Multiple Myeloma

"Multiple myeloma is a clonal plasma cell proliferative disorder characterized by the abnormal increase of monoclonal immunoglobulins. Unchecked, the excess production of these plasma cells can ultimately lead to specific end-organ damage." In patient terms: "Multiple myeloma cells are abnormal plasma cells (a type of white blood cell) that build up in the bone marrow and form tumors in many bones of the body."

It almost always starts silently. "Virtually all cases of multiple myeloma are preceded by a gradually rising level of MGUS" — monoclonal gammopathy of undetermined significance, "the detection of monoclonal immunoglobulins in the blood or urine without evidence of end-organ damage," found "in over 3% of people aged 50 or older." MGUS carries "a risk of progression to multiple myeloma of about 1% per year" (StatPearls); NCI: "The annual risk of progression of MGUS to a lymphoid or plasma cell malignancy ranges from 0.5% to 1.0% in population-based cohorts." StatPearls, relaying NCCN, divides the spectrum into "MGUS, smoldering myeloma (asymptomatic), and multiple myeloma (symptomatic)"; progression may come from "additional cytogenetic lesions acquired by the original plasma cell clone."

The numbers separate the stages. MGUS: "Serum monoclonal protein less than 3 g/dl Clonal bone marrow plasma cells are less than 10% No end-organ damage." Smoldering: M protein ≥ 3 g/dL or 10% to 59% clonal marrow plasma cells, still with no end-organ damage. "Patients with MGUS or asymptomatic smoldering myeloma do not require immediate treatment but must be followed carefully for signs of disease progression." Myeloma is diagnosed when clonal plasma cells are ≥ 10% plus at least one CRAB feature or one of the newer "SLiM" markers.

Bone and calcium. "The interaction between myeloma cells and the bone microenvironment ultimately leads to osteoclast activation and osteoblast suppression, resulting in bone loss." "Myeloma bone disease is thought to result from overexpression of RANKL by bone marrow stroma. RANKL activates osteoclasts, which resorb bone. Bone breakdown leads to calcium release into the blood, leading to hypercalcemia." The lytic lesions "are often described as punched-out, round, radiolucent lesions," and "Bone pain resulting from the osteolytic lesions often results in pathologic fractures and vertebral collapse, reducing height, spinal cord compression, radicular pain, or kyphosis."

Kidney. Small light chains pass the glomerulus: "The concentration of protein in the tubules increases as water is reabsorbed. This leads to precipitation of proteins and the formation of tubular casts, which may injure the tubular cells." StatPearls adds light-chain deposition, amyloidosis, "hypercalcemia, hyperuricemia, or dehydration" as renal mechanisms. Blood. Marrow occupation "usually manifests as anemia, thrombocytopenia, and leukopenia"; anemia "develops likely secondary to bone marrow replacement, or decreased erythropoietin levels."

Infection and thick blood. Infection risk rises from "impaired lymphocyte function, suppression of normal plasma cell function, hypogammaglobulinemia, and chemotherapy-induced neutropenia" — NCI calls this immunoparesis, "the reciprocal depression of the other Ig classes." That excess protein causes "hyperviscosity, platelet dysfunction, and renal tubular damage" — "leading to neurologic derangements, bleeding, and renal failure, respectively."

First, look for what cannot wait. "Initial management of multiple myeloma should include evaluation for acute issues that require immediate stabilization. Some of these may include administration of isotonic saline for volume expansion, calcitonin, and/or bisphosphonates to address severe hypercalcemia." Spinal cord compression "is a medical emergency that should be managed aggressively by neurosurgery or orthopedic consultation and possible radiation therapy," and hyperviscosity "is considered an emergency, and plasmapheresis should be initiated immediately to relieve symptoms promptly."

Then fitness decides the path, not age alone. NCI now divides patients into "patients in good or well-controlled health (previously referred to as the fit, transplant-eligible patient)" and "the less-fit patient with significant comorbidities or advanced age." Fit patients "may receive induction chemotherapy with a four-drug (quadruplet) or three-drug (triplet) approach that includes bortezomib" — most commonly D-VRd (daratumumab, bortezomib, lenalidomide, dexamethasone) or VRd — and CyBorD "is preferred in the presence of significant renal dysfunction." Transplant-eligible patients then have stem cells harvested, an autologous stem cell transplant, and "Maintenance therapy is then implemented until the time of relapse" — though NCI notes routine transplant consolidation "has been questioned" after a trial showed no overall-survival benefit.

Alongside every regimen: "Most patients also receive a bisphosphonate or RANKL inhibitor to prevent skeletal-related complications," and infection prevention "includes vaccination, antimicrobial prophylaxis, and immunoglobulin replacement (in a small subset of patients)." The outlook has transformed — "median survivals now exceeding 10 years" — but "Multiple myeloma is highly treatable but rarely curable."