Multiple Myeloma

Multiple myeloma (MM) is characterized by the malignant proliferation of plasma cells in the bone marrow resulting in bone destruction.

Normal plasma cells (derived from B lymphocytes) are responsible for producing immunoglobulins (Ig), which are antibodies that help neutralize foreign pathogens like viruses and bacteria. These immunoglobulins are typically produced in a polyclonal fashion, meaning the body generates a variety of immunoglobulins to defend against a broad range of pathogens. In contrast, cancerous plasma cells in MM produce an excess of one type of immunoglobulin, often referred to as monoclonal protein or M protein or paraprotein.

The hallmark of MM is the production of an excess amount of the same immunoglobulin. In most cases, this involves IgG (either IgG kappa or IgG lambda), but other immunoglobulin types (e.g., IgA or IgM) can also be involved. The immunoglobulin molecule consists of two identical heavy chains and two identical light chains (either Kappa or Lambda) connected by disulfide bonds. In certain cases, MM cells produce only the light chains of immunoglobulins, either kappa or lambda, without the corresponding heavy chains. This form of MM is known as light chain myeloma. The light chains can be detected in the urine of MM patients as Bence Jones protein, which can be a helpful marker in the diagnosis and monitoring of the disease.

In rare cases, MM patients may not produce measurable M protein or light chain at all. This form of MM is known as non-secretory MM, and it presents a unique challenge in diagnosis because traditional tests for monoclonal protein may not be useful.

Extramedullary disease (EMD) refers to the growth of cancerous plasma cells outside the bone marrow. These cells can form tumors in soft tissues and organs, often leading to complications and a more aggressive course of the disease. EMD can be present at the time of an initial diagnosis or may develop during relapse. It is associated with a poorer prognosis. In paramedullary myeloma, plasmacytomas (tumors of plasma cells) originate within bone marrow but extend into the surrounding soft tissue. However, the disease still maintains a direct connection to the bone, distinguishing it from purely extramedullary disease.

A solitary plasmacytoma refers to a single tumor, either in the bone marrow (solitary bone plasmacytoma) or in soft tissues (extramedullary plasmacytoma), that occurs in isolation, without signs of systemic disease. This is different from MM, which is characterized by diffuse, patchy disease involving multiple areas of bone marrow.

Precursor conditions to MM

MGUS stands for Monoclonal Gammopathy of Undetermined Significance. It is a precursor to MM, and It is typically discovered through routine blood tests, and usually asymptomatic (fig. 1).

Smoldering Multiple Myeloma (SMM) is an early, asymptomatic stage of multiple myeloma. It is considered an intermediate condition that lies between MGUS and active MM (fig.1).

Clinical Features

Worldwide, there are approximately 180,000 cases and 117,000 deaths per year attributed to MM1. It is more common in males than females, and more common among individuals of African American descent. The median age at diagnosis is 60-70 years. Most signs or symptoms related to the infiltration of plasma cells into the bone or other organs or to kidney damage from immunoglobulin deposition in subacute presentation but rarely it may be acute such as spinal cord compression or kidney failure. The acronym “CRAB” is sometimes used to describe myeloma-defining events: calcium elevation; renal insufficiency; anemia; and bone disease.

Hypercalcemia — Hypercalcemia can occur in MM because of bone demineralization.

Renal insufficiency — The serum creatinine concentration is increased in almost one-half of patients at diagnosis. Other causes of kidney failure in a patient with MM include concurrent light chain (AL) amyloidosis and light chain deposition disease.

Anemia — A normocytic, normochromic anemia causing fatigue and pallor.

Bone pain — and pathologic fractures.

Diagnosis

The diagnosis of MM requires fulfillment of the following criterion²:

Clonal bone marrow plasma cells ≥10 percent or biopsy-proven bony or soft tissue plasmacytoma – Clonality should be confirmed by a light chain restriction (either kappa or lambda) on tissue evaluated.

Plus, one of the seven following findings (Fig. 1):

Presence of related organ damage (CRAB) related to underlying MM.

1. Anemia or
2. Hypercalcemia or
3. Renal insufficiency or
4. Bone lesions or

Presence of a feature with high likelihood of developing end-organ damage (acronym “SLiM,” representing “Sixty,” “Light chain ratio,” MRI)
5. ≥60 % clonal plasma cells in the bone marrow or
6. Involved/uninvolved serum free light chain ratio ≥100 or
7. MRI with more than one focal lesion

Fig 1. Revised International Myeloma Working Group diagnostic criteria for multiple myeloma and smoldering multiple myeloma

Laboratory Tests needed for initial diagnosis as well as response assessment: Serum protein electrophoresis with immunofixation to measure M protein. 24 hr Urine protein electrophoresis, Kappa/Lambda free light chains and ratio, Quantitative immunoglobulins (IgG, IgA, and IgM). Both serum albumin and beta-2 microglobulin are required (Table 1) for staging system. ESR may be high, but it is a non-specific test.

