Concise Review of Relapsed and Refractory Myeloma

Founded in 1990, the International Myeloma Foundation (IMF) is the first and largest organization focusing specifically on myeloma. The IMF’s reach extends to more than 525,000 members in 140 countries. The IMF is dedicated to improving the quality of life of myeloma patients while working toward prevention and a cure through our four founding principles: Research, Education, Support, and Advocacy.

RESEARCH

The IMF is dedicated to finding a cure for myeloma, and we have a range of initiatives to make this happen. The International Myeloma Working Group, which emerged from the IMF’s Scientific Advisory Board established in 1995, is the most prestigious organization with nearly 300 myeloma researchers conducting collaborative research to improve outcomes for patients while providing critically appraised consensus guidelines that are followed around the world. Our Black Swan Research Initiative® is bridging the gap from long-term remission to cure. Our annual Brian D. Novis Research Grant Program is supporting the most promising projects by junior and senior investigators. Our Nurse Leadership Board, comprised of nurses from leading myeloma treatment centers, develops recommendations for the nursing care of myeloma patients.

EDUCATION

The IMF’s webinars, seminars, and workshops provide up-to-date information presented by leading myeloma scientists and clinicians directly to patients and their families. We have a library of more than 100 publications for patients, care partners, and healthcare professionals. IMF publications are always free-of-charge, and available in English and select other languages.

SUPPORT The IMF InfoLine responds to your myeloma-related questions and concerns via phone and email, providing the most accurate information in a caring and compassionate manner. We also sustain a network of myeloma support groups, training hundreds of dedicated patients, care partners, and nurses who volunteer to lead these groups in their communities.

ADVOCACY

We empower thousands of individuals who make a positive impact each year on issues critical to the myeloma community. In the U.S., we lead coalitions to represent the interests of the myeloma community at both federal and state levels. Outside the U.S., the IMF’s Global Myeloma Action Network works to help patients gain access to treatment.

Learn more about the ways the IMF is helping to improve the quality of life of myeloma patients while working toward prevention and a cure. Call us at 1.818.487.7455 or 1.800.452.CURE, or visit myeloma.org .

You are not alone

The International Myeloma Foundation is here to help you. The IMF is committed to providing information and support for patients with multiple myeloma (which we refer to simply as “myeloma”) and their care partners, friends, and family. We achieve this through a broad range of resources available on our website myeloma.org, the IMF InfoLine, seminars, webinars, workshops, and other programs and services.

What you will learn from this booklet

Myeloma is a cancer that is not known to most patients at the time of diagnosis. To play an active role in your own medical care and to make good decisions about your care with your doctor, it is important and helpful to learn about this disease, as well as its treatment options and supportive care measures.

The information in this booklet can guide you in your discussions with your doctor. It is not intended to be a substitute for medical advice. Your doctor is best able to answer questions about your specific healthcare management plan.

The IMF Concise Review of Relapsed and Refractory Myeloma is an overview of myeloma for patients with relapsed or refractory disease. It includes a discussion of epidemiology, clinical features, pathophysiology, drugs currently in use for myeloma in the U.S., response or remission, relapsing or refractory disease, and supportive care.

If you are newly diagnosed with myeloma, we suggest that you first read the IMF’s publication Patient Handbook for the Newly Diagnosed, which will help you to better understand this complex disease, its possible causes or triggers, diagnostic criteria, staging, types of myeloma, its effects inside and outside the bone marrow, treatment for newly diagnosed myeloma, and supportive care.

If you have been diagnosed with an asymptomatic precursor condition and not with active myeloma, read the IMF’s publication Understanding MGUS and Smoldering Multiple Myeloma.

If you are a myeloma patient in the United States who is in discussions with your treating doctors about the possibility of having an autologous stem cell transplant (ASCT) as part of your overall treatment strategy, read the IMF’s publication Understanding Stem Cell Transplant in Myeloma.

Words in bold+blue type are explained in the “Terms and definitions” section at the end of this booklet. A more comprehensive glossary can be found in the IMF’s publication Understanding Myeloma Vocabulary, which is located online at glossary.myeloma.org.

If you are reading this booklet in electronic format, the light blue links will take you to the corresponding resources. All IMF publications are free-of-charge and can be downloaded or requested in printed form at publications.myeloma.org.

Epidemiology

In the United States, according to recent data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute (NCI) at seer.cancer.gov 35,730 new cases of myeloma are estimated for 2023, representing 1.8% of all new cancer cases. There were an estimated 170,405 people living with myeloma in the US in 2020.

As published in the journal Oncologist in 2020, the global incidence of myeloma shows significant disparities, indicating under-recognition and suboptimal treatment in many parts of the world. The article highlights the importance of economic resources, access to and quality of healthcare, and patient education for improving diagnosis and survival of patients with myeloma worldwide.

Myeloma is most frequently diagnosed in individuals who are 65–74 years old, but it is also being diagnosed in people younger than 50. Only 5%–10% of myeloma patients are under the age of 40. Myeloma in children is extremely rare.

Men are more likely than women to develop myeloma. The disease is twice as common in people of African descent. It appears that the incidence of myeloma is increasing in several parts of the world, especially in Asia.

Approximately 5%–7% of myeloma diagnoses occur in individuals with a close relative diagnosed with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or myeloma. If you have MGUS, SMM, or myeloma, have your relatives inform their doctors to include your diagnosis in their medical history. If you have a close relative with such a diagnosis, tell your primary care doctor to include this information in your medical record.

Figure 1. Myeloma cells in the bone marrow

Figure 2. Disease phases

Table 1. IMWG Diagnostic Criteria

DISORDER DEFINITION

MGUS All criteria must be met

1. Presence of M-protein in the serum < 3 g/dL,

2. Presence of monoclonal plasma cells in the bone marrow < 10%, and

3. Absence of CRAB criteria – elevated Calcium, Renal (kidney) damage, Anemia, or Bone disease.

Light chain MGUS All criteria must be met

1. Abnormal FLC ratio < 0.26 or > 1.65,

2. Level of the appropriate involved light chain (increased kappa FLC in patients with ratio > 1.65 and increased lambda FLC in patients with ratio < 0.26),

3. No Ig heavy chain expression on immunofixation,

4. Absence of CRAB criteria,

5. Presence of monoclonal plasma cells in the bone marrow < 10%, and

6. Presence of M-protein in the urine based on a 24-hour collection < 500 mg.

SMM Both criteria must be met

1. Presence of M-protein in the serum (IgG or IgA) ≥ 3 g/dL, or urinary M-protein ≥ 500 mg per 24-hour collection, and/or presence of monoclonal plasma cells in the bone marrow 10%–60%, and

2. Absence of myeloma-defining events (MDE) or amyloidosis.

Myeloma Both criteria must be met

1. Presence of monoclonal plasma cells in the bone marrow ≥ 10%, or biopsy-proven bony or extramedullary plasmacytoma, and

2. Any one or more of the following myeloma-defining events (MDE):

 Presence of CRAB criteria,

 Presence of monoclonal plasma cells in the bone marrow ≥ 60%,

 Ratio of involved-to-uninvolved serum FLC ≥ 100 (involved FLC level must be ≥ 100 mg/L and urine M-protein level must be at least 200 mg per 24-hour collection on UPEP),

 One or more focal lesions on MRI studies (at least 5mm in size),

 One or more osteolytic lesions on skeletal radiography, CT, or PET-CT

Modified from Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncology 2014.

Clinical features of myeloma

Myeloma is a cancer of the bone marrow plasma cells, white blood cells (WBC) that make antibodies, also called immunoglobulins (Ig). Healthy plasma cells are an important part of the immune system. Myeloma cells are malignant (cancerous) plasma cells that do not make functioning antibodies, but instead produce an abnormal monoclonal protein (myeloma protein, M-protein).

Myeloma has been recognized since Ancient Times. In 1844, Dr. Samuel Solly referred to “soft and fragile bones” in his description of a case of myeloma. In 1845, the first well-documented patient, Thomas Alexander McBean, was diagnosed by Dr. William Macintyre. In 1846, Dr. John Dalrymple determined that the diseased bones contained cells subsequently shown to be plasma cells. The unusual urine problem discovered by Dr. Macintyre was investigated by Dr. Henry Bence Jones, who published his findings in 1848.

Figure 3. Structures of immunoglobulins

Figure 4. Immunoglobulin molecule structure

In 1873, Johann von Rustizky introduced the term “multiple myeloma” to designate the presence of multiple plasma cell lesions in bone. In 1889, Otto Kahler published a detailed clinical description of “Kahler’s disease” (multiple myeloma). The routine diagnosis of myeloma remained difficult until bone marrow aspiration was used on a broader scale in the 1930s.

The major features of myeloma result from the abnormal accumulation of malignant (cancerous) plasma cells within the bone marrow. Known as the “CRAB criteria,” these features include an elevated level of calcium in the blood, renal (kidney) damage, anemia or low red blood cell count, and bone damage are criteria used to diagnose myeloma along with “Myeloma-defining event (MDE).”

 Disruption of normal bone marrow function reflected by anemia, low white blood cell (WBC) count, and/or low platelet count (thrombocytopenia).

 Invasion and destruction of bone and areas surrounding the bone marrow involvement.

 Production and secretion (release) of monoclonal protein from the myeloma cells into the bloodstream and/or into the urine.

