Understanding MGUS and Smoldering Multiple Myeloma
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You are not alone
The International Myeloma Foundation (IMF) 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 its precursor states, smoldering multiple myeloma (SMM, pronounced “essem-EM”) and monoclonal gammopathy of undetermined significance (MGUS, pronounced “EM-gus”). The IMF also serves the patient’s care partners, friends, and family members.
We achieve this through a broad range of resources available on our website myeloma.org, and through numerous programs and services such as seminars, webinars, workshops, and the IMF InfoLine, which 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.
What you will learn from this booklet
All patients who develop myeloma have previously had MGUS followed by SMM. If you have been diagnosed with MGUS or SMM, this publication has information that you may find to be helpful. MGUS and SMM are not known to most patients at the time of diagnosis. It is important for you to learn about your diagnosis in order to play an active role in your own medical care and to make good decisions about your care in partnership with your doctor.
We also recommend that you read the IMF’s publication, Understanding Your Test Results, which helps explain how you will be monitored and assessed by your healthcare team. All IMF publications are free-ofcharge and can be read, downloaded, or requested in printed form at publications.myeloma.org.
Words in bold+blue type in IMF publications are explained in the companion booklet, Understanding Myeloma Vocabulary, a comprehensive glossary that also can be helpful in discussions with your doctor. If you are reading this booklet in electronic format, the light blue links will take you to the corresponding resources.
MGUS
MGUS is a benign condition. It is not malignant (cancerous). If it is suspected that you have MGUS or if you are already diagnosed with MGUS, it is essential that you see an experienced hematologist, a doctor who specializes in the problems of blood and bone marrow.
MGUS occurs in 3% to 5% of the population in the United States. This rate is higher for individuals who are 50 years of age or older. MGUS can arise from either plasma cells or lymphoid cells, and these two types of MGUS are biologically different.
The plasma cell type of MGUS is the earliest disease state associated with the possible subsequent development of myeloma. MGUS can progress to become myeloma, amyloidosis, or light chain deposition disease (LCDD).
Plasma cells are a key part of the immune system. Plasma cells develop from a type of white blood cell (WBC) called B cells (B lymphocytes). B cells mature into plasma cells in the bone marrow, where plasma cells produce antibodies that attach to antigens that enter the body.
How MGUS is diagnosed
MGUS is generally asymptomatic. It is usually discovered through lab testing that is either routine or performed for other phenomena.
Patients with MGUS have relatively low levels of monoclonal protein (myeloma protein, M-protein) in the serum and/or urine. Bone marrow plasma cell levels are less than 10%. SLiM-CRAB criteria features are absent.
The laboratory tests used to measure the amount of M-protein are serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP). The amount of M-protein reflects the activity of abnormal plasma cells in the bone marrow. SPEP and/or UPEP should be repeated 3 to 6 months after MGUS is diagnosed. If your level of M-protein remains stable and there are no symptoms or other health changes, your doctor can extend the time between follow-up testing. Be sure to report any change in your health to your doctor.
Immunofixation electrophoresis (IFE) is an immunologic test of the serum or urine used to identify the exact heavy-chain and light-chain type of M-protein that is present. Your plasma cells can produce one of five classes (isotypes) of immunoglobulin (Ig). If you have the IgM type of M-protein, ask your doctor about a computed axial tomography (CAT
plasma cells in bone marrow
Presence of myeloma defining events no no yes
Likelihood of progression ~1% per year ~10% per year not applicable
Treatment or observation observation only observation; treatment* treatment
*Treatment in the setting of a clinical trial or for high-risk patients likely to progress to active myeloma within 2 years.
1. Kyle et al. N Engl J Med. 2007;356:2582-2590.
2. International Myeloma Working Group. Br J Haematol. 2003;121:749-57.
3. Jagannath et al. Clin Lymphoma Myeloma Leuk. 2010;10:28-43.
4. Kyle et al. Curr Hematol Malig Rep. 2010;5:62-69.
5. Mateos et al. Blood 2009;114: abstract 614.
6. Durie and Salmon. Cancer 1975;36:842-854.
7. Durie et al. Leukemia 2006;20:1467-1473.
8. Rajkumar et al. Lancet Oncol. 2014;15:e538-e548.
Table 1. MGUS, SMM, and active myeloma
or CT) of the abdomen to check for lymph node enlargement.
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 by chemical bonds or it may be unbound and “free” to enter the bloodstream. Free light chains that circulate in the blood 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.
