Hypercalcemia and Multiple Myeloma

Today's morning report case was very interesting and tied together a number of diagnostic and management entities seen commonly on our wards.

The case featured a 72-year-old man who was brought into hospital for polyuria for around one week’s duration.  Upon further questioning, the polyuria preceded polydipsia, and he had an unquantified amount of weight loss, some bony pains, and alterations in mental status/confusion.  His physical examination was remarkable for volume contraction, but an absence of lymphadenopathy or any signs of endocrinopathy.  His initial bloodwork showd a mild macrocytic anemia, leukocytosis with a lymphocytosis, significant acute renal injury with a creatinine of 180umol/L, and profound hypercalcemia of 4.01mmol/L corrected.  His serum phosphate was elevated at 1.6mmol/L. Chest X-ray demonstrated rib fractures.  Based on the suspicion of a clonal plasma cell disorder, a serum and urine protein electrophoresis was sent, which yielded negative results.  A serum free light chain assay was then sent which showed an abnormal ratio.  The patient’s peripheral blood was sent for flow cytometry which showed a clonal population of T-cells consistent with HTLV-1-mediated adult t-cell leukemia-lymphoma.  Because the T-cell population wouldn’t explain the free light chains (but may explain the hypercalcemia), he may have both a plasma cell disorder and a t-cell disorder.

Despite the seemingly complex nature of the case, there were multiple learning points:

-One of our trainees pointed out correctly that, in a patient with multiple “non-specific” findings that do not seem to relate to a single organ, a systemic process should be suspected.  These often include endocrinopathies (thyroid disease, adrenal disease), hypercalcemia, and renal failure.

-Hypercalcemia has a wide differential diagnosis.  The first step is to differentiate whether the process is PTH-dependent or not, which can be done by ordering a serum intact PTH level.  If the PTH is elevated (or even normal) in the presence of hypercalcemia, that is inappropriate and suggest a PTH-mediated process like primary hyperparathyroidism (adenoma, MEN syndromes, etc) or familial hypocalciuric hypercalcemia (FHH).  If the PTH is low (suppressed appropriately) then the process can either be malignant, related to granulomatous disease (through excessive 1-a-hydroxylase activity and hypervitaminosis D), or related to exogenous Vitamin D overdose.  In the malignant realm, it is helpful to differentiate between causes related to solid tumours (direct bone destruction or humoural effects such as PTH-related peptide secretion) and hematologic malignancies (direct bone involvement as in multiple myeloma, or humoural effects due to 1-a-hydroxylase activity in lymphoma cells).

-Hypercalcemia produces high urinary losses through multiple mechanisms.  The least significant is osmotic, but it also affects the NKCC channels producing a “Lasix-like” effect and produces a nephrogenic Diabetes Insipidus which may lead to hypovolemia and dehydration.

-The treatment of hypercalcemia involves fluids.  Resuscitation fluids like normal saline will act to expand plasma, diluting the calcium.  They will also increase renal calcium delivery, and distal tubular sodium delivery allowing it to be exchanged with calcium.  Diuretics should only be given if patients are volume overloaded and it will allow increased fluid delivery.

-Multiple Myeloma exists in a continuum of diagnoses of clonal plasma cell disorders.  Secretory B-cell clones produce immunoglobulins which may lead to a clonal “spike” on a serum protein electrophoresis.  This “M-spike” can be quantified.  The clinical consequences of myeloma are the CRAB features (hypercalcemia, renal failure, anemia, and bony lytic lesions).  A clonal spike associated with CRAB features is diagnostic of multiple myeloma.  A clonal spike without CRAB features is either MGUS (Monoclonal Gammopathy of undetermined significance) or Smoldering Multiple Myeloma depending on whether there is more than 30g/L M-protein and whether there is more than 10% clonal plasma cells in the bone marrow.  The clinical significance of this is the annual rate of progression to multiple myeloma.  The newest myeloma definitions state that, whether CRAB is present or not, greater than 60% marrow infiltrated with plasma cells is a “myeloma defining event.”  Keep in mind that not all myeloma is secretory meaning that there may be no SPEP.  Also, the quantities of the M-spike may be insufficient, in which case a serum free light chain ratio can be helpful in detecting a clonal B-cell disorder.  Finally, AL amyloidosis does not necessary indicate multiple myeloma per se.

Further reading:

Neely, S. M. (1989). Adult T-cell leukemia-lymphoma. Western Journal of Medicine, 150(5), 557.

Rajkumar, S. V., Dimopoulos, M. A., Palumbo, A., Blade, J., Merlini, G., Mateos, M. V., ... & San Miguel, J. F. (2014). International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. The Lancet Oncology, 15(12), e538-e548.

Stewart, A. F. (2005). Hypercalcemia associated with cancer. New England Journal of Medicine, 352(4), 373-379.

Marcocci, C., & Cetani, F. (2011). Primary hyperparathyroidism. New England Journal of Medicine, 365(25), 2389-2397.

Taylor, G. P., & Matsuoka, M. (2005). Natural history of adult T-cell leukemia/lymphoma and approaches to therapy. Oncogene, 24(39), 6047-6057.