How Triple-Refractory Multiple Myeloma Is Diagnosed

If you have triple-refractory multiple myeloma (TRMM), you likely have had multiple myeloma for some time and have completed several different treatment regimens unsuccessfully.

TRMM is multiple myeloma that does not respond to any of the three classes of drugs used to treat multiple myeloma, which are:

• Immunomodulatory drugs: Such as Revlimid (lenalidomide) or Pomalyst (pomalidomide)
• Proteasome inhibitor: Such as Velcade (bortezomib) or Kyprolis (carfilzomib)
• Monoclonal antibody: Such as anti-CD38

This article discusses how triple-refractory multiple myeloma is diagnosed.

Physical Examination

The classic clinical presentation of multiple myeloma commonly involves an older adult—usually about 50 or 60 years old—who reports symptoms of unexplained bone or back pain and fatigue for two or more weeks that don’t resolve with conventional treatments.

Monoclonal myeloma cells overproduce a protein called an M protein, referred to as an M-spike. The overproduction can produce monoclonal antibodies, such as immunoglobulin (Ig) G (IgG), IgM, or IgA (and rarely IgE or IgD). However, overproduction of monoclonal antibodies can occur, such as in the overproduction of monoclonal light chains. Light chains are a component of antibodies and exist as kappa or lambda light chains.

Together these proteins can cause end-organ damage. The monoclonal proteins can increase the viscosity (thickness) of the blood, which can reduce blood flow to organs. For instance, the light chains can deposit in organs, mainly the kidney, resulting in end-stage renal disease.

In addition, there is increased osteoclastic (bone-breakdown) activity and decreased osteoblastic (bone-forming) activity in multiple myeloma, leading to invasive osteolytic lesions.

Your healthcare provider will therefore perform a focused physical exam and ask about your symptoms of bone pain and fatigue, and looking for signs of:

• Anemia (low red blood cell count)
• Recurrent infections (the repeated invasion and growth of germs in the body)
• Fractures (broken bones)
• Osteoporosis (weak and brittle bones)
• Hypercalcemia (high calcium levels in the blood)

Labs and Tests

Sometimes a diagnosis of multiple myeloma is made incidentally, after taking a blood test for another condition. Usually, though, the diagnosis of multiple myeloma is made using a combination of findings from laboratory tests, imaging scans, and a biopsy (the removal of a tissue sample for analysis in a lab).

Complete Blood Cell Count

Myeloma cells can crowd out healthy cells in the bone marrow, leading to decreases in plasma and red and white blood cells.

A complete blood cell count (CBC), a fast and relatively inexpensive blood test, can help detect changes in the body that may account for your signs of anemia (like fatigue and pallor) or frequent infections.

Chemistry Panel

Multiple myeloma symptoms are usually non-localizing (not restricted to a specific area) and nonspecific.

Symptoms of fatigue, weakness, and weight loss are usually explained by a condition other than multiple myeloma.

A chemistry panel—which looks at 14 substances involved with metabolism and chemical balance—can look for electrolyte deficiencies that may explain your symptoms.

Vitamin D, parathyroid, and thyroid hormone levels, albeit not officially a part of the chemistry panel, are often checked at the same time because aberrations (atypical changes) can throw off your electrolyte levels or help to explain the cause of your symptoms.

Urine Analysis

Your kidneys are the primary organ impacted by the abnormal rapid growth of monoclonal proteins from myeloma cells.

Bence Jones proteins, an accumulation of abnormal light chain proteins that are too big to pass through the filtration system of the kidneys (the glomeruli), can clog and damage the kidneys.

A urine analysis is a relatively inexpensive and quick test to check the function of the kidneys. A 24-hour urine test can check for Bence Jones proteins.

Serum and Urine Protein Electrophoresis

Serum protein electrophoresis (SPEP) is a test that can detect spikes in M proteins (monoclonal gammopathy), indicating high levels of heavy chain monoclonal protein. This may be indicative of multiple myeloma in the presence of underlying symptoms.

Serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) are commonly used tests for the detection of monoclonal proteins because of their availability and low cost.

The SPEP is used to identify a buildup of excess light chain proteins.

The UPEP is often used to detect the presence of Bence Jones proteins.

Of note, spikes in M proteins are common in cases of multiple myeloma but cannot be used alone to diagnose TRMM. If you have symptoms that raise suspicion of multiple myeloma, the diagnosis should still be looked into even in the absence of M spikes on SPEP or UPEP. 

Biopsy

Bone marrow biopsy and aspiration (taking a sample of the liquid part of bone marrow for lab analysis) is usually performed in people with abnormal serum or urine protein levels on electrophoresis. 

Imaging

Studies have shown that up to 80% of all multiple myeloma cases involve the bone so an X-ray or magnetic resonance imaging (MRI) is usually performed whether you have symptoms of bone pain or not.

A skeletal survey—a series of X-rays that analyze the bones of the entire body—including the hips, spine, ribs, and extremities—is generally recommended if it is available.

An echocardiogram may also be used to assess the function of the heart and visualize signs of amyloidosis, a condition in which abnormal proteins cause the heart muscle to stiffen and pump blood inefficiently. 

Self-Checks/At-Home Testing

Currently, there are no home self-checks or home testing for triple refractory multiple myeloma.

If you are experiencing persistent fatigue, weakness, or bone pain that does not resolve with over-the-counter (OTC) medications and rest, you should seek immediate medical attention from a healthcare provider. 

Differential Diagnosis

The symptoms of triple refractory multiple myeloma are usually nonspecific and can be explained by a number of conditions.

Checking your labs—blood cell counts, vitamin levels, inflammatory markers, hormone levels, and serum and urine protein levels—can rule out other conditions.

The following conditions may be considered if you have a suspicion of multiple myeloma:

• Vitamin D deficiency
• Hyperparathyroidism (overactive parathyroid glands)
• Polymyalgia rheumatica (inflammatory disorder causing muscle pain and stiffness)
• Bone metastasis (cancer that spreads to the bone)
• Monoclonal gammopathy of undetermined significance (MGUS) (an abnormal protein in the blood)
• Plasma cell disorders such as solitary plasmacytoma or smoldering myeloma
• Waldenström macroglobulinemia (rare blood cancer with an abnormally large amount of white blood cells in bone marrow)
• Amyloid light chain (ALC) amyloidosis that is not due to multiple myeloma
• Osteosclerotic myeloma, also known as POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes syndrome) (a rare blood disorder that damages nerves)
• B-cell non-Hodgkin's lymphoma (common type of cancer of the lymphatic system)
• Plasma cell leukemia (rare and aggressive form of cancer of the bone marrow)
  

Summary

The diagnosis of triple-refractory multiple myeloma (TRMM) is made after using three or more multiple myeloma treatments unsuccessfully. Multiple myeloma is diagnosed using a combination of laboratory, imaging, and biopsy findings.

A Word From Verywell

Triple-refractory multiple myeloma poses unique challenges because there must be a delicate balance in diagnosis between starting aggressive treatment and finding novel (new) agents that are most effective at treating it. New approaches that encourage immune cells called T cells to help fight cancer, like CAR T-cell therapy, offer hope in improving outcomes for those with TRMM.