If testing reveals evidence of myeloma or Waldenström macroglobulinemia (WM), you will be tested for levels of lactate dehydrogenase (LDH), beta-2 microglobulin (β2-microglobulin, β2M, or β2M), and C-reactive protein (CRP). If the test results are within normal ranges, you will be tested again in 6 months with SPEP and a complete blood count (CBC), and then annually for life or until any changes occur.
Figure 1. SPEP test results albumin
Normal SPEP result
Abnormal result with myeloma cells producing the M-protein, creating an M-spike in the beta-2 zone
Abnormal result with myeloma cells producing the M-protein, creating an M-spike in the gamma zone
If MGUS is diagnosed or suspected, then additional testing may be performed at the discretion of your doctor. This includes bone marrow testing and imaging studies of bone (to rule out early bone disease). A bone marrow biopsy is always required if the patient has CRAB criteria: unexplained hypercalcemia, kidney dysfunction, anemia, bone lesions, or a suspicion of amyloid light- chain (AL) amyloidosis.
For a diagnosis of MGUS, all of the following 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%,
3. Absence of CRAB criteria.
For a diagnosis of light chain MGUS, all of the following criteria must be met:
1. Abnormal free light chain (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 immunoglobulin heavy chain expression on IFE,
4. Absence of CRAB criteria,
5. Presence of monoclonal plasma cells in the bone marrow < 10%,
6. Presence of M-protein in the urine based on a 24-hour collection < 500 mg.
Risk of progression from MGUS to myeloma
Progression from MGUS to active myeloma occurs at the low rate of only 1% per year. Researchers are gaining a better understanding of the biologic events that take place when MGUS develops into myeloma, but it is not yet known what triggers the progression in some patients but not in others, or how to prevent progression. The IMF International Myeloma Working Group (IMWG) has established the following risk factors for MGUS progressing to myeloma:
1. M-protein level is more than 1.5 g/dL (can also be written as 15 g/L),
2. M-protein type is IgA or IgM, and
3. Abnormal FLC ratio of kappa to lambda FLCs.
Risk of progression from MGUS to active myeloma:
¡ Low-intermediate-risk MGUS has one of the risk factors.
¡ High-intermediate-risk MGUS has two of the risk factors.
¡ High-risk MGUS has all three of the risk factors.
If you are diagnosed with intermediate-risk or high-risk MGUS during your baseline testing, you should also have a bone marrow aspiration and bone marrow biopsy. The same bone marrow sample that is obtained should also be used for cytogenetic studies. For more information about the tests used to identify and quantify M-protein, read the IMF’s publication Understanding Your Test Results.
Management for MGUS
At this time, there are no treatments for MGUS that are approved by the U.S. Food and Drug Administration (FDA). Monitoring MGUS as described above can determine if any progression is occurring and if any additional testing is required. The vast majority of MGUS patients are monitored for many years without the need for additional medical attention.
CRAB Criteria
Myeloma-de ning events (MDE)
Bone marrow plasma cells ≥ 60%
Ratio of monoclonal to normal light chains ≥100
>1 focal lesion on MRI
Spanish Criteria
Mayo Criteria
MM Multiple Myeloma
Early Active Myeloma Ultra-High-Risk Smoldering Myeloma
HR SMM High-Risk Smoldering Multiple Myeloma
LR SMM Low-Risk Smoldering Multiple Myeloma
MGUS Monoclonal Gammopathy of Undetermined Signi cance
The iStopMM screening study
Launched in November 2016, iStopMM® (Iceland Screens Treats or Prevents Multiple Myeloma) is the largest-ever population-based screening study for MGUS, SMM, and myeloma. The iStopMM study invited the approximately 140,000 residents of Iceland who are over age 40 to be screened for the presence of M-protein in the serum or urine.
More than half of the invited population volunteered to take part, and the iStopMM research team, led by Dr. Sigurður Kristinsson (University of Iceland, Reykjavík), is observing patterns of occurrence in order to better understand disease biology and to identify the genes that drive disease progression. Monitoring patients with MGUS for many years will demonstrate which prognostic tests are most reliable and which patients may benefit from early intervention.
The iStopMM study has defined, for the first time, epidemiological and clinical characteristics of SMM. An important early finding was that the prevalence of SMM is higher than expected: 0.53% in persons 40 years or older, 0.67% in men and 0.39% in women, with the prevalence increasing with age. This finding enhances the potential value of screening in that early interventions can be offered with hopes of improved outcomes.
Collectively, the iStopMM study findings point to many new paradigms in the evaluation and management of M-protein disorders. This is the
beginning of a new era in the study of early disease entities which can be precursors to myeloma.
