Mieloma Multipel

01Pathophysiology

Multiple myeloma begins with the clonal expansion of a single malignant plasma cell within the bone marrow. This abnormal clone arises through a stepwise process, often preceded by MGUS, which progresses to smoldering myeloma and eventually to symptomatic disease. The fundamental defect involves genetic hits such as immunoglobulin heavy chain translocations (commonly t(4;14), t(14;16), t(11;14)) or hyperdiploidy that give the plasma cell clone a survival and proliferative advantage.

The malignant plasma cells secrete a monoclonal immunoglobulin (the M protein), which is a nonfunctional antibody. Because the bone marrow is occupied by these clonal cells, normal hematopoiesis is suppressed. This directly explains the anemia (decreased red cell production), leukopenia (increased susceptibility to infections, particularly encapsulated organisms like Streptococcus pneumoniae), and thrombocytopenia seen in advanced disease.

Bone destruction is one of the hallmark features and results from osteoclast activation paired with osteoblast suppression. Myeloma cells secrete RANKL (receptor activator of nuclear factor kappa-B ligand), MIP-1 alpha, and other cytokines that stimulate osteoclasts while simultaneously producing DKK1 and sclerostin, which inhibit osteoblast activity. This uncoupled bone remodeling produces the classic punched-out lytic lesions on imaging. Because osteoblasts are suppressed, bone scans (which rely on osteoblastic activity) are typically negative or falsely normal in myeloma, a frequently tested concept.

The extensive bone resorption releases calcium into the bloodstream, causing hypercalcemia. This produces symptoms such as confusion, constipation, polyuria, polydipsia, and shortened QT interval on ECG. On exam vignettes, an elderly patient with bone pain, confusion, and elevated calcium should immediately raise suspicion for myeloma.

Renal insufficiency in myeloma has multiple contributing mechanisms. The most important is myeloma cast nephropathy (also called myeloma kidney), where free light chains (Bence Jones proteins) precipitate in the renal tubules and form obstructing casts. Additional renal insults include hypercalcemia-induced nephrogenic diabetes insipidus, amyloid deposition (AL amyloidosis), light chain deposition disease, hyperuricemia, and use of nephrotoxic agents including contrast dye and NSAIDs.

The overproduction of monoclonal immunoglobulin also causes rouleaux formation of red blood cells on the peripheral smear due to increased serum viscosity and altered surface charge. In some cases, particularly with IgM (though IgM-secreting myeloma is exceedingly rare; IgM monoclonal protein more commonly indicates Waldenstrom macroglobulinemia), hyperviscosity syndrome can develop with visual disturbances, neurologic symptoms, and bleeding.

A critical concept: despite having very high levels of one immunoglobulin type, patients are functionally immunosuppressed because the M protein is nonfunctional and production of normal polyclonal immunoglobulins is suppressed. This "immunoparesis" is why recurrent bacterial infections are a leading cause of morbidity and mortality.

02Classification and Clinical Manifestation

Disease Spectrum

CRAB Criteria (End-Organ Damage)

Immunoglobulin Subtype

Revised International Staging System (R-ISS)

03Diagnostic Workup

When a vignette describes an elderly patient with unexplained back pain, anemia, and elevated creatinine, the first step is ordering a SPEP. This is the best initial test for suspected myeloma. The SPEP separates serum proteins by charge and will show a tall, narrow peak called the M spike in the gamma globulin region. An important caveat: in light-chain-only myeloma, the SPEP may appear normal or show only hypogammaglobulinemia because intact immunoglobulin is not being produced. This is why the serum free light chain assay is a critical companion test and should be ordered alongside SPEP in every suspected case.

Once an M spike is identified, the next step is serum immunofixation, which identifies the exact heavy and light chain class. This distinguishes IgG kappa from IgA lambda, for example, and is more sensitive than SPEP for detecting small M proteins.

A 24-hour urine collection for UPEP and immunofixation detects Bence Jones proteins (free light chains filtered by the kidneys). This is important both diagnostically and for assessing renal risk, since these light chains cause tubular damage.

The confirmatory test and gold standard is bone marrow biopsy with aspiration. The finding of ≥10% clonal plasma cells confirms the diagnosis. The marrow specimen should also be sent for FISH (fluorescence in situ hybridization) to identify high-risk cytogenetic abnormalities such as del(17p), t(4;14), and t(14;16), which are critical for prognosis and treatment planning.

For bone disease assessment, the traditional skeletal survey (plain radiographs of the skull, spine, pelvis, and long bones) has been largely replaced by low-dose whole-body CT or PET-CT, which are more sensitive. The classic imaging finding is punched-out lytic lesions without surrounding sclerosis (because osteoblasts are suppressed). A high-yield test concept: bone scintigraphy (nuclear bone scan) is NOT useful in myeloma because it depends on osteoblastic activity, which is suppressed.