 Recurrent and frequent infections due to the reduction of normal immune function resulting from reduced levels of normal immunoglobulins.

Plasmacytomas are localized tumors composed of plasma cells, which can grow inside bone

Site of biopsy

© 2015 Slaybaugh Studios

Figure 6. Bone marrow aspiration

+ Myeloma cells Lytic lesion

MULTIPLE MYELOMA

Figure 5. Healthy bone compared to bone damaged by myeloma

© 2017 Slaybaugh Studios

(intramedullary) or in soft tissue outside bone (extramedullary). When there are multiple plasmacytomas, this condition is also called myeloma.

Production and release of M-protein

The amount of M-protein produced by myeloma cells varies from patient to patient. It is very important to determine if a patient’s myeloma cells are high producers of M-protein, low producers (hyposecretory or oligosecretory myeloma), or non-secretory. Approximately 1% of myeloma patients do not have detectable M-protein in the blood and urine. Some of these patients can be successfully monitored using the serum free light chain (FLC) assay; others may be monitored with bone marrow biopsy and/or PET-CT scan. The myeloma therapies used for patients with nonsecretory myeloma are the same as those used for patients who secrete detectable levels of M-protein.

Once the relationship between the M-protein level and the amount of myeloma in the bone marrow is known, it is possible to interpret and understand the relationship between a particular protein level and the myeloma tumor burden. The M-spike that occurs on protein electrophoresis laboratory tests is a marker for the activity of myeloma cells.

The M-protein is an immunoglobulin or a fragment of an immunoglobulin. In myeloma cells, mutations have occurred in the genes responsible for immunoglobulin production, and the M-proteins have an abnormal amino acid sequence and protein structure. Typically, the normal antibody function of the immunoglobulin is lost, and the 3-dimensional structure of the molecule may be abnormal. Increased production of abnormal immunoglobulin results in the following:

 Excess M-protein accumulates in the bloodstream and/or is excreted in the urine and can be measured by an M-spike.

 The abnormal monoclonal molecules can adhere to each other and/or to

* This includes different types of myeloma, MGUS, as well as Waldenström macroglobulemia (per data collected and analyzed by W Pruzanski and MA Ogryzlo, 1970).

Table 3. Medical problems related to myeloma

E FFECTS OF INCREASED MYELOMA CELLS IN BONE MARROW CRAB criteria

CAUSE IMPACT ON PATIENT

C – Increase in blood Calcium Release of calcium from damaged bone into bloodstream.

• Mental confusion

• Dehydration

• Constipation

• Fatigue

• Weakness

• Renal (kidney) damage

R – Renal problems –kidney damage

Abnormal M-proteins produced by the myeloma cells are released into the bloodstream and can pass into the urine, causing kidney damage. High blood calcium, infections, and other factors can also cause or increase the severity of kidney damage.

• Sluggish circulation

• Fatigue

• Mental confusion

A – Anemia

B – Bone Damage

• Thinning (osteoporosis) or

• Areas of more severe damage (called lytic lesions), fracture, or collapse of a vertebra

Additional types of organ dysfunction

Decrease in number and activity of red blood cell-producing cells in the bone marrow.

The myeloma cells activate osteoclast cells, which destroy bone and block osteoblast cells, which normally repair damaged bone.

• Fatigue

• Weakness

• Bone pain

• Fracture or collapse of a bone

• Bone swelling

• Nerve or spinal cord damage

Local or systemic effects of myeloma, other than CRAB features.

• Neuropathy

• Recurrent infections

• Bleeding problems

• Other individual problems

Abnormal immune function

The myeloma cells reduce the number and activity of normal plasma cells capable of producing antibodies against infection.

• Susceptibility to infection

• Delayed recovery from infection

other tissues (e.g., blood cells, blood vessel walls, and other blood components). This can reduce blood flow and circulation, causing hyperviscosity syndrome (HVS). It is important to be aware that HVS can alter results of myeloma blood test samples and special processing may be needed.

 More light chains are produced than are needed to combine with the heavy chains to create a whole immunoglobulin molecule. These excess light chains are called Bence-Jones proteins. Free Bence-Jones proteins have a molecular weight of 22,000 daltons and are small enough to pass into the urine.

 The abnormal M-proteins can have other properties, including:

 Binding to normal blood clotting factors, resulting in increased bleeding tendency, enhanced blood clotting, or phlebitis (inflammation of a vein).

 Binding to nerves to cause neuropathy, or to circulating hormones to cause metabolic dysfunction.

Abnormal result with myeloma cells producing the M-protein, creating an M-spike in the beta-2 region

Abnormal result with myeloma cells producing the M-protein, creating an M-spike in the gamma region

 Free Bence-Jones proteins can adhere to each other or to other tissues – same as an immunoglobulin molecule – and may cause one of the following:

 Amyloid light chain (AL) amyloidosis

AL amyloidosis is a plasma cell disorder in which light chain proteins are not excreted by the kidneys, but become crosslinked

Figure 7. SPEP test results

with each other, and these amyloid fibrils are then deposited in tissues and organs.

 Monoclonal immunoglobulin deposition disease (MIDD)

MIDD is caused by deposition of heavy chains, light chains, or both heavy and light chains in organs. MIDD usually affects the kidneys but can affect other organs, and the goal of treating MIDD is to slow damage to organs.

 Light chain deposition disease (LCDD) is a type of MIDD, characterized by deposition of complete or partial monoclonal light chains in organs.

 Heavy chain deposition disease (HCDD) is a type of MIDD, characterized by deposition of monoclonal heavy chains in organs.

Pathophysiology

The uncontrolled growth of myeloma cells has many consequences, including skeletal destruction, increased plasma volume and viscosity, suppression of normal immunoglobulin production, and renal (kidney) insufficiency. Nonetheless, myeloma can be asymptomatic for many years. With symptomatic myeloma, the most common complaints are bone pain and fatigue. The serum and/or urine M-protein is elevated and typically rising at the time of diagnosis.

Hypercalcemia

Calcium is a mineral found mainly in the hard part of bone matrix (hydroxyapatite). If produced or released in excess, it can build up in the bloodstream. Hypercalcemia is a higher-than-normal level of calcium in the blood, which usually results from bone breakdown that releases calcium into the bloodstream. In myeloma, hypercalcemia is the most frequent metabolic complication, and it is more common with extensive bone involvement.

Hypercalcemia can cause a number of symptoms, including loss of appetite, nausea, thirst, fatigue, muscle weakness, restlessness, and confusion. In patients with hypercalcemia due to myeloma, there is often impaired renal (kidney) function, which can complicate recovery from kidney injury.

Renal (kidney) dysfunction

Impairment of kidney function is a common complication in patients with myeloma. However, not every patient will have this problem. In some patients, M-proteins (especially Bence-Jones proteins) cause renal injury by a variety of mechanisms, ranging from tubular damage (resulting from large

accumulations of precipitated light chains) to selective tubular damage (resulting in the metabolic effects of Fanconi syndrome), and to M-proteins deposited as amyloid. Increased levels of calcium or uric acid, as well as infection can lead to impaired kidney function.

Other important considerations related to kidney dysfunction include hydration status, and the effects of drugs such as nephrotoxic antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), or contrast agents or dyes used for imaging studies. Gadolinium-based contrast agents used with MRI have a potentially toxic effect, and patients with kidney problems should first discuss their use with their doctor. Awareness of potential kidney damage and maintenance of sufficient fluid intake are especially important for patients with myeloma to help avert the damaging effects of these various factors.

Anemia

Anemia is a characteristic feature of myeloma. Red blood cells (RBC) contain hemoglobin, a protein that carries oxygen to the body’s tissues and organs. Anemia is usually defined as a decrease in hemoglobin < 10 g/dL or as a decrease of ≥ 2 g/dL from the normal level for an individual. More than 13–14 g/dL is considered normal. Low levels of oxygen in the body may cause shortness of breath and feelings of exhaustion. Many newly diagnosed myeloma patients have anemia.

Although physical displacement of bone marrow RBC precursors is a factor, the specific inhibition of RBC production by micro-environmental cytokines and adhesion molecules is a more functional explanation. Improvement in anemia occurs with successful treatment of the myeloma. Recombinant epoietin alpha should be used with caution, as reports have noted the association of epoietin with increased tumor growth and reduced survival in cancer patients, and the identification of epoietin receptors on myeloma cells.

Bone disease

Ever since the first recognition of myeloma in 1844, there has been awareness of its unique type of bone disease. It has taken until quite recently to determine the mechanisms involved. The first clue was that both myeloma cells and increased numbers of osteoclasts are present at sites of bone destruction. Many details of the mechanisms of bone disease in myeloma are now understood, including the following:

 Myeloma cells produce osteoclast-activating factors (OAFs) while inhibiting osteoblasts. “Coupling” between osteoclast and osteoblast function is responsible for normal bone remodeling and repair. Both Velcade® (bortezomib) and Revlimid® (lenalidomide) have been

shown to promote bone healing in addition to exerting potent antimyeloma activity.

 Cytokines (i.e., interleukin -1β, interleukin-6, tumor necrosis factor -α, and tumor necrosis factor-β), chemokines such as MIP-α, and cell-cell adhesion processes involving β3 integrin are all involved in producing increased numbers and activity of osteoclasts.