The many outcomes from the iStopMM study will benefit not only Iceland but the myeloma community around the world. iStopMM is supported by the IMF Black Swan Research Initiative® (BSRI®). To learn more about iStopMM, visit myeloma.org/black-swan-research-initiative/istopmm.
SMM
Smoldering multiple myeloma (SMM) is an asymptomatic (no signs or symptoms) precursor state of active myeloma. Patients with SMM have between 10% and 60% myeloma cells present in the bone marrow.
The average risk of progression from SMM to myeloma is 10% per year. Unlike active myeloma, patients with SMM do not have CRAB criteria features indicating organ damage.
Patients with SMM must be monitored carefully by an experienced hematologist-oncologist. This is done more frequently than for patients with MGUS because the risk of progression from SMM to active myeloma is higher than with MGUS. For example, you may be evaluated every 4 to 6 months for the first year. Then, depending on your SMM status and your doctor’s judgment, the evaluation may be performed less frequently (e.g., every 6 to 12 months).
Diagnostic criteria for SMM
For a diagnosis of SMM, both of the following 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%,
2. Absence of myeloma-defining events (MDE) or amyloidosis.
Myeloma-defining events (MDE) include the following:
¡ 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 magnetic resonance imaging (MRI) studies.
Of the 193 participants in the iStopMM study who were diagnosed with SMM, the median age was 70 years (range 44–92) and 60% were males. Using the 2/20/20 clinical risk stratification criteria for SMM, 126 (65%) patients were low-risk, 52 (27%) intermediate-risk, and 15 (8%) high-risk.
The 2/20/20 criteria published by Mayo Clinic in 2018 are based on the data for patients who had none, one, or two to three of the risk factors that were most associated with a short time to progression from SMM to active myeloma:
¡ Serum M-protein > 2 g/dL,
¡ Bone marrow plasma cell (BMPC) infiltration > 20%, and/or
¡ Ratio of involved-to-uninvolved serum FLC > 20.
SMM may be diagnosed in a patient who is being observed for MGUS, or detected when an individual seeks healthcare due to an unrelated condition, or in the course of a routine medical exam. Once SMM is diagnosed, current clinical guidelines recommend stratification to determine the risk of progression to myeloma, as well as lifelong monitoring for progression.
The current understanding of the biology and behavior of SMM enables doctors to avoid treating patients who do not need to be treated, but to intervene promptly if a patient is at a high risk of progression to myeloma. The doctor’s experience and judgment are crucial to differentiating MGUS from SMM and from active myeloma. A primary consultation or second opinion with a myeloma expert is highly recommended.
The diagnostic process includes SPEP, CBC, and measurement of calcium and creatinine values. Twenty-four-hour urine collection for electrophoresis and immunofixation should be performed at diagnosis and within 2 to 3 months after the initial recognition of SMM. A baseline bone marrow biopsy and skeletal survey must be performed. An MRI of the spine and pelvis are highly recommended because these sensitive studies are better able to predict for more rapid progression to active myeloma.
Skeletal X-rays are no longer the standard of care in the diagnostic process of SMM because they only pick up bone lesions after approximately 30% of the cancellous bone has been destroyed. Whole-body low-dose CT (WBLDCT) is now the standard of care to detect and document early bone disease. WBLDCT is the preferred baseline imaging study for newly diagnosed myeloma because it does not require the use of contrast agents and also uses much less radiation than conventional CT.
Possible evolution of SMM to active myeloma
Research is ongoing to identify the risk factors for progressing from SMM to active myeloma but a system of precise criteria does not exist at this time.
In 2014, The Lancet published the IMWG updated criteria for the diagnosis of myeloma. SMM patients with 80% or greater risk of progression to myeloma within 2 years were defined as having early active myeloma.
In 2018, Blood Cancer Journal published a statistical analysis of variables among patients with SMM at Mayo Clinic in Rochester, Minnesota. Further
refinements to the 2/20/20 criteria were made with the addition of the following two high-risk factors:
¡ chromosomal abnormality +1q (a gain of chromosome 1q),
¡ chromosomal abnormality del13q (a deletion of chromosome 13q).
If one or both of these abnormalities are found by fluorescence in situ hybridization (FISH) testing of myeloma cells, the risk of disease progression is increased.
In 2020, Blood Cancer Journal published the IMWG risk stratification model for SMM that can be applied across the globe using easily available data.
