Treatment of Stage I & "Smoldering" Multiple Myeloma

Monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma, and stage I multiple myeloma.

Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor updated 3/2019

Stage I multiple myeloma occurs when there is a relatively small amount of cancer in the body.

The major decisions concerning treatment of stage I multiple myeloma are if and when treatment should be initiated. It may be useful to think of monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma, and stage I multiple myeloma as a continuation or gradual progression of multiple myeloma. Patients with these conditions may not require immediate treatment, as these conditions may persist and be stable for several years. Patients should however be followed at regular intervals by their physician in order to detect clinical signs or symptoms that indicate myeloma progression.(1)

Signs of progression and common reasons for initial treatment of myeloma include the following:

  • A steady increase in the amount of serum or urine monoclonal or M-protein.
  • Development of bone lesions.
  • Worsening kidney function.
  • Anemia
  • Hypercalcemia

What is MGUS?

Monoclonal gammopathy of undetermined significance (MGUS) is a precancerous disorder of plasma cells (a type of white blood cell that produces antibodies). In patients with MGUS, abnormal plasma cells in the bone marrow produce a specific protein that can be detected in blood or urine. MGUS is thought to be a precursor to multiple myeloma and other malignancies of the blood.

It is estimated that ~ 3.2% of persons 50 years of age or older have MGUS but only a subset of these individuals will develop myeloma. Among patients with MGUS, the risk of developing myeloma or another blood-related cancer is approximately 1% per year.(2)

  • Rates of MGUS increase with age. MGUS was identified in 5.3% of subjects 70 years of age or older and in 7.5% of subjects 85 years of age or older.
  • The chance of progression to multiple myeloma or other related disorders was approximately 1% per year, 12% at 10 years, 25% at 20 years and 30% at 25 years. It is important to keep in mind that the majority of patients with MGUS are elderly and are ultimately more likely to die from causes not related to their disease.(3)

Smoldering Myeloma

Smoldering myeloma is considered to be a pre-cancerous condition, in which patients do not yet display any symptoms of multiple myeloma, but are at a high risk of progressing to multiple myeloma. The criteria for smoldering myeloma are:

  • Serum monoclonal protein level of 3 grams per deciliter or more
  • Proportion of plasma cells in the bone marrow of 10% or more.
  • No other end-organ damage. End-organ damage that can result from plasma-cell proliferation includes high calcium levels, kidney problems, anemia, bone changes, and repeated bacterial infections.

To describe the clinical course and prognosis of individuals with smoldering multiple myeloma, researchers at the Mayo Clinic evaluated the medical records of patients who had been diagnosed between 1970 and 1995.

  • Overall, the probability of progressing to active multiple myeloma or amyloidosis was 51% after five years, 66% after 10 years, and 73% after 15 years.
    • Among patients with a high proportion of bone marrow plasma cells (10% or higher) and high serum monoclonal protein (3 grams per deciliter or higher), the 15-year risk of developing active multiple myeloma or amyloidosis was 87%.
    • Among patients with a high proportion of bone marrow plasma cells (10% or higher) and lower serum monoclonal protein (less than 3 grams per deciliter), the 15-year risk of developing active multiple myeloma or amyloidosis was 70%.
    • Among patients with a low proportion of bone marrow plasma cells (less than 10%) and high serum monoclonal protein (3 grams per deciliter or higher), the 15-year risk of developing active multiple myeloma or amyloidosis was 39%.

The researchers conclude that the risk of progressing from smoldering to active multiple myeloma varies with the proportion of bone marrow plasma cells and the serum monoclonal protein level at diagnosis.(4)

Early Treatment in Smoldering Myeloma Improves Long-Term Outcomes

The standard treatment approach for smoldering myeloma has been observation, whereby patients were monitored through tests and the presence of symptoms to determine whether their condition had actually progressed to multiple myeloma. If so, patients could then begin treatment.(5)

With the advent of newer medications that result in fewer side effects researchers have begun evaluating the long-term outcomes of patients being treated during their smoldering myeloma phase. Specifically, researchers are exploring whether early treatment can reduce or delay the progression from smoldering myeloma to multiple.