 The identification of a substance called RANK ligand (RANKL) as a critical mediator of osteoclast activation.

For more information, read the IMF’s publication Understanding Treatment of Myeloma Bone Disease.

Other dysfunction

Myeloma cells can accumulate in bone marrow or in tissue and produce a broad range of potential complications, including the following:

 Infections

Besides bone disease, the predisposition to infections is perhaps the single most characteristic feature of myeloma. Patients with myeloma are susceptible to a broad range of opportunistic infections. Risk factors for infection in myeloma patients are reduced immunity and low white blood cell counts due to active disease and/or the impact of treatment. The mechanisms responsible for infection susceptibility are not fully understood. The presence of active myeloma in the bone marrow results in impairment of normal immune function, including inhibition of normal antibody production reflected by hypogammaglobulinemia, impaired T cell (T lymphocyte) function, and activated yet aberrant monocyte or macrophage function.

Some studies indicate that a factor resulting from the activated macrophages both enhances the activity of the myeloma cells and inhibits normal Ig production and T-cell function. Infection might be potentially life-threatening and must be promptly addressed. There may be a need for immediate supportive care, such as treatment with antibacterial or antiviral therapy, or even hospitalization. Both neutropenia and hypogammaglobulinemia increase the likelihood of infections.

 Neurologic effects

Myeloma patients are susceptible to viral infections of nerve tissue, most particularly varicella zoster (“shingles”), herpes zoster (“cold sores”), Epstein-Barr virus (mononucleosis), cytomegalovirus (which may result in partial facial paralysis called Bell’s Palsy), or other complications.

In myeloma patients, nerve tissue is often affected either by the direct antibody effects of M-proteins against nerves (e.g., myelin sheaths)

or by deposition of amyloid fibrils on nerves, thus impairing function. These effects result in peripheral neuropathies that must be distinguished from other causes of neuropathy (e.g., diabetes mellitus, multiple sclerosis, Parkinson’s disease).

Neurologic problems in myeloma depend on the location of affected nerves. For example, spinal cord compression and meningitis are the result of plasma cell tumor formation or infiltration, and carpal tunnel syndrome usually results from deposition of Bence Jones proteins.

 Plasmacytomas

Both in bone and in soft tissue, plasmacytomas can result in compression or displacement of nerves, the spinal cord, or even brain tissue. These pressure effects often represent a medical emergency that requires immediate treatment with radiation therapy, neurosurgery, and/or high-dose steroids or other medications.

Table 4. Schema of pathophysiology

Skeletal findings

• Solitary or multiple osteolytic lesions

Associated effects of bone destruction

• Elevated serum calcium

• Bone fractures

Extramedullary (extraskeletal) myeloma

• Diffuse osteoporosis (osteopenia)

• Hypercaliuria (calcium increase in urine)

• Loss of height (vertebral collapse)

Soft tissue involvement, mostly common in head/neck area (e.g., nasopharynx); also in liver, kidney, and other soft tissue sites including skin

Peripheral blood

• Anemia

• Abnormal clotting

• Leukopenia

Plasma protein changes

• Thrombocytopenia

• Plasma cell leukemia

• Circulating plasma cells

• Hyperproteinemia (elevated protein)

• Hypervolemia (expanded volume)

• Monoclonal immunoglobulins (IgG, IgA, IgD, IgE, IgM or light chains only)

Kidney abnormalities

• Proteinuria, casts without leukocytes or erythrocytes

• Tubular dysfunction with acidosis (Fanconi syndrome)

• Circulating monoclonal B lymphocytes (precursors of myeloma cells)

• Narrowed anion gap (low serum sodium)

• Elevated serum β2-microglobulin

• Decreased serum albumin

• Elevated serum IL-6 and C-reactive protein (CRP)

• Uremia (kidney failure)

• Amyloidosis or light chain deposition disease and renal dysfunction

 Hyperviscosity

Hyperviscosity resulting from high levels of M-protein can cause problems such as bruising, nose bleeding, hazy vision, headaches, gastrointestinal bleeding, sleepiness, and a variety of ischemic neurological symptoms caused by reduced blood and oxygen supply to the nerve tissue. Hyperviscosity occurs in less than 10% of patients with myeloma and in about 50% of patients with Waldenström macroglobulinemia (WM). Increased bleeding is often exacerbated by thrombocytopenia as well as by binding of M-proteins to clotting factors or platelets.

Response or remission

Response or remission are interchangeable terms to describe the complete or partial disappearance of the signs and symptoms of myeloma. Remission is generally considered to be at least a partial response (PR, ≥ 50% improvement) which lasts for at least 6 months. These are the terms used to classify the depth of response to treatment:

 Stringent complete response (sCR) sCR is CR (as defined below) plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence.

 Complete response (CR)

For myeloma, CR is negative immunofixation on serum (blood) and urine, and disappearance of any soft tissue plasmacytomas, and ≤ 5% plasma cells in bone marrow. CR is not the same as a cure.

 Very good partial response (VGPR)

VGPR is less than CR. VGPR is serum M-protein and urine M-protein detectable by immunofixation but not on electrophoresis, or 90% or greater reduction in serum M-protein, plus urine M-protein less than 100 mg per 24 hours.

 Partial response (PR)

PR is a level of response in which there is at least a 50% reduction in M-protein, and reduction in 24-hour urinary M-protein by at least 90% (or to less than 200 mg per 24 hours).

As treatment has improved, it has become more important to assess response to treatment as accurately as possible. Besides the depth of response, one must now consider even deeper responses as well as duration of response. With the increasing efficacy of new combination therapies, response is now assessed in terms of minimal residual disease (MRD) and MRD-negative status. Concepts that were previously unattainable and unmeasurable in myeloma, MRD levels are now verifiable with bone marrow testing. If or when approved by the FDA, MRD testing will become the new clinical trial

Table 5. Clinical trial phases

I Early testing to assess dosing, tolerance, and toxicity in patients

II Further testing to evaluate how effective treatment is at the dose and schedule selected

III Comparison of the new treatment with prior treatment(s) to determine if the new treatment is superior

IV Usually carried out after FDA approval to assess cost-effectiveness, quality of life impact, and other comparative issues

endpoint, the standard means to measure depth of response in US-based myeloma clinical trials.

Improvements in M-protein must be associated with evidence of clinical improvement, such as reduced bone pain or improved RBC counts. It is important to keep in mind that a higher percent regression in disease does not automatically confer longer survival. When there is residual disease, the characteristics of the remaining drug-resistant myeloma cells determine the outcome. These remaining myeloma cells may or may not have a tendency for immediate regrowth. If there is no regrowth, this is called “plateau phase” or “residual but stable disease.”

The fraction of resistant myeloma cells is primarily dependent upon the intrinsic molecular features of the individual myeloma and the pretreatment tumor burden or stage. Responding patients go from a high-risk status to a lower-risk status until, ideally, no signs of myeloma are left, or they reach a stable plateau phase, but with measurable residual disease. The time required to reach the plateau phase is variable, ranging from rapid response in 3 to 6 months, to slow response in 12 to 18 months.

Important terms in assessing response are:

 Time-to-progression (TTP)

The time from start of treatment until relapse occurs.

 Progression-free survival (PFS)

The length of time during and after the treatment of myeloma that a patient lives with the disease but the myeloma does not get worse. In a clinical trial, PFS is one way to measure how well the treatment is working.

 PFS1 – The time from the start of therapy to the occurrence of first relapse.

 PFS2 – The time from start of therapy to the occurrence of second relapse, incorporating the duration of both first and second remissions.

 Progressive disease

Myeloma that is becoming worse or relapsing, as documented by tests. Defined as an increase of ≥ 25% from the lowest confirmed response value in the myeloma protein level and/or new evidence of disease. For additional information, read the IMF’s Understanding Your Test Results booklet that explains the tests used to monitor and assess myeloma status throughout the disease course, and which tests are used to detect response and relapse.

Relapsing or refractory myeloma Relapsing disease

Relapse is the reappearance of signs and symptoms of myeloma after a period of improvement. Patients with relapsed disease have been treated, then developed signs and symptoms of myeloma at least 60 days after treatment ended. In myeloma, it is not uncommon to experience a relapse of disease following a remission. In fact, there can be multiple periods of response and remission following treatment with consecutive lines of therapy. Fortunately, a growing number of effective protocols are FDAapproved for relapsing disease, a significantly broader range of treatment options than in years past.

The aim of treatment at each relapse is to achieve optimal response with the least toxicity. This is what leads to the best long-term outcome possible for each patient with myeloma. Therapy for relapsed disease should be based on underlying disease biology and patient characteristics. If risk factors were identified when the patient was newly diagnosed and the initial treatment choice was made, this knowledge will have an impact on the choice of treatment when myeloma relapses. Additional risk factors

Table 6. Prognostic factors

Serum β2 microglobulin (S β2M)

Serum albumin (S ALB)

C-reactive protein (CRP)

The higher the level, the more advanced the stage.

The lower the level, the more advanced the stage.

Increased with active disease.

Serum lactate dehydrogenase (LDH) Increased with active disease.

Abnormal chromosomes on bone marrow cytogenetics and fluorescence in situ hybridization (FISH)

Several chromosome deletions or translocations are considered high-risk; can be associated with shorter duration of remission.

may also become evident at the time of relapse. Assessed individually and taken together, these factors play a role in selecting treatment protocol for refractory myeloma.