Dr. María-Victoria Mateos and colleagues assembled an international cohort of 1,996 patients with SMM who met the revised IMWG criteria. Patients with ≥ 80% risk of progression at 2 years were excluded because they are considered to have active myeloma by current definition.
Three independent factors were identified predicting high-risk SMM (HR SMM) progression to active myeloma at 2 years based on the 2/20/20 criteria. This translates into 3 categories with an increasing 2-year progression risk:
¡ 6% for low-risk patients with no risk factors,
¡ 18% for intermediate-risk patients who have 1 factor, and
¡ 44% for high-risk patients who have 2 or more factors).
In addition, presence of chromosomal abnormalities t(4;14), t(14;16), +1q, and/or del13q allowed for further separation into the following 4 groups:
1. Low-risk SMM patients had no cytogenetic abnormalities. Low risk of progression to active myeloma.
2. Low intermediate-risk SMM patients with 1 cytogenetic abnormality had the progression risk at 2 years of 23%.
3. Intermediate-risk SMM patients with 2 cytogenetic abnormalities had the progression risk at 2 years of 46%.
4. High-risk SMM (HR-SMM) patients with 3 or more cytogenetic abnormalities had the progression risk at 2 years of 63%.
Recent clinical trial experience with SMM
Currently, there are no FDA-approved treatment options for patients with SMM. However, there are a number of clinical trials investigating SMM. A clinical trial is a medical research study with people who volunteer to test scientific approaches to a new treatment or a new combination therapy. Each clinical trial is designed to find better ways to prevent, detect, diagnose, or treat a disease or condition, and to answer scientific questions.
If you have SMM and are considering participation in a clinical trial, it is important to discuss with your doctor all the potential risks and benefits
in your particular case, including the physical and psychological aspects of treatment as opposed to observation.
The ASCENT clinical trial is a pilot effort to see whether early aggressive therapy can be potentially curative for patients with HR-SMM. This study is no longer accepting new patients. Enrolled patients are receiving treatment with Kyprolis® (carfilzomib) + Revlimid® (lenalidomide) + dexamethasone [KRd] followed by transplant, KRd consolidation therapy, and Rd maintenance therapy.
At the December 2024 annual meeting of the American Society of Hematology (ASH), two additional important studies offered insights about the standard of care for HR-SMM.
Darzalex monotherapy vs. monitoring for HR-SMM
Primary results were presented from the AQUILA phase III randomized clinical trial comparing Darzalex® (daratumumab) monotherapy vs. active monitoring (observation) in patients with HR-SMM. This ongoing study is taking place at 124 participating sites in 23 countries. Data presented at ASH demonstrates that it is possible to delay the progression from HR-SMM to active myeloma.
A total of 390 patients with HR-SMM were randomized to two study arms: 194 in the treatment arm and 196 in the observation arm. In the Darzalex monotherapy arm of the study, patients received 1,800 mg of Darzalex Faspro® (daratumumab + hyaluronidase-fihj) by subcutaneous (SQ) injection onceweekly during 28-day Cycles 1 and 2, once every 2 weeks during Cycles 3 through 6, and once every 4 weeks thereafter up to 39 cycles in 36 months. In the observation arm of the study, patients had no disease-specific treatment and were monitored every 6 months for survival for up to 36 months until the end of study.
Follow-up continued until disease progression to myeloma, which was based on the IMWG SLiM-CRAB criteria. At 24 months, 79.9% of patients in the Darzalex arm still had not progressed to myeloma, compared to only 63.3% of patients in the observation arm. At 5 years, 63.1% of patients in the Darzalex arm still had not progressed to myeloma, compared to only 40.8% of patients in the observation arm.
Treatment with Darzalex prolonged time until frontline therapy for myeloma, with 33.2% of patients in the Darzalex arm initiating frontline therapy vs. 53.6% of patients in the observation arm. Darzalex monotherapy improved PFS on frontline therapy vs. active monitoring and did not appear to impair later treatment with Darzalex.
Early intervention with Darzalex monotherapy extended overall survival (OS) and reduced the risk of progression to myeloma or death by 51%
when compared to active monitoring. At 5 years, 93% of patients in the Darzalex arm were still alive vs. 86.9% of patients in the observation arm, so the survival benefit continued beyond 36 months of the study. No new safety concerns were identified.
Carvykti CAR T-cell therapy in HR-SMM
Carvykti® (ciltacabtagene autoleucel) is a chimeric antigen receptor (CAR) T-cell therapy currently approved by the FDA for patients with relapsed or refractory multiple myeloma (RRMM) who have received at least 1 prior line of therapy, and this approach is delivering deep and durable responses for many patients. The CAR-PRISM phase II, single arm clinical trial investigated early safety and efficacy of Carvykti in patients with HR-SMM.
