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Distinguishing between amyloidosis and myeloma is crucial due to significant differences in patient outcomes and treatment responses. Patients with amyloidosis may not have active myeloma but can suffer severe end-organ damage in the heart, nerves, and kidneys. Treatment responses vary between amyloidosis and myeloma, necessitating careful selection of medications to avoid organ toxicity. Early differentiation is vital for appropriate prognostic and diagnostic considerations.