Nonsecretory myeloma is a topic shrouded in apprehension and mystery.

Patients with nonsecretory myeloma have a host of questions.  How do I track the progress of my disease? Should nonsecretory myeloma be treated differently than “standard” myeloma?  Is my prognosis different because I am nonsecretory?

Among myeloma patients with secretory disease, nonsecretory myeloma is something they often have heard of, but they are not always sure what it is, or whether it is really relevant to them.

Given the many questions and concerns related to nonsecretory myeloma, I thought I would devote my first column here at The Myeloma Beacon to the subject.

Some Basics

Less than 5 percent of all patients with multiple myeloma have nonsecretory myeloma. Their disease cannot be diagnosed or tracked by the presence of monoclonal (M) protein in the blood and urine or immunofixation studies; however, it can be detected in the bone marrow or upon biopsy of bone lesions.

In the past decade, since a blood test called the serum free light chain assay became widely available, it has been noted that about 60 percent of patients who were previously considered to have nonsecretory myeloma produce light chains, which means that they are not truly “nonsecretory”. However, most studies include this group of patients when they refer to patients with nonsecretory myeloma, so for the purpose of this discussion, I will include this group as well.

Patients with nonsecretory myeloma can be divided into two categories:

1. True Nonsecretory (or “Producer”) Myeloma - Patients who have M-protein detectable in malignant plasma cells by special stains; however, the patients do not secrete M-protein.  These patients make up 85 percent of all patients with nonsecretory myeloma
2. Nonproducer Myeloma - Patients who do not have any detectable M-protein even within the malignant plasma cells.  These patients make up 15 percent of all patients with nonsecretory myeloma.

Diagnosis and Follow-up

The absence of proteins in the blood and urine can sometimes delay the diagnosis of myeloma.  So it is important when patients undergo initial workup for bone lesions noted on scans that the possibility of nonsecretory myeloma is considered, even if blood and urine do not show evidence of the disease. Biopsy of bone lesions or the bone marrow will usually lead to a correct diagnosis.

Once a patient has been diagnosed with nonsecretory myeloma, the initial diagnostic evaluations and assessment of response should be tailored specifically for nonsecretory myeloma. Since blood and urine studies are not helpful, we have to rely on bone marrow examination, myeloma survey (X-ray), positron emission tomography (PET), and magnetic resonance imaging (MRI) to evaluate this type of disease.

In patients who have detectable free light chains in the blood, free light chain assays should be used to monitor the disease.

At the University of Arkansas for Medical Sciences (UAMS), we do bone marrow exams, PET, and MRI about once every month or every other month during induction therapy and transplants. The exams are scheduled every three months during the maintenance phase and eventually once a year when the disease has been in remission for more than five years.

Treatment

Patients with nonsecretory multiple myeloma are treated the same way as other patients with multiple myeloma. The first step in the treatment process is to determine if a particular patient is eligible for autologous stem cell transplantation or not.

The decision is based on several factors, including age, activity level of the patient, and condition of heart, lungs, liver, and kidneys. The age threshold for transplants varies across institutions; at our institution, we do transplants in patients of up to 75 years of age.

The initial induction therapy for patients who are eligible for autologous transplantation generally consists of a two- or three-drug combination of the following agents: Velcade ^[1] (bortezomib), thalidomide ^[2] (Thalomid), Revlimid ^[3] (lenalidomide), dexamethasone ^[4] (Decadron), cyclophosphamide ^[5] (Cytoxan), and doxorubicin ^[6] (Adriamycin).

After induction therapy, stem cells are collected using cyclophosphamide and white blood cell growth factors. The autologous stem cell transplant is usually done with melphalan at a dose of 200mg/m².

In the past, the practice was to observe patients after the transplant without the use of maintenance therapy. More recently, several studies have shown the benefits of maintenance therapy with Revlimid, thalidomide, Velcade, and dexamethasone.

In patients who are not eligible for autologous stem cell transplantation, low doses of melphalan can be added to the above mentioned combination therapy options. The reason why low-dose melphalan is not used upfront in patients being considered for autologous stem cell transplantation is that it can impair the ability to collect stem cells.

In addition to the drugs mentioned above, it is important that myeloma patients receive bisphosphonates such as Aredia ^[7] (pamidronate) and Zometa ^[8] (zoledronic acid) to decrease risk of skeletal events such as fractures.

Prognosis

The commonly used prognostic factors for multiple myeloma, such as staging, karyotype analysis, and fluorescence in situ hybridization (FISH) are also applicable to patients with nonsecretory disease. At our institution, we also routinely use a technique called gene expression profiling to determine prognosis and strategize treatment.

Although the nature and presentation of nonsecretory myeloma is different from secretory multiple myeloma, we do not see an overall difference in survival outcomes in this group of patients compared to the other patients with myeloma.  However, it is useful to note that the patients with nonsecretory myeloma are less likely to have myeloma-related kidney damage.

A study from the Center for International Blood and Marrow Transplant Registry (CIBMTR) in patients treated between 1989 to 2003 demonstrated that patients with nonsecretory and secretory myeloma have similar outcomes with average survival time of about five years. I should note, however, that the widespread use of newer drugs such as Velcade, thalidomide, and Revlimid started after the period covered by the CIBMTR study.  Thus, outcomes are likely better in patients who are currently undergoing treatment.

Secretory Myeloma Can Become Nonsecretory

It is important to note that patients who have secretory myeloma at the time of initial diagnosis may sometimes become nonsecretory at the time of relapse.  Imaging techniques, such as PET and MRI, should therefore be considered when tracking response/remission status, even in patients with secretory disease.

Dr. Bijay Nair is an assistant professor of medicine at the University of Arkansas for Medical Sciences Myeloma Institute for Research and Therapy in Little Rock, Arkansas.  His research focuses on developing new treatments for patients with relapsed and refractory myeloma.  Dr. Nair writes a quarterly column for The Myeloma Beacon.