradation in MM may be targets for the action of vitamin K in maintaining bone health.

There are many other types of proliferative disorders of the bone marrow (eg, dyscrasias and leukemias), but only the clonal populations of plasma cells associated with MM are marked by the destruction of bone in the nearby microenvironment. This characteristic trait has been proposed as a crux of the plasma cell proliferation process in plasmacytomas/MM. While a singular definitive mechanism shared by all MM cases has yet to be found, it is clear that there is an imbalance in the expression of bone regulating proteins that stimulate or inhibit osteoclastic and osteoblastic actions (Table 11).

Table 11: Overexpressed Proteins Correlating with Severity of Bone Degradation in Those with MM*

Produced by	Inhibit nearby Osteoblasts	Stimulate nearby Osteoclasts
MM cells	DKK1, SRP-3, HGF, MIP-1alpha	MIP 1-alpha, IL-32, BDNF
Stromal cells	Activin A	RANKL, GDF15, BDNF

*Compiled from Why Do Myeloma Patients Have Bone Disease: A Historical Perspective by Borset et al.⁵⁰⁷

Vitamin K also appears to affect bone turnover favorably through dual actions on osteoclasts and osteoblasts derived from its inhibition of NF-κB activation.⁵⁰⁸

Preliminary evidence from an in vitro study suggests vitamin K2 may exert some anti-myeloma effects in addition to its benefits for bone health. When myeloma cells were incubated with various concentrations of vitamin K2, their growth was inhibited and apoptosis increased.¹⁷⁰

Plumbagin, an analogue of vitamin K derived from Plumbago zeylanica, an Ayurvedic medical plant, has been shown to inhibit RANKL and suppress osteoclastogenesis in a rodent model of multiple myeloma.⁵⁰⁹ Further studies should be done in humans before any conclusions are drawn on its use.