[14] Multiple myeloma is the result of a multi-step malignant transformation, and almost universally originates from the pre-malignant stage monoclonal gammopathy of undetermined significance (MGUS).

The CRAB criteria were formerly the benchmark used to establish the presence of active multiple myeloma (as opposed to an earlier, generally asymptomatic, "smoldering" form of the disease).

[28] Collateral infections are common with multiple myeloma since the disease impairs the functioning of blood components that normally resist pathogens.

[30] Clinical evaluation of a person's immune response is typically performed by a lab test that measures the levels of different immunoglobulins in the blood.

[34] When the measure of effective antibodies drops below a threshold (a condition termed hypogammaglobulinemia),[35] supplemental immunoglobulins may be provided by periodic infusions to reduce the risk of collateral infections.

[citation needed] When the disease is well-controlled, neurological symptoms may result from current treatments, some of which may cause peripheral neuropathy, manifesting itself as numbness or pain in the hands, feet, and lower legs.

[citation needed] The initial symptoms may involve pain, numbness, swelling, expansion of the jaw, tooth mobility, and radiolucency.

[14] Rarely, Epstein–Barr virus (EBV) is associated with multiple myeloma, particularly in individuals who have an immunodeficiency due to e.g. HIV/AIDS, organ transplantation, or a chronic inflammatory condition such as rheumatoid arthritis.

The observed methylation pattern of CpG within intronic regions with enhancer-related chromatin marks in multiple myeloma is similar to undifferentiated precursor and stem cells.

These results may represent a de novo epigenetic reprogramming in multiple myeloma, leading to the acquisition of a methylation pattern related to stemness.

[56] Other studies have identified a multiple myeloma specific gene silencing pattern associated with abnormal histone modifications caused by dysregulation of the polycomb repressive complex 2 (PRC2).

[57][58] Increased expression of the PRC2 subunit, EZH2 have been described to be a common feature in multiple myeloma, resulting in an accumulation and redistribution of histone H3 lysine 27 trimethylation which advances with disease severity.

[62] Subsequent genetic and epigenetic changes lead to a new, more aggressive clone of plasma cells, which causes further rises in the level of the circulating myeloma protein, further rises in the number of bone marrow plasma cells, or the development of one or more of a specific set of "CRAB" symptoms, which are the basis for diagnosing malignant multiple myeloma and treating the disease.

[67] Additional findings may include a raised calcium level (when osteoclasts are breaking down bone, releasing it into the bloodstream), raised serum creatinine level due to reduced kidney function, which is mainly due to casts of paraprotein deposition in the kidney, although the cast may also contain complete immunoglobulins, Tamm-Horsfall protein and albumin.

[68] Other useful laboratory tests include quantitative measurement of IgA, IgG, and IgM to look for immune paresis, and beta-2 microglobulin, which provides prognostic information.

Initial research also suggests that measurement of free light chains may also be used, in conjunction with other markers, for assessment of the risk of progression from MGUS to multiple myeloma.

[21] Flow cytometry is often used to establish the clonal nature of the plasma cells, which will generally express only kappa or lambda light chain.

Recently, however, the surface antigen CD319 (SLAMF7) was discovered to be considerably more stable and allows robust isolation of malignant plasma cells from delayed or even cryopreserved samples.

[74] People with deletion of chromosome 13 or hypodiploidy by conventional cytogenetics, t(4;14), t(14;16), t(14;20) or 17p- by molecular genetic studies, or with a high plasma cell labeling index (3% or more) are considered to have high-risk myeloma.

[77] Magnetic resonance imaging is more sensitive than simple X-rays in the detection of lytic lesions, and may supersede a skeletal survey, especially when vertebral disease is suspected.

Many such groupings include one or more of a monoclonal antibody (e.g., isatuximab or daratumumab), an immunomodulatory agent (e.g., lenalidomide or pomalidomide), and a proteasome inhibitor (e.g., or bortezomib, carfilzomib or ixazomib), in combination with a steroid (e.g., dexamethasone).

[86] (Emerging practice is not to call such drugs "chemotherapy" because they are not the traditional non-specific intracellular poisons that operate in the classic "chemo" fashion of inhibiting mitosis or inducing DNA damage.

However, this procedure is not available for frail patients,[93] as it essentially resets aspects of the immune system and requires redevelopment of natural defenses, such as by administering childhood vaccines.

If there are no symptoms, but a paraprotein typical of myeloma and diagnostic bone marrow is present without end-organ damage, treatment is usually deferred or restricted to clinical trials.

[135] The evidence suggests that MSCs for prophylactic reason result in little to no difference in all-cause mortality, in the relapse of malignant diseases, and in the incidence of acute GvHD.

In addition to addressing symptoms of cancer, palliative care helps manage unwanted side effects, such as pain and nausea related to treatments.

[144][145] Oral prophylaxis, hygiene instruction, and elimination of sources of infection within the mouth before beginning cancer treatment can reduce the risk of infectious complications.

Before starting bisphosphonate therapy, the person's dental health should be evaluated to assess the risk factors to prevent the development of medication-related osteonecrosis of the jaw (MRONJ).

If there are any symptoms or radiographic appearance of MRONJ, such as jaw pain, loose tooth, or mucosal swelling, early referral to an oral surgeon is recommended.

African Americans and Native Pacific Islanders have the highest reported number of new cases of this disease in the United States and Asians have the lowest.