 Duration and depth of initial therapy

Patients with myeloma experience their first relapse at variable intervals after achieving their first remission. The duration and depth of a patient’s response to initial therapy will help guide the selection of the next course of treatment and is often predictive of long-term efficacy in managing myeloma. Several phase III clinical trials have demonstrated that patients who achieve MRD-negativity status have a better PFS.

 Re-utilizing the frontline regimen

If the first relapse occurs after a remission of at least 6 months, the initial strategy for the management of relapsing disease is to consider re-utilizing the patient’s frontline therapy that produced the remission in the first place. NCCN guidelines for myeloma treatment state that

Table 7. IMWG criteria for response assessment including criteria for MRD

IMWG MRD criteria (requires a complete response as defined below)

Sustained MRD-negative

MRD (minimal residual disease) negativity in the marrow – NGF (next-generation flow), or NGS (next-generation sequencing), or both – and by imaging as defined below, confirmed minimum of 1 year apart. Subsequent evaluations can be used to further specify the duration of negativity (eg, MRD-negative at 5 years)

Flow MRD-negative

Absence of phenotypically aberrant clonal plasma cells by NGF on bone marrow aspirates using the EuroFlow standard operation procedure for MRD detection in multiple myeloma (or validated equivalent method) with a minimum sensitivity of 1 in 10 5 nucleated cells or higher

Sequencing MRD-negative

Absence of clonal plasma cells by NGS on bone marrow aspirate in which presence of a clone is defined as less than two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using the LymphoSIGHT platform (or validated equivalent method) with a minimum sensitivity of 1 in 10 5 nucleated cells or higher

Imaging-positive MRD-negative

MRD negativity as defined by NGF or NGS plus disappearance of every area of increased tracer uptake found at baseline or a preceding PET/CT or decrease to less mediastinal blood pool SUV (maximum standardized uptake value) or decrease to less than that of surrounding normal tissue

(Table 7 continues on next page)

Table 7. IMWG criteria for response assessment including criteria for MRD

(continued from previous page)

Standard IMWG response criteria

Stringent complete response

Complete response as defined below plus normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry (κ/λ ratio ≤ 4:1 or ≥ 1:2 for κ and λ patients, respectively, after counting ≥ 100 plasma cells)

Complete response

Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow aspirates

Very good partial response

Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein plus urine M-protein level < 100 mg per 24 h

Partial response

• ≥ 50% reduction of serum M-protein plus reduction in 24 h urinary M-protein by ≥ 90% or to < 200 mg per 24 h;

• If the serum and urine M-protein are unmeasurable, a ≥ 50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria;

• If serum and urine M-protein are unmeasurable, and serum-free light assay is also unmeasurable, ≥ 50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma-cell percentage was ≥ 30%;

• In addition to these criteria, if present at baseline, a ≥50% reduction in the SPD (sum of the products of the maximal perpendicular diameters of measured lesions) of soft tissue plasmacytomas is also required

Minimal response

• ≥25% but ≤49% reduction of serum M-protein and reduction in 24-h urine M-protein by 50%–89%;

• In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size (SPD) of soft tissue plasmacytomas is also required

Stable disease

Not recommended for use as an indicator of response; stability of disease is best described by providing the time-to-progression estimates. Not meeting criteria for complete response, very good partial response, partial response, minimal response, or progressive disease

(Table 7 continues on next page)

Table 7. IMWG criteria for response assessment including criteria for MRD (continued

from previous page)

Standard IMWG response criteria (continued)

Progressive disease

Increase of 25% from lowest confirmed response value in any one or more of the following criteria:

• Serum M-protein (absolute increase must be ≥ 0.5 g/dL);

• Serum M-protein increase ≥ 1 g/dL, if the lowest M component was ≥ 5 g/dL;

• Urine M-protein (absolute increase must be ≥ 200 mg/24 h);

• In patients without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg/dL);

• In patients without measurable serum and urine M-protein levels and without measurable involved FLC levels, bone marrow plasma-cell percentage irrespective of baseline status (absolute increase must be ≥ 10%);

• Appearance of a new lesion(s), ≥ 50% increase from nadir in SPD of > 1 lesion, or ≥ 50% increase in the longest diameter of a previous lesion > 1 cm in short axis;

• ≥ 50% increase in circulating plasma cells (minimum of 200 cells per μL) if this is the only measure of disease

Clinical relapse

Clinical relapse requires one or more of the following criteria:

• Direct indicators of increasing disease and/or end organ dysfunction (CRAB features) related to the underlying clonal plasma-cell proliferative disorder. It is not used in calculation of time to progression or progression-free survival but is listed as something that can be reported optionally or for use in clinical practice;

• Development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures do not constitute progression);

• Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and ≥ 1 cm) increase as measured serially by the SPD of the measurable lesion;

• Hypercalcemia (> 11 mg/dL);

• Decrease in hemoglobin of ≥ 2 g/dL not related to therapy or other non-myeloma-related conditions;

• Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and attributable to myeloma;

• Hyperviscosity related to serum paraprotein

Relapse from complete response (to be used only if the end point is disease-free survival)

Any one or more of the following criteria:

• Reappearance of serum or urine M-protein by immunofixation or electrophoresis;

• Development of ≥ 5% plasma cells in the bone marrow;

• Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcemia see above)

Relapse from MRD negative (to be used only if the end point is disease-free survival)

Any one or more of the following criteria:

• Loss of MRD negative state (evidence of clonal plasma cells on NGF or NGS, or positive imaging study for recurrence of myeloma);

• Reappearance of serum or urine M-protein by immunofixation or electrophoresis;

• Development of ≥ 5% clonal plasma cells in the bone marrow;

• Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcemia)

“if the relapse occurs greater than 6 months after completion of the initial primary therapy, patients may be retreated with the same primary regimen.”

Approximately 50% of patients will experience a second remission with the same therapy that produced the first remission. This is particularly true for patients whose disease is in remission for more than 1 year following the initial treatment.

 Biochemical relapse vs. clinical relapse

One factor to consider is the type of relapse. Is it biochemical or clinical?

Biochemical relapse means there is disease progression based on increase in M-protein levels, but no myeloma-related symptoms of organ dysfunction. Still, a biochemical relapse may have a negative impact on the patient’s quality of life. A biochemical relapse requires monitoring of M-protein levels to catch disease progression if or when it occurs. In high-risk myeloma, treatment should be initiated early after biochemical relapse is diagnosed to avoid progression to

Table 8. Tests required to monitor therapy responses

Blood tests

• Routine blood counts

• Chemistry panel

• Liver function tests

• Serum β2 microglobulin

• C-reactive protein

• Serum erythropoietin level

Urine

• Routine urinalysis

• Myeloma protein measurements (serum protein electrophoresis plus quantitative immunoglobulins)

• Serum free light chain assays (Freelite®)

• Heavy/light chain assay (Hevylite®)

• Peripheral blood labeling index (LI)

• 24-hour urine for measurement of total protein, electrophoresis, and immunoelectrophoresis

• 24-hour urine for creatinine clearance if serum creatinine elevated

Bone evaluation

• Skeletal survey by X-ray

• MRI/CT scan for special problems

Bone marrow

• Whole body FDG/PET scan if disease status unclear

• Bone density measurement (DEXA scan) as baseline and to assess benefit of bisphosphonates

• Aspiration and biopsy for diagnosis and periodic monitoring

• Special testing to assess prognosis looking for multiple potential karyotypic and FISH abnormalities (number of chromosomes, translocations, deletions – e.g., FISH 13q-, t[4;14], 1q21, etc.)

Other testing (special circumstances)

• Amyloidosis

• Neuropathy

• Renal or infectious complications

symptomatic disease. Treatment of biochemical relapse is indicated if the following is detected:

 Doubling of serum M-protein,

 Increase of serum M-protein by 1 g/dL or more,

 Increase of urine M-protein by 500 mg per 24 hours or more,

 Increase of involved serum-free light chains (FLC) level by 20 mg/dL or more,

 Abnormal ratio by 2 measurements taken 2 months apart. Clinical relapse interventions vary depending upon the factors that are present. For example, if there are new soft-tissue plasmacytomas or bone lesions, your doctor may suggest radiation as a potentially satisfactory way to manage the relapse. Treatment of clinical relapse is indicated if the following is detected:

 Increase of 50% or more in size of existing plasmacytomas or bone lesions,

 Hypercalcemia,

 Decrease in hemoglobin of 2 g/dL or more (due to myeloma),

 Increase in serum creatinine by 2 mg/dL or more (due to myeloma),

 Hyperviscosity requiring intervention.

 Relapse with renal damage

Relapse in myeloma patients with renal damage, whether pre-existing or newly identified, requires careful consideration of which protocol may be most appropriate. There are several effective treatments that can be used safely, including immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies. In fact, data from a subgroup of patients in the ICARIA-MM clinical trial demonstrate that complete renal response can be achieved with a combination of an anti-CD38 monoclonal antibody and a proteasome inhibitor. Other clinical trials have demonstrated similar findings but with smaller groups of patients.