The primary objective of the CAR-PRISM study is to determine the safety of Carvykti in HR-SMM. The secondary objectives are to assess efficacy, minimal residual disease (MRD) negativity rates and progression-free survival (PFS). Six patients have been treated, with a median follow-up of 6 months (60 days to 1 year). Accrual of additional patients is ongoing.
All patients achieved MRD-negativity at 10-6 by day 28 and MRDnegativity was sustained in all patients to date of ASH presentation without any evidence of disease progression. The overall response rate (ORR) is 100%, with a complete response rate of 50% and responses deepening over time. All patients experienced cytokine release syndrome (CRS): 67% experienced Grade 1 and 33% experienced Grade 2. Tocilizumab was administered to 4 patients and 2 patients received dexamethasone.
Long-term follow up is required to determine if the study responses will be sustained.
Active myeloma
Myeloma is a cancer of the bone marrow plasma cells, white blood cells that make antibodies. If your SMM is progressing to active myeloma, this is a key time to seek an opinion (or a second opinion) from a myeloma specialist.
A local hematologist or oncologist might see a few myeloma patients or none at all. Myeloma specialists at large “high-volume” treatment centers or academic institutions treat hundreds of myeloma patients, conduct clinical trials with new drugs and new combination therapies, and develop the expertise needed to make appropriate decisions.
There are many highly effective therapies for the treatment of myeloma. Patients with myeloma can lead full and productive lives for years, even decades, after diagnosis. Survival and quality of life of myeloma patients
are improving steadily. Learning about myeloma and understanding how it is treated can help patients and their loved ones reduce their anxiety, gain a sense of control, and make it easier to come to terms with the diagnosis.
Support groups
The IMF provides educational guidance to a network of in-person and virtual myeloma-specific support groups in the U.S. that offer empowerment, empathy, and encouragement to patients and their care partners. In addition, there are groups that serve patients with MGUS or SMM, as well as their loved ones. Visit support.myeloma.org or email sgteam@myeloma.org to find a group that best meets your needs or to launch a new group with help from the IMF.
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 a good quality of life through effective treatment of your myeloma, you must play an active role in your own medical care. We encourage you to visit myeloma.org for more information and to join the Myeloma Knowledge Platform at myprofile.myeloma.org.
To receive the most up-to-date information about myeloma in a caring and compassionate manner, call the IMF InfoLine at 1.818.487.7455, email InfoLine@myeloma.org, or schedule a time to talk with an IMF InfoLine Coordinator at mmsm.link/infoline.
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The International Myeloma Foundation (IMF) is the global leader in myeloma. Our mission is to improve the quality of life of myeloma patients while working toward prevention and a cure. Since 1990, the IMF has been serving the myeloma community through the following four pillars:
RESEARCH At the IMF, finding a cure for myeloma is our top priority. The IMF Scientific Advisory Board (SAB) of leading myeloma experts identifies key opportunities to drive research forward. The IMF Black Swan Research Initiative® (BSRI®) is pushing the boundaries with early screening for a precursor condition of myeloma as well as cure-focused myeloma clinical trials. The IMF International Myeloma Working Group (IMWG) provides trusted guidelines for diagnosing, treating, and managing myeloma. We also fund innovative research through the IMF Brian D. Novis Research Grants.
EDUCATION Myeloma is a complex and unique journey for each patient. The IMF offers hundreds of videos and free publications in multiple languages to inform and empower patients and care partners to navigate their myeloma journey. All IMF seminars, webinars, and workshops are free-of-charge and designed to directly connect the patient community with expert myeloma clinicians. The IMF Nurse Leadership Board (NLB) provides recommendations for the management of myeloma. The IMF M-Power Project works to break down barriers and ensure health equity in underserved populations.
SUPPORT Studies show that social support can greatly improve the quality of life of people with cancer. The IMF offers more than 160 myeloma support groups across North America, including specialized groups for Spanish-speakers, people with smoldering myeloma, care partners of patients with myeloma, and patients who do not have care partners. The IMF InfoLine answers myeloma-related questions. Myelo®, the IMF’s generative AI assistant, is available 24/7 to help you find the right resources.
ADVOCACY In the U.S., the IMF Advocacy team represents your interests at the federal and state levels. Internationally, the IMF Global Myeloma Action Network (GMAN) works to improve patient access to treatments.