On basic labs, expect the total protein to be elevated (from the M protein) while albumin is low (due to chronic disease and hepatic suppression by cytokines). This produces the classic reversed albumin-to-globulin ratio. The peripheral smear often shows rouleaux formation, which is not diagnostic but should raise suspicion. An elevated ESR is also commonly seen for the same reason (increased protein alters red cell aggregation).

04Management and Treatment

Acute stabilization focuses on the most immediately dangerous complications. Hypercalcemia is treated with aggressive IV saline hydration as the first step (this is the "next best step" if a vignette describes confusion, elevated calcium, and dehydration). Add IV zoledronic acid and calcitonin (works within hours while bisphosphonates take 2-3 days to reach full effect). Dexamethasone helps lower calcium by directly killing myeloma cells and reducing cytokine production.

For severe renal failure, rapid initiation of bortezomib-based chemotherapy is essential because bortezomib is hepatically metabolized and does not require dose adjustment in renal impairment. Lenalidomide requires dose reduction in renal insufficiency. If the patient presents with dialysis-level renal failure, plasmapheresis may be considered for removing free light chains, though evidence is mixed.

Definitive treatment hinges on transplant eligibility. The standard induction regimen is VRd (bortezomib, lenalidomide, dexamethasone), given for 3 to 4 cycles before stem cell collection and ASCT. Bortezomib is administered subcutaneously at 1.3 mg/m² on days 1, 4, 8, and 11 of a 21-day cycle. Lenalidomide is given at 25 mg daily on days 1 through 14, and dexamethasone at 40 mg weekly (days 1, 8, 15, 22). After transplant, patients receive lenalidomide maintenance (typically 10-15 mg daily) until disease progression or intolerance, as this has been shown to improve overall survival.

For transplant-ineligible patients, DRd (daratumumab, lenalidomide, dexamethasone) is increasingly favored as first-line therapy based on the MAIA trial, which demonstrated a significant progression-free survival benefit. Treatment continues until disease progression.

Key side effects to know for exam questions: bortezomib causes peripheral neuropathy (subcutaneous administration reduces this risk compared to IV) and herpes zoster reactivation (requiring VZV prophylaxis). Lenalidomide causes cytopenias and venous thromboembolism (requiring thromboprophylaxis). Dexamethasone causes hyperglycemia, insomnia, and immunosuppression.

Contraindications and adjustments: in patients with pre-existing peripheral neuropathy, bortezomib should be used cautiously or substituted with carfilzomib (which has less neurotoxicity but more cardiotoxicity). In renal impairment, lenalidomide dose must be reduced (5-10 mg daily depending on creatinine clearance). In patients with high VTE risk, full-dose anticoagulation with LMWH replaces aspirin.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common way students get questions about multiple myeloma wrong is by missing the diagnosis entirely when the vignette does not use the word "myeloma" and instead presents the disease through one of its complications. A vignette describing an elderly man with back pain and a compression fracture may seem orthopedic until you notice the anemia and elevated creatinine. Another classic trap is the patient with "recurrent pneumonia" and fatigue, where the underlying immunoparesis from myeloma is the real answer.

A second major trap involves ordering a bone scan for suspected myeloma. Test-writers love to include bone scintigraphy as an answer choice alongside skeletal survey or PET-CT. Students who remember that bone scans are useful for metastatic disease will incorrectly select it. The key concept being tested is that myeloma suppresses osteoblastic activity, making bone scans unreliable and often falsely negative. Always choose skeletal survey, low-dose whole-body CT, or PET-CT.

Students also commonly confuse myeloma with Waldenstrom macroglobulinemia. If the vignette mentions IgM monoclonal protein, hyperviscosity symptoms (blurred vision, headache, bleeding), and absence of bone lesions, the answer is Waldenstrom, not myeloma. If the M protein is IgG or IgA and there are lytic bone lesions, it is myeloma.

Another frequent error is confusing MGUS with myeloma. The discriminator is always end-organ damage. If the vignette describes an incidental M spike found on routine labs in a patient who feels well, has normal calcium, normal renal function, normal hemoglobin, and no bone lesions, the answer is MGUS, and the management is observation (no treatment).

Regarding treatment, a common pitfall is selecting thalidomide or melphalan-based regimens as first-line therapy. While historically used, current standard of care is VRd-based induction. Also, do not forget that all patients on bortezomib require antiviral prophylaxis for herpes zoster, and all patients on lenalidomide require thromboprophylaxis.

Finally, recognize that the question may test the concept of light-chain myeloma. If the SPEP is normal but the patient clearly has CRAB features, the next step is serum free light chain assay and urine studies, not repeating the SPEP or dismissing the diagnosis. Light-chain-only myeloma accounts for approximately 15-20% of cases and will have an abnormal free light chain ratio with a normal or only mildly abnormal SPEP.

The core competency being tested across myeloma questions is pattern recognition of the CRAB features, correct sequencing of the diagnostic workup (SPEP first, then immunofixation and free light chains, then bone marrow biopsy as the confirmatory test), understanding why bone scans fail in this disease, and knowing the standard treatment backbone.