 Relapse with extramedullary disease

Relapse in patients with extramedullary myeloma is addressed following the same principles as the management of high-risk disease with chromosomal abnormalities. Limited data is available on relapse with extramedullary disease as few clinical trials include such patients. However, treatment with immunomodulatory agents and proteasome inhibitors has demonstrated efficacy. Local radiation for local disease control and pain relief, as well as surgical intervention should be considered. PET/CT imaging is key to evaluating and monitoring extramedullary myeloma.

Figure 9. Fluorescence in situ hybridization (FISH) of a myeloma cell

Figure 8. Karyotype analysis of human chromosomes

Figure 10. Chromosomal abnormalities in high-risk myeloma Deletion Translocation

 Relapse after a transplant

In many cases of myeloma, relapse following a transplant has a pattern similar to relapse following non-transplant treatment approaches. A patient who had a durable remission of at least 2 years after a first transplant should discuss with their doctor if having a second transplant at relapse is a recommended strategery for achieving the next remission.

 Sequence of treatment regimens

The sequencing of treatment regimens for a relapsing patient is viewed primarily based on the drugs to which the patient has become refractory.

Standard-of-care (SOC) regimens currently used for relapsed myeloma include the following:

1. DPd – Darzalex® (daratumumab) + Pomalyst® (pomalidomide) + dexamethasone,

2. DVd – Darzalex + Velcade® (bortezomib) + dexamethasone,

3. IRd – Ninlaro® (ixazomib) + Revlimid® (lenalidomide) + dexamethasone,

4. Kd – Kyprolis® (carfilzomib) + dexamethasone,

5. EPd – Empliciti® (elotuzumab) + Pomalyst + dexamethasone.

Relapse is a key time to revisit the discussion you likely had with your doctor at the time of your diagnosis about the overall strategy that is most appropriate for you and your myeloma. This is also a key time to seek a consultation with a myeloma specialist.

Refractory disease

Myeloma is considered to be refractory in patients who have had progressive disease either during treatment or within 60 days following treatment. Patients who have short remissions tend to have poor outcomes and are considered to have high-risk myeloma.

Unfortunately, a subset of patients with myeloma may develop refractory disease that is no longer responsive to standard treatments. However, myeloma that is refractory to one agent in a drug class may be responsive to another agent in the same drug class or to an agent from a different class. The efficacy of a treatment protocol is dependent on the patient’s prior exposure to a specific myeloma drug, as well as to other drugs in the same class.

Patients with refractory myeloma must select from a narrower range of FDA-approved effective therapy options. The number of regimens a patient has been exposed to and the length of time for a regimen to lose efficacy are predictive of the outcome of therapy. The development of drug resistance may emerge over time. Patients who are refractory to their initial therapy tend to have poor outcomes and are considered to have high-risk myeloma.

Figure 11. Myeloma treatment options at first relapse1

1. Treatment outside of a clinical trial 2. Consider salvage ASCT in transplant-eligible patients who have not had transplant 3. Monoclonal antibody 4. Darzalex® (daratumumab) + Revlimid® (lenalidomide) + dexamethasone 5. Preferred proteasome inhibitor is Velcade® (bortezomib) or Kyprolis® (carfilzomib)

6. Revlimid® (lenalidomide) + dexamethasone 7. Cyclophosphamide + dexamethasone

8. Pomalyst® (pomalidomide) + dexamethasone

Type 1, refractory to:

• Velcade® (bortezomib)

• Revlimid® (lenalidomide)

• anti-CD38 moAB 2

Treat with:

• KPd 3

• KCd 4

• venetoclax-based therapy 5

Type 2 , refractory to:

• Velcade® (bortezomib)

• Kyprolis® (car lzomib)

• Revlimid® (lenalidomide)

• anti-CD38 moAB 2

Treat with:

• PCd 6

• EPd 7

• venetoclax-based therapy 5

Type 3, refractory to:

• Velcade® (bortezomib)

• Kyprolis® (car lzomib)

• Revlimid® (lenalidomide)

• Pomalyst® (pomalidomide)

• anti-CD38 moAB 2

Treat with:

• anti-BCMA CAR T-cell therapy

• bispeci c antibody

• venetoclax-based therapy 5

1. Treatment outside of a clinical trial; patients who have not had transplant can consider ASCT

2. Monoclonal antibody 3. Kyprolis® (carfilzomib) + Pomalyst® (pomalidomide) + dexamethasone

4. Kyprolis® (carfilzomib) + cyclophosphamide + dexamethasone 5. If the patient has chromosomal translocation t(11;14) 6. Pomalyst® (pomalidomide) + cyclophosphamide + dexamethasone

7. Empliciti® (elotuzumab) + Pomalyst® (pomalidomide) + dexamethasone

In patients with chromosomal abnormalities or mutations, myeloma is more likely to relapse quickly after treatment or to be refractory to treatment.

High-risk myeloma is defined by the chromosomal abnormalities t(4;14), t(14;16), t(14;20), del 17p, and 1q gain, along with Revised International Staging System (R-ISS) Stage III disease, and/or a high-risk gene expression profile (GEP) signature. If this describes your myeloma, ask your doctor which specific drugs and combinations have demonstrated the most efficacy. Currently, there is no standard protocol for this group of patients, and clinical trials are ongoing.

Figure 12. Myeloma treatment options at second or later relapse 1

Adapted with permission ©Dingli

Given the use of combination therapies, it may be challenging to identify which agent in a “triplet” (3-drug) or “quadruplet” (4-drug) protocol the patient is refractory to, or to find effective protocol for patients who have already received at least 2 prior lines of therapy as they may have already used all the FDA-approved agents during their initial line of therapy and at their first relapse. It is difficult to combine more than 4 drugs at a time due to issues of toxicity. This may be a time to discuss with your doctor the possible benefits of clinical trial participation.

Research indicates that immunotherapy treatments that enhance the body’s natural defenses to fight cancer are the new wave of progress in treatment approaches for myeloma. Monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADC), and chimeric antigen receptor (CAR) T-cell therapies have demonstrated improved outcomes in patients with refractory myeloma.

In late-stage relapse and with refractory disease, attaining stable disease can have clinical benefits for the patient.

Table

OBJECTIVE Countering the life-threatening disruptions to body chemistry and the immune system

EXAMPLES

• Plasmapheresis to thin the blood and avoid stroke

• Hemodialysis when kidney function is impaired

• Drugs to reduce hypercalcemia (may include chemotherapy)

Relieving discomfort and increasing the patient’s ability to function

• Radiation to stop bone destruction

• Red cell transfusion to relieve anemia

• Orthopedic surgery to repair and/or strengthen bone

TIME TO DECIDE Hours to Days Days to Months

TYPE OF TREATMENT Remission-Inducing

OBJECTIVE

EXAMPLES

Improving symptoms, slowing or arresting the course of the disease

• Therapy to kill malignant cells throughout the body

• Radiation to kill malignant cells at a tumor site

TIME TO DECIDE Weeks to Months

Permanent remission*

• Stem cell transplants as a means of delivering high-dose chemotherapy

Weeks to Months

*Cure means permanent eradication of disease. “Functional cure” is a term that has been used to describe an excellent response to treatment, when the patient is stable and in remission for many years from diagnosis, but the myeloma is not completely eradicated.

9. Treatment goals and timely decision-making

Drugs in use for myeloma

Various combination regimens have been used to treat myeloma since melphalan, an alkylating agent, was first introduced in 1962. In the 1980s and 1990s, high-dose therapy (HDT) with melphalan followed by stem cell rescue was one of the few techniques available to reduce a patient’s myeloma tumor burden and achieve better outcomes. Melphalan continues to be the conditioning regimen of choice for autologous stem cell transplants.

Thalidomide, an oral immunomodulatory agent that has been studied since at least the 1950s, was first used to treat myeloma in a 1997 clinical trial, ushering in the age of “novel therapies” in myeloma. In 2006, thalidomide was approved by the FDA for patients with newly diagnosed myeloma. Although thalidomide is now infrequently used in the U.S., many myeloma patients around the globe have benefited from this therapy. Thalidomide also gave rise to a next generation of immunomodulatory agents with increased efficacy and reduced side effects, the drugs Revlimid® (lenalidomide) and Pomalyst® (pomalidomide).

Below is a list of drugs approved for use in myeloma by the FDA in the era of novel agents. The list is current as of the printing of this booklet and is organized alphabetically.

1. Abecma® (idecabtagene vicleucel or “ide-cel”) is a first-in-class B-cell maturation antigen (BCMA) -directed CAR T-cell immunotherapy approved by the FDA (March 2021) for relapsed or refractory myeloma after 4 or more prior lines of therapy. Abecma is being studied in earlier disease settings. Abecma is a personalized immunotherapy delivered as a one-time infusion of the patient’s own T cells that have been “harvested” from the bloodstream and engineered to identify and destroy the myeloma cells.

2. Aredia® (pamidronate) is a bisphosphonate approved by the FDA (September 1998) to treat myeloma bone disease and that of other types of cancer.

3. Carvykti® (ciltacabtagene autoleucel or “cilta-cel”) is the second BCMA-directed CAR T-cell therapy approved by the FDA (February 2022) for relapsed or refractory myeloma after 4 or more prior lines of therapy. Data from clinical trials in earlier disease settings demonstrate impressive results at first relapse. Carvykti is manufactured for each individual patient using the patient’s own T cells, then delivered as a one-time infusion.