Imaging: Skeletal survey is less sensitive than low dose whole body CT or PET/CT scan or MRI whole body to detect lytic lesions.

Bone marrow biopsy is essential to confirm diagnosis as well as to obtain Cytogenetics including Fluorescence in situ hybridization (FISH) and next generation sequencing to detect genetic mutations and alterations. Peripheral blood smear may show Rouleaux formation (red cells appear a stack of coins) due to elevated serum protein levels.

Prognosis

The Revised International Staging System (R-ISS)3 is the most widely used staging system for MM (Table 1) which provides prognostic value independent of patient age and therapy received.

Table 1. Revised International Staging System (RISS) for MM

Risk Stratification of Newly Diagnosed MM

It is based on FISH for specific translocations and certain other tests (table 2). This stratification impacts treatment choice as well as prognosis. A new genomic based (using genome sequencing)4staging system was updated recently.

Table 2. mSMART (Mayo Clinic) 4.0: Classification of Active MM5

Treatment

MM is so far not curable. The aims of treatment are to alleviate symptoms, decrease end-organ damage, achieve a sustained response, improve quality of life, and prolong survival. Treatment choices are affected by MM risk group as well as transplant eligibility.

The first step is to determine eligibility for autologous stem cell transplant (ASCT). ASCT eligibility varies across countries and institutions depending on age, organ functions, risk-benefit assessment and the needs and wishes of the patient. In most European countries, the upper age limit for ASCT is 65 years of age but in the US, a strict age limit is not used. Instead, the “physiological age” is used for case-by-case decision making and it varies across institutions. In most centers in the US, patients with one or more of the following factors may be considered not eligible for ASCT for MM.

• Age >77 years
• Frank cirrhosis of the liver
• Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain
• New York Heart Association (NYHA) functional status class III or IV

When compared with chemotherapy alone, ASCT results in :

1. Superior PFS, with an improvement in median PFS >20 months (with more pronounced benefit in high-risk disease) without clinically significant overall survival benefit6
2. Manageable short-term toxicities with a low nonrelapse mortality
3. Similar overall rates of second primary malignancies, and an increase in myeloid malignancies such as Acute Myeloid leukemia

Initial Therapy

Induction chemotherapy is administered for four to six months (cycles) prior to stem cell collection to reduce the number of cancer cells, to control symptoms, and reverse end-organ damage. The regimen chosen is based on risk stratification, comorbid conditions, and resources available, and limits exposure to agents that may impair stem cell collection (Figure 2).⁵

Myeloma therapy has improved with the development of novel agents, initially the immunomodulatory (IMiD) agent thalidomide and proteosome inhibitors bortezomib and carfilzomib followed by newer IMiDs lenalidomide and pomalidomide and CD 38 antibodies daratumumab and Isatuximab.

In patients with renal failure, CyborD (cyclophosphamide + bortezomib + dexamethasone) can be used. In resource-poor areas⁷, alkylating agents (e.g., cyclophosphamide or melphalan) and/or first-generation immunomodulatory agents (e.g., thalidomide) may be used. If the patient is not eligible for ASCT, the treatment is again based on risk stratification (Figure 3).⁵ Prior to each treatment cycle, patients with MM are evaluated for disease response as well as potential treatment related toxicities.

Fig 2. Treatment Algorithm (mSMART) for transplant eligible patients

Fig 3. Treatment Algorithm (mSMART) for transplant ineligible patients.

Relapsed MM

ASCT must be considered in transplant-eligible patients with relapsed MM, particularly those who delayed ASCT.

Most patients experience serial relapses over time and the choice of therapy is influenced by prior therapies received, response and toxicities to those therapies, and possibility of the disease being refractory to specific agents8. In general, refractory disease is defined as having progressive disease on or within 60 days of receiving standard doses of a specific therapy. The same agent can be tried again if it was stopped without meeting the definition of refractoriness.