Researchers recently provided an update on the long-term outcomes from a phase III clinical trial directly comparing treatment consisting of Revlimid/dexamethasone to no treatment among patients with smoldering myeloma who were at a high risk of developing multiple myeloma (QuickRedex Study).(6,7)

The trial included 125 patients with smoldering myeloma; one group was treated with Revlimid/dexamethasone and the second group underwent observation. The median follow-up for surviving patients was 75 months.

  • The median time to progression to myeloma had not yet been reached in the group of patients treated with Revlimid/dexamethasone
  • The median time to progression to myeloma was 23 months for patients undergoing observation.
  • Progression to multiple myeloma occurred in 39% of patients treated with Revlimid/dexamethasone, compared with 86% of patients undergoing observation.
  • At 6 years of follow-up, 86% of patients treated with Revlimid/dexamethasone are alive, compared with 62% of patients undergoing observation only.
  • Early treatment with Revlimid/dexamethasone did not appear to create resistance to subsequent treatments

The researchers concluded that these appear to support the use of early treatment for patients with high-risk disease in the near future.”

Darzalex - Effective Treatment for Smoldering Multiple Myeloma

Researchers have also conducted a clinical trial to evaluate the potential effectiveness of Darzalex (daratumumab) in the treatment of smoldering myeloma. The trial included 123 patients with smoldering myeloma considered to be at intermediate or high risk of transforming to active multiple myeloma.(8)

Patients were treated with either a long, medium, or short dosing schedule of Darzalex and directly compared.

  • Overall response rates to treatment were greatest in the group treated with the long-dosing schedule and although the data are not yet mature, it is estimated that at 12 months following initiation of treatment 98% of patients treated with the long-dosing schedule will be alive without progression of their disease, compared with 93% for those treated with the intermediate-dosing schedule; and 89% for those treated with the low-dosing schedule.

A larger clinical trial to further evaluate the use of Darzalex in smoldering MM to explore its effectiveness in delaying the time to progression to active MM.

For a general discussion of the treatment options that exist for patients experiencing myeloma progression, proceed to the Treatment Overview of Stage II-III Multiple Myeloma.

References:

  1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Multiple Myeloma. V.1.2008. © National Comprehensive Cancer Network, Inc. 2005/2006. NCCN and NATIONAL COMPREHENSIVE CANCER NETWORK are registered trademarks of National Comprehensive Cancer Network, Inc.
  2. Reference: Kyle RA, Therneau TM, Rajkumar SV et al. Prevalence of Monoclonal Gammopathy of Undetermined Significance. New England Journal of Medicine . 2006;354:1362-9.
  3. New England Journal of Medicine, Vol 346, No 8, pp 564-569, 2002.
  4. Kyle RA, Remstein ED, Therneau EM et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. New England Journal of Medicine. 2007;356:2582-90.
  5. Mateos M, Hernandez M, Giraldo P, et al. Sustained Overall Survival Benefit with lenslidomide Plus Dexamethasone Versus No Treatment in Patients with Smoldering Myeloma at High Risk of Progression to Myeloma: Long Term Analysis. Proceedings from the 2016 annual meeting of the American Society of Hematology. Abstract #3308.
  6. Mateos M, Hernandez M, Giraldo P, et al. lenalidomide plus Dexamethasome in Patients with High-Risk Smouldering Multiple Myeloma (QuiRedex): long-term follow-up of a randomized, controlled phase 3 clinical trial.
  7. The Lancet Oncology. DOI: [http://dx.doi.org/10.1016/S1470-2045(16)30124-3](http://dx.doi.org/10.1016/S1470-2045(16%2930124-3). Available at:: [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30124-3/abstract](http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16%2930124-3/abstract). Accessed January 31, 2017.
  8. Hofmeister C, Chari A, Cohen Y, et al. Daratumumab monotherapy for patients with intermediate or high-risk smoldering multiple myeloma (SMM): Centaurus, a randomized, open-label multicenter phase 2 study. Proceedings from the 59th annual meeting of the American Society of Hematology. Abstract #510. Retrieved from
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