4. Darzalex® (daratumumab) is the first-in-class monoclonal antibody that targets the CD38 protein on the surface of myeloma cells. It was approved by the FDA (November 2015) as an intravenous (IV) infusion.

Darzalex Faspro® (daratumumab and hyaluronidase-fihj) is a newer formulation approved by the FDA (May 2020) as a subcutaneous (SQ) injection under the skin. Either formulation of Darzalex can be used for newly diagnosed myeloma and throughout the disease course.

5. Dexamethasone is a generic steroid also known by several brand names. It is one of the most frequent medications used in myeloma combination therapies.

6. Elrexfio™ (elranatamab-bcmm) is the first “off-the-shelf” fixed-dose subcutaneous BCMA-directed agent approved by the FDA (August 2023) for adult patients with relapsed or refractory myeloma who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

7. Empliciti® (elotuzumab) is the first immunostimulatory monoclonal antibody approved by the FDA (November 2015) for the treatment of myeloma after 1 to 3 prior therapies.

8. Kyprolis® (carfilzomib) is the second proteasome inhibitor approved for myeloma by the FDA (July 2012). Kyprolis was originally approved for the treatment of myeloma after at least 2 prior therapies; now it can be used at first relapse. It is given by intravenous (IV) infusion.

9. Ninlaro® (ixazomib) is the third proteasome inhibitor approved by the FDA (November 2015) and it is the first proteasome inhibitor that is taken orally (by mouth). Ninlaro can be used for relapsed or refractory myeloma after at least 1 prior therapy.

10. Pomalyst® (pomalidomide) is the third immunomodulatory agent approved by the FDA (February 2013) for use in myeloma. It is taken orally and can be used for relapsed or refractory myeloma after at least 2 prior therapies.

11. Revlimid® (lenalidomide) is an immunomodulatory agent, the first oral medication for myeloma approved by the FDA (June 2006). Revlimid was originally approved for use in patients who had received at least 1 prior therapy. In February 2015, the FDA expanded this indication to a broad approval for use throughout the myeloma disease course, from diagnosis through relapse. In February 2017, Revlimid was approved as maintenance therapy after ASCT. Revlimid is part of standard of care (SOC) regimens.

12. Sarclisa® (isatuximab-irfc) is an anti-CD38 monoclonal antibody approved by the FDA (March 2020) for patients with relapsed or refractory myeloma who have received at least 1 prior therapy. Sarclisa is given as an IV infusion.

13. Talvey™ (talquetamab-tgvs) is a first-in-class bispecific antibody approved by the FDA (August 2023) for the treatment of adult patients with relapsed or refractory myeloma who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody.

14. Tecvayli™ (teclistamab-cqyv) is a first-in-class bispecific BCMAdirected CD3 T-cell engager approved by the FDA (October 2022). This “off-the-shelf” immunotherapy is delivered by injection.

15. Velcade® (bortezomib) is the first-in class proteasome inhibitor approved by the FDA (May 2003). Velcade is available for administration by IV infusion or SQ shot under the skin. Velcade is used throughout the myeloma disease course, from diagnosis through relapse, and is part of SOC regimens.

16. Xgeva® (denosumab) is a RANK ligand inhibitor approved by the FDA (January 2018) for the prevention of skeletal-related events in patients with myeloma.

17. Xpovio® (selinexor) is a first-in-class selective inhibitor of nuclear export (SINE) compound approved by the FDA (July 2019) for the treatment of patients with relapsed or refractory myeloma who have received at least 4 prior therapies. In December 2020, the FDA approved the use of Xpovio after at least 1 prior therapy. Xpovio is taken in tablet form.

18. Zometa® (zoledronic acid) is a bisphosphonate approved by the FDA (February 2002) to treat myeloma bone disease and that of other types of cancer.

A myeloma patient must have a careful and detailed discussion with their doctor about treatment choices that are most appropriate for them. Open dialogue to discuss the pros and cons of each option is crucial. The addition of many new agents to the myeloma armamentarium has presented doctors with the challenge of determining the best combinations as well as the optimal sequencing of treatment for each patient.

What has become clear is that no single therapy is likely to be effective for every myeloma patient, nor is any single agent likely to achieve a cure on its own. Rather, the combination approach that attacks myeloma cells with multiple drugs through multiple pathways has thus far demonstrated superior efficacy.

There is no simple answer to the question of “the best” treatment options available today. Fortunately, there are numerous regimens that can produce very deep and durable responses, with remissions lasting 2 or more years,

and improved overall survival (OS). The best choice for each patient depends upon individual factors, including age, stage of myeloma, genetic features, kidney status, comorbidities, cost, and of course, personal preference.

Radiation therapy

Local radiation can be dramatically effective. This is an important modality of treatment for myeloma patients with severe local problems, such as bone destruction, pain, and/or pressure on nerves or the spinal cord. The major disadvantage, however, is that radiation therapy permanently damages normal bone marrow stem cells in the area of treatment. Wide-field radiation encompassing large amounts of normal bone marrow should be avoided. A general strategy is to rely on systemic treatment to achieve overall disease control, limiting the use of local radiation therapy to areas with particular problems.

Clinical trials

Myeloma researchers around the world are working to improve patient survival as well as their quality of life. There is tangible progress in the search for a cure, and we are getting closer to a functional cure, a term used to describe a patient in a prolonged remission, with a small amount of myeloma still detectable but not causing relapse or disease progression.

The rapid rate of development of new therapies for myeloma, as well as investigation of new combinations of existing and emerging agents, can make clinical trials an appropriate option for patients with relapsed or refractory myeloma. Some clinical trials may be a potentially beneficial option for patients in late relapse. Other clinical trials may be a good fit for patients who experience early relapse after 1 or 2 lines of therapy.

To learn more about clinical trials and to determine if enrollment in a study is the right decision for you, we encourage you to discuss your specific options with the doctor treating your myeloma and to read the IMF’s publication Understanding Clinical Trials.

Supportive care

A full range of supportive care measures is crucial for the management of the disease and to alleviate the physical and emotional impact of living with myeloma. The following IMF publications may be helpful:

 Understanding Treatment of Myeloma Bone Disease

 Understanding Fatigue

 Understanding Peripheral Neuropathy in Myeloma

 Understanding Treatment of Myeloma-Induced Vertebral Compression Fractures

Beyond the management of specific symptoms, other supportive measures are also important:

 Antibiotics and antivirals

Infections are a common and recurrent problem in patients with myeloma, and having a strategy for infection management is essential. Ask your doctor about antibiotic therapy if active infection is suspected, and if prophylactic antiviral therapy and/or the Shingrix® vaccine should be considered in your case. For the latest updates and information for myeloma patients about the COVID-19 virus, vaccines, boosters, treatments, and more, please visit myeloma.org/covid19-myeloma-patients.

 Physical activity

Check with your doctor to clarify if full physical activity is feasible or if adjustments must be made due to bone disease or bone damage. Usually, some physical activity can be planned, such as walking or swimming, flexibility and strength exercises, and/or a personalized yoga program.

 Diet

No specific diet has been developed for myeloma patients, although research has clearly demonstrated the link between obesity and myeloma. We recommend a healthy, Mediterranean diet emphasizing fruits, vegetables, fish, other lean animal proteins, whole grains, and unprocessed “real” foods. Avoid foods that include processed sugars and artificial trans fats. Caution should be used in two areas:

 Herbal and vitamin supplements – Check with your doctor or pharmacist before taking supplements while receiving treatment for myeloma. Some interactions between drugs and/or supplements can prevent myeloma treatments from working effectively and some interactions can create serious medical problems. Pharmacies have reference resources to help identify potential interactions.

 Vitamin C – Doses greater than 1000 mg per day may be counterproductive in myeloma and can increase the risk of kidney damage.

 Mental health

Your mental health is critical as you move forward with planned treatment. Make sure you’re comfortable with the treatment plan. Schedule an appointment with a mental health professional if you believe that you might be anxious or depressed or if others are concerned that you might be depressed. This is a normal response to a cancer and most cancer patients will need some help at one time or another. Support among peers is vital at this time, and a myeloma

support group can be helpful in this context. For a referral to a myeloma support group, visit support.myeloma.org and contact the IMF InfoLine at 1.818.487.7455 or InfoLine@myeloma.org.

 Regular sleep

This is very important for your immune system.

 Make adjustments

If possible, reduce stress in job, family, or social situations, and avoid crowds and close contact with school-age children. Wash your hands frequently. Your immune system is compromised both by the disease and the treatments. Management of your myeloma is the top priority until remission, or until a stable situation has been reached.

In closing

This booklet is not meant to replace the advice of your doctors and nurses who are best able to answer questions about your specific healthcare management plan. The IMF intends only to provide you with information that will guide you in discussions with your healthcare team. To help ensure effective treatment with good quality of life, you must play an active role in your own medical care.

We encourage you to visit myeloma.org for more information about myeloma and to contact the IMF InfoLine with your myeloma-related questions and concerns. The IMF InfoLine consistently provides the most up-to-date and accurate information about myeloma in a caring and compassionate manner. Contact the IMF InfoLine at 1.818.487.7455 or InfoLine@myeloma.org.

Terms and definitions

The following selected terms are used in this booklet, while a more complete glossary can be found in the IMF’s publication Understanding Myeloma Vocabulary, which is located online at glossary.myeloma.org.

Anemia: Red blood cells contain hemoglobin, a protein that carries oxygen to the body’s tissues and organs. Anemia is usually defined as a decrease in hemoglobin < 10 g/dL or as a decrease of ≥ 2 g/dL from the normal level for an individual. More than 13–14 g/dL is considered normal. Low levels of oxygen in the body may cause shortness of breath and feelings of exhaustion. Many newly diagnosed myeloma patients have anemia.

Antibody: A protein produced by plasma cells in response to an antigen that enters the body. See “ Immunoglobulin (Ig).”

Antibody-drug conjugate (ADC): An anti-cancer therapy that links a monoclonal antibody directed at cancer cells with a drug that is toxic to cancer cells.

Antigen: Any foreign substance that causes the immune system to produce natural antibodies. Examples of antigens include bacteria, viruses, parasites, fungi, and toxins.

B-cell maturation antigen (BCMA): A protein involved in myeloma cell growth and survival. BCMA is found on the surface of cells in all patients with myeloma. Also called “tumor necrosis factor receptor superfamily member 17 (TNFRSF17).”

Bence-Jones myeloma: Myeloma characterized by the presence of BenceJones protein, an abnormal protein in urine made up of free kappa or lambda light chains. See “Bence-Jones protein.”

Bence-Jones protein: A myeloma monoclonal protein. The protein is composed of either free kappa or free lambda light chains. Because of their small size, Bence-Jones light chains can be filtered through the kidneys and pass into the urine. The amount of Bence-Jones protein in the urine is expressed in terms of grams per 24 hours. Normally, a very small amount of protein (< 0.1 g/24 h) can be present in the urine, but this is albumin rather than Bence-Jones protein. The presence of any Bence-Jones protein in the urine is abnormal. Myeloma protein heavy chains are too large to be filtered through the kidneys. See “ Bence-Jones myeloma.”

Biopsy: The collection of tissue for microscopic examination to aid in diagnosis.

Bispecific antibody: An artificial antibody that binds to two (“bi”) targeted cells.

Bisphosphonate: A type of drug that protects against osteoclast activity (bone breakdown) and binds to the surface of bone where it is being resorbed or destroyed.

Bone marrow: The soft, spongy tissue in the center of bones that produces white blood cells, red blood cells, and platelets. When myeloma is growing, myeloma cells build up in the bone marrow.

Bone marrow aspiration: The removal, by a needle, of a sample of fluid and cells from the bone marrow for examination under a microscope.

Calcium: A mineral found mainly in the hard part of bone matrix (hydroxyapatite). If produced or released in excess, it can build up in the bloodstream. See “ Hypercalcemia.”

Cancer: A term for diseases in which malignant cells divide without control. Cancer cells can invade nearby tissues and spread through the bloodstream and lymphatic system to other parts of the body.

Chemokine: A type of secreted protein within the cytokine family whose function is to induce cell migration. See “Cytokine.”

Chimeric antigen receptor (CAR) T-cell therapy: In myeloma, this immunotherapy involves collecting the patient’s T cells, and engineering them to attack the patient’s own cancer cells.

Chromosome: A strand of DNA and proteins in the nucleus of a cell. Chromosomes contain genes and function in the transmission of genetic information. Normally, human cells contain 46 chromosomes (23 pairs).

• Chromosomal deletion – Genetic mutation in which part or all of a chromosome is lost during DNA replication. Chromosomal deletions that occur in myeloma include loss of the long arm of chromosome 13 (written as 13q–) or loss of the short arm of chromosome 17 (written as 17p–).

• Chromosomal translocation – Genetic mutation in which parts of different chromosomes are rearranged. Written with a lowercase “t” followed by the numbers of the chromosomes with translocated genetic material. Translocations that occur in myeloma include t(4;14), t(11;14), t(14;16), and t(14;20).

Conditioning regimen: A treatment given to a patient to destroy cancer cells prior to stem cell transplant. The most common conditioning regimen given to myeloma patients is 200 mg of melphalan per square meter of body mass.

CRAB criteria: An elevated level of Calcium in the blood, Renal (kidney) damage, Anemia or low red blood cell count, and Bone damage are criteria used to diagnose myeloma along with “Myeloma-defining event (MDE).”

Cytokine: A protein that circulates in the bloodstream, usually in response to infection. Cytokines can stimulate or inhibit the growth or activity in other cells.

Electrophoresis: A laboratory test used both for diagnosis and for monitoring, in which a patient’s serum (blood) or urine proteins are subjected to separation according to their size and electrical charge. Serum or urine electrophoresis (SPEP or UPEP) enables both the calculation of the amount of myeloma protein and the identification of the type of M-spike for each patient.

Extramedullary plasmacytoma: A tumor of monoclonal plasma cells that is found in soft tissue outside of the bone marrow and separate from bone.

Fanconi syndrome: A type of selective kidney tubular damage that affects how kidneys reabsorb certain essential substances. Leakage of amino acids and phosphates into the urine, then exiting your body in the urine, can cause metabolic bone disease.

Free light chain (FLC): An immunoglobulin light chain is the smaller of two units that make up an antibody. There are two types of light chain: kappa and lambda. A light chain may be bound to a heavy chain or it may be unbound (free). Free light chains circulate in the blood and are small enough to pass into the kidneys, where they may be filtered out into the urine or may stick together and block the kidney’s tubules.

Heavy chain: An immunoglobulin protein produced by plasma cells is made up of 2 heavy chains and 2 light chains, with the heavy chains being the larger of the two units. The 5 types of heavy chains (G, A, D, E, or M) are based on the class (isotype) of immunoglobulin produced by the myeloma cell. See “ Immunoglobulin (Ig).”

Hypercalcemia: A higher than normal level of calcium in the blood. In myeloma patients, it usually results from bone breakdown with release of calcium from the bone into the bloodstream. This condition can cause a number of symptoms, including loss of appetite, nausea, thirst, fatigue, muscle weakness, restlessness, and confusion. See “Calcium.”

Hyperviscosity syndrome (HVS): When blood becomes so thick that the reduced blood flow in smaller vessels causes complications, which can be life-threatening. Treatment and management include intravenous fluids and plasmapheresis.

Hypogammaglobulinemia: A laboratory diagnosis made when the immune system is not producing enough immunoglobulin G (IgG) in the blood.

Immune system: A complex network of cells, tissues, organs, and the substances they make. The immune system helps the body defend itself by destroying infected and diseased cells and removing cellular debris, while protecting healthy cells.

Immunoglobulin (Ig): A protein produced by plasma cells; an essential part of the body’s immune system. Immunoglobulins attach to foreign substances (antigens) and assist in destroying them. The classes (isotypes) of immunoglobulins are IgG, IgA, IgD, IgE, and IgM. Each type of immunoglobulin has a different function in the body. See “Antibody ” and “Antigen.”

• IgG, IgA – The two most common types of myeloma. The G and A refer to the immunoglobulin heavy chain produced by the myeloma cells.

• IgD, IgE – These types of myeloma occur less frequently.

• IgM – This is a rare type of myeloma. IgM myeloma is not the same as Waldenström macroglobulinemia.

Interleukin: A naturally produced chemical released by the body, or a substance used in biological therapy. Interleukins stimulate the growth and activities of certain kinds of white blood cells. Interleukin-2 (IL-2) is a

type of biological response modifier that stimulates the growth of certain blood cells in the immune system that can fight some types of cancer.

Interleukin-6 (IL-6) is a cytokine that is a potent stimulus to osteoclast and plasma cell growth.

Lesion: An area of abnormal tissue; a lump or abscess that may be caused by injury or disease, such as cancer. In myeloma, “lesion” can refer to a plasmacytoma or a hole in the bone.

• Diffuse lesion – A spread-out pattern of myeloma bone marrow involvement in an area of bone.

• Focal lesion – An abnormal area seen in the bone marrow on MRI or PET-CT study. In order to be considered a “myeloma-defining event,” there must be more than 1 focal lesion of at least 5mm in size.

• Lytic lesion – The damaged area of a bone that appears as a dark spot on an X-ray when at least 30% of the healthy bone in any one area is eaten away. Lytic lesions look like holes in the bone and are evidence that the bone is being weakened. See “ Lytic (lysis).”

Light chain: An immunoglobulin light chain is the smaller of two units of an antibody. The light chains are bound by chemical bonds to the ends of the heavy chains, but we make extra light chains that enter the bloodstream. These are called “free light chains.” There are two types of light chains: kappa and lambda.

Lytic (lysis): Dissolution or destruction of cells or tissues.

M-spike: A monoclonal spike, the sharp pattern that occurs on protein electrophoresis tests, is a marker for the activity of myeloma cells. See “Monoclonal” and “Monoclonal protein.”

Macrophage: An immune system cell whose job it is to engulf and devour any cell (including a cancer cell) that does not have proteins on its surface that identify it as a healthy body cell.

Metabolism: The conversion of one compound into another compound, which occurs during a living organism’s life-sustaining chemical processes. See ”Metabolite.”

Metabolite: Any substance that is formed during metabolism or that is necessary for metabolism. See ”Metabolism.”

Minimal residual disease (MRD): The presence of residual tumor cells after treatment has been completed and complete response (CR) has been attained. Even patients who have attained a stringent CR (sCR) may have MRD. Highly sensitive testing methods are able to detect 1 myeloma cell among 1,000,000 sampled cells in blood or bone marrow. See “MRD-negative.”

Molecule: The smallest particle that retains all the properties of the substance. A molecule is an electrically neutral group composed of two or more atoms held together by chemical bonds.

Monoclonal: A monoclone is a duplicate derived from a single cell. Myeloma cells are monoclonal, derived from a single malignant plasma cell in the bone marrow. The type of myeloma protein produced is also monoclonal, a single form rather than many forms (polyclonal). The important practical aspect of a monoclonal protein is that it shows up as a sharp spike on the protein electrophoresis test. See “M-spike.”

Monoclonal antibody: An antibody manufactured in a lab rather than produced in the human body. Monoclonal antibodies are specifically designed to find and bind to cancer cells and/or immune system cells for diagnostic or treatment purposes. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to tumor cells.

Monoclonal gammopathy of undetermined significance (MGUS): A plasma cell disorder characterized by comparatively low levels of monoclonal protein in the blood and/or urine. Bone marrow plasma cell levels are less than 10%. SLiM-CRAB criteria features are absent. See “SLiM-CRAB criteria.”

Monoclonal protein (myeloma protein, M-protein): An abnormal protein produced by myeloma cells that accumulates in and damages bone and bone marrow. It is found in unusually large amounts in the blood and/or urine of myeloma patients. See “Monoclonal ” and “M-spike.”

Monocyte: A type of white blood cell found in the circulation. Also called a macrophage when present in tissues.

MRD-negative: Minimal residual disease-negative. Depending on the test, not even one myeloma cell found in 100,000 or 1,000,000 sampled bone marrow plasma cells. See “Minimal residual disease (MRD).”

Multiple myeloma: A cancer of the bone marrow plasma cells, white blood cells that make antibodies. Cancerous plasma cells are called myeloma cells.

Neuropathy: A feeling of numbness, tingling, burning, and/or pain caused by nerve damage. See “ Peripheral neuropathy.”

Neutropenia: A reduced level of neutrophils, a type of white blood cell necessary to combat bacterial infection. Having too few neutrophils can lead to infection. Fever is the most common sign of neutropenia. If you have a fever, you must get immediate medical attention.

Non-secretory myeloma: Approximately 1% of myeloma patients do not have detectable M-protein in the blood (serum) and urine. Some of these patients can be successfully monitored using the serum free light chain assay; others may be monitored with bone marrow biopsy and/or PET-CT scan. Patients with non-secretory myeloma are treated in the same fashion as those with M-protein-secreting disease.

Osteoblast: A bone cell associated with production of bone tissue. Osteoblasts produce osteoid, which then becomes mineralized with calcium to form new hard bone.

Osteoclast: A cell found at the junction between the bone marrow and the bone. It is responsible for breaking down or remodeling old bone tissue. In myeloma, the osteoclasts are overstimulated, while osteoblast activity is blocked. The combination of accelerated bone resorption and blocked new bone formation results in lytic lesions.

Peripheral neuropathy (PN): Peripheral neuropathy is a serious condition that affects nerves in the hands, feet, lower legs, and/or arms. Patients may experience PN from the effects of the myeloma itself and/or from treatments for myeloma. Symptoms may include a feeling of numbness, tingling, burning, and/or pain.

Plasma cells: White blood cells that produce antibodies. Myeloma cells are cancerous plasma cells, which produce monoclonal protein (myeloma protein, M-protein) that can lead to organ and tissue damage (anemia, kidney damage, bone disease, and nerve damage).

Plasmacytoma: See “ Extramedullary plasmacytoma” and “Solitary plasmacytoma of bone (SPB).”

Plasmapheresis: The process of removing certain proteins from the blood. Plasmapheresis can be used to remove high levels of M-protein from the blood of myeloma patients.

Platelets: One of the three major types of blood cells, the others being red blood cells and white blood cells. Platelets plug up breaks in the blood vessel walls and release substances that stimulate blood clot formation. Platelets are the major defense against bleeding. Also called thrombocytes.

Proteasome: A joined group (“complex”) of enzymes (“proteases”) that break down the damaged or unwanted proteins in both normal cells and cancer cells into smaller components. Proteasomes also carry out the regulated breakdown of undamaged proteins in the cell, a process that is necessary for the control of many critical cellular functions. These smaller protein components are then used to create new proteins required by the cell. This is important for maintaining balance within the cell and for regulating cell growth.

Proteasome inhibitor: Any drug that interferes with the normal function of the proteasome. See “ Proteasome.”

Radiation therapy: Treatment with X-rays, gamma rays, or electrons to damage or kill malignant cells. Radiation may be delivered from outside the body or from radioactive materials implanted directly in the tumor.

Red blood cells (RBC): Also called erythrocytes, these cells in the blood contain hemoglobin, deliver oxygen to all parts of the body, and take away carbon dioxide. Red blood cell production is stimulated by a hormone (erythropoietin) produced by the kidneys. Myeloma patients with damaged kidneys don’t produce enough erythropoietin and can become anemic. Myeloma patients can also become anemic because of myeloma cells’ effect on the ability of bone marrow to make new red blood cells.

Relapse: The reappearance of signs and symptoms of myeloma after a period of improvement. Patients with relapsed disease have been treated, then developed signs and symptoms of myeloma at least 60 days after treatment ended. Most clinical trials for advanced myeloma are for patients with relapsed and/or refractory disease.

Selective inhibitor of nuclear export (SINE): A compound that prevents cells from expelling tumor suppressor proteins, which help protect the cell from cancer. When tumor suppressors accumulate in a myeloma cell, they can counteract the pathways that allow cancer cells to grow and divide, which leads to myeloma cell death. Also known as XPO1 inhibitors.

SLiM-CRAB criteria: This acronym outlines myeloma-defining events (MDE) where patients have 10% or more plasma cells, plus one of the following features.

• S – Sixty percent (60%) plasma cells,

• Li – Light chains involved:uninvolved ratio of 100 or more,

• M – MRI imaging of more than 1 focal lesion in bone marrow,

• C – Calcium elevation due to myeloma,

• R – Renal (kidney) insufficiency due to myeloma,

• A – Anemia (low red blood cell count) due to myeloma,

• B – Bone disease attributable to myeloma.

Smoldering multiple myeloma (SMM): SMM is a higher level of disease than monoclonal gammopathy of undetermined significance (MGUS). Patients with SMM have 10% or greater clonal plasma cells in the bone marrow but do not have SLiM-CRAB criteria features. Patients with SMM should be seen at regular intervals by a hematologist/oncologist, preferably by a myeloma specialist. Standard-risk SMM does not require treatment, but patients with high-risk SMM should discuss with their doctor if treatment would be beneficial. See “SLiM-CRAB criteria.”

Solitary plasmacytoma of bone (SPB): A discrete, single mass of monoclonal plasma cells in a bone. The diagnosis of SPB requires a solitary bone lesion, a biopsy of which shows infiltration by plasma cells; negative imaging results for other bone lesions; absence of clonal plasma cells in a random sample of bone marrow; and no evidence of anemia, hypercalcemia, or renal involvement suggesting systemic myeloma.

Stem cells (hematopoietic stem cells): The immature cells from which all blood cells develop. Normal stem cells give rise to normal blood components, including red cells, white cells, and platelets. Stem cells are normally located in the bone marrow and can be harvested for transplant.

Steroid: A type of hormone. Steroidal hormones are produced by the body. Synthetic analogues (equivalents) of some steroids can be manufactured in a laboratory. Dexamethasone, prednisone, and methylprednisolone are synthetic steroids that have multiple effects and are used for many conditions, including myeloma.

T cell (T lymphocyte): A type of white blood cell that plays a central role in the immune system. T cells can be distinguished from other lymphocytes, such as B cells and natural killer (NK) cells, by the presence of a T-cell receptor (TCR) on the cell surface. They are called T cells because they mature in the thymus, although some also mature in the tonsils.

Thrombocytopenia: A low number of platelets in the blood. Platelets help blood to clot; fewer platelets can lead to easier bruising, bleeding, and slower healing. The “normal” level of platelets varies from laboratory to laboratory. For example, at Mayo Clinic the “normal” level is 150,000 or more platelets per microliter of circulating blood. Bleeding problems could occur if the count is less than 50,000 platelets. Major bleeding is usually associated with a reduction to less than 10,000 platelets.

Tumor: An abnormal mass of tissue that results from excessive cell division. In myeloma, a tumor is referred to as a plasmacytoma.

Tumor necrosis factor (TNF): A cell signaling protein (cytokine) involved in systemic inflammation and bone resorption. TNF alpha (TNF-α) is elevated in myeloma patients.

Waldenström macroglobulinemia (WM): A rare type of non-Hodgkin’s lymphoma (NHL) that affects plasma cells. Excessive amounts of IgM protein are produced. WM is not a type of myeloma.

White blood cells (WBC): General term for a variety of leukocytes responsible for fighting invading germs, infections, and allergy-causing agents. These cells begin their development in bone marrow and then travel to other parts of the body. Specific white blood cells include neutrophils, basophils, eosinophils, lymphocytes, and monocytes.