Table 3. Selection of MM therapy at first relapse

DKd: daratumumab, carfilzomib, and dexamethasone; DPd: daratumumab, pomalidomide, and dexamethasone; DRd: daratumumab, lenalidomide, and dexamethasone; DVd: daratumumab, bortezomib, and dexamethasone; ERd: elotuzumab, lenalidomide, and dexamethasone; HCT: hematopoietic cell transplantation; IRd: ixazomib, lenalidomide, and dexamethasone; IsaKd: isatuximab, carfilzomib, and dexamethasone; IsaPd: isatuximab, pomalidomide, and dexamethasone; KPd: carfilzomib, pomalidomide, and dexamethasone; KRd: carfilzomib, lenalidomide, and dexamethasone; MM: multiple myeloma; SVd: selinexor, bortezomib, and dexamethasone; VCd: bortezomib, cyclophosphamide, and dexamethasone; VPd: bortezomib, pomalidomide, and dexamethasone. (UpToDate 2025)

If a patient progresses on proteosome inhibitors, IMiDs and CD 38 antibodies, CAR T cells (Ide-cel⁹ or cilta-cel¹⁰), and bispecific antibodies such as Teclistamab¹¹ or Talquetamab¹² may be an option.

Supportive care¹³

Osteoclast inhibitors (e.g., bisphosphonate therapy or denosumab) should be used to prevent skeletal events. Long term use of these drugs may cause osteonecrosis of Jawbone and regular dental check/care is crucial.

Infection prevention includes Zoster prevention with Acyclovir prophylaxis, and PJP prophylaxis with Bactrim, up to date with vaccinations, and intravenous immune globulin for patients with hypogammaglobulinemia and/or recurrent infections.

Treatment with IMiDs increases thromboembolism risk. Aspirin or other anticoagulation should be used.

All patients with MM should take preventive measures to minimize kidney injury (e.g., avoid nephrotoxins such as NSAIDs) and maintain adequate hydration.

Reference

1. The International Agency for Research on Cancer (IARC) (no date) Global Cancer Observatory. https://gco.iarc.fr/en.
2. Rajkumar, S.V. et al. (2014b) ‘International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma,’ The Lancet Oncology, 15(12), pp. e538–e548. https://doi.org/10.1016/s1470-2045(14)70442-5.
3. Palumbo, A. et al. (2015) ‘Revised International staging system for multiple myeloma: A report from International Myeloma Working Group,’ Journal of Clinical Oncology, 33(26), pp. 2863–2869. https://doi.org/10.1200/jco.2015.61.2267.
4. Avet-Loiseau H. et al. (2025) ‘International Myeloma Society/International Myeloma Working Group Consensus Recommendations on the Definition of High-Risk Multiple Myeloma,’ J Clin Oncol, JCO2401893. doi: 10.1200/JCO-24-01893. Epub ahead of print.
5. Treatment Guidelines — MSMART (no date). https://www.msmart.org/mm-treatment-guidelines.
6. Richardson, P.G. et al. (2022) ‘Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma,’ New England Journal of Medicine, 387(2), pp. 132–147. https://doi.org/10.1056/nejmoa2204925.
7. De Magalhães Filho, R.J.P. et al. (2018) ‘Analysis of availability and access of anti-myeloma drugs and impact on the management of multiple myeloma in Latin American countries,’ Clinical Lymphoma Myeloma & Leukemia, 19(1), pp. e43–e50. https://doi.org/10.1016/j.clml.2018.08.005.
8. Bhatt, P., Kloock, C. and Comenzo, R. (2023) ‘Relapsed/Refractory Multiple Myeloma: A review of available therapies and clinical scenarios encountered in myeloma relapse,’ Current Oncology, 30(2), pp. 2322–2347. https://doi.org/10.3390/curroncol30020179.
9. Munshi, N.C. et al. (2021) ‘Idecabtagene vicleucel in relapsed and refractory multiple myeloma,’ New England Journal of Medicine, 384(8), pp. 705–716. https://doi.org/10.1056/nejmoa2024850.
10. Berdeja, J.G. et al. (2021) ‘Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study,’ The Lancet, 398(10297), pp. 314–324. https://doi.org/10.1016/s0140-6736(21)00933-8.
11. Moreau, P. et al. (2022) ‘Teclistamab in relapsed or refractory multiple myeloma,’ New England Journal of Medicine, 387(6), pp. 495–505. https://doi.org/10.1056/nejmoa2203478.
12. Chari, A. et al. (2022) ‘Talquetamab, a T-Cell–Redirecting GPRC5D bispecific antibody for multiple myeloma,’ New England Journal of Medicine, 387(24), pp. 2232–2244. https://doi.org/10.1056/nejmoa2204591.
13. Kumar, S.K. et al. (2023) ‘Multiple Myeloma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology,’ Journal of the National Comprehensive Cancer Network, 21(12), pp. 1281–1301. https://doi.org/10.6004/jnccn.2023.0061.

Author Information

Myo Htut (M.D.)
Associate Professor, Division of Myeloma,
Medical Director, Immune Effector Cell therapy program in Multiple Myeloma
Associate Chair, Clinical Cellular Immunotherapy Committee
Department of Hematology/Hematopoietic Cell Transplantation
City of Hope Medical Center