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Spanish Expert Recommends Early Treatment For High-Risk Smoldering Myeloma (IMW 2013)

By: Maike Haehle; Published: April 26, 2013 @ 2:04 pm | Comments Disabled

During a session at the International Myeloma Workshop (IMW) held in Japan earlier this month, Dr. María-Victoria Mateos of the University Hospital in Sala­manca, Spain, discussed whether smoldering multiple myeloma patients should be actively treated.

The current standard of care is to monitor smoldering myeloma [1] patients and to begin treatment only when their disease progresses to sympto­matic multiple myeloma.

However, in Dr. Mateos's opinion, smoldering myeloma patients who are at high risk of progressing to symptomatic myeloma should be offered early treatment.

During the IMW, Dr. Mateos presented updated results from a study she and other Spanish researchers have been conducting, show­ing that Revlimid [2] (lenalidomide) in combination with dexamethasone [3] (Deca­dron) delays disease pro­gres­sion and improves overall survival in high-risk smoldering myeloma patients.

Based on these results and other recent research, Dr. Mateos believe high-risk smoldering myeloma should be called "early multiple myeloma," which leads to the following new treatment paradigm: early treat­ment for early multiple myeloma patients.

Dr. Mateos's recommendation, however, is likely to be viewed as controversial by many myeloma special­ists, as most continue to recommend against active treatment of smoldering myeloma except in cases where a patient is participating in a clinical trial.

Background

Smoldering, or asymptomatic, multiple myeloma is a precursor to multiple myeloma in which the patient experiences none of the symptoms typically associated with active (symptomatic) multiple myeloma (ele­vated calcium levels, kidney failure, anemia, or bone lesions).

Smoldering myeloma is characterized by an excess of monoclonal protein in the blood and urine. A diag­nosis of smoldering multiple myeloma is made when a patient’s monoclonal protein level is at least 30 g/L or the proportion of plasma cells in the bone marrow is at least 10 percent, but the patient does not experience any of the typical myeloma symptoms.

The risk of progression from smoldering myeloma to symptomatic disease is around 10 percent during each of the first five years after diagnosis, and decreases to 3 percent per year for the following five years, and to 1 percent per year thereafter, which means that the median time to progression is about five years.

Although smoldering myeloma patients are at a higher risk of developing active myeloma than the general public, the current standard of care is the so-called “watch and wait” approach, in which smoldering myeloma patients are regularly monitored and treatment only begins once the disease progresses to multiple myeloma.

However, certain factors have been shown to be associated with an increased risk of progression to symp­to­matic disease in patients with smoldering multiple myeloma. These include: a monoclonal protein level exceeding 30 g/L; plasma cells exceeding 10 percent in the bone marrow; an elevated level of abnormal plasma cells in the bone marrow; an abnormal ratio of small parts of antibodies (known as an abnormal free light chain ratio); the presence of chromosomal abnormalities in the plasma cells; and lower-than normal levels of one or more types of immunoglobulin.

Studies at the Mayo Clinic and in Spain have found that patients with several of these risk factors can be considered to have "high risk" smoldering myeloma, meaning that the patients have a higher risk of progressing to symptomatic myeloma than other smoldering myeloma patients.

In a Spanish study, for example, smoldering myeloma patients with several "high risk" disease factors had a median time to progression of about two years.

Previous Research On The Treatment Of Smoldering Myeloma

Dr. Mateos mentioned that several clinical trials during the past 30 years have investigated the effects of melphalan [4] (Alkeran) plus prednisone [5]thalidomide [6] (Thalomid), and/or bisphosphonates in patients with smoldering multiple myeloma. According to Dr. Mateos, none of these trials supported early treatment of smoldering myeloma patients.

For example, an Italian trial [7] in the early 1990s looked at whether early treatment im­proved survival among patients with what, at the time, was known as "Stage I" multiple myeloma.  Most of those patients today would be classified as having smoldering myeloma.

In the trial, half the patients were treated with melphalan and prednisone immediately, while the other half had treatment deferred until they showed signs of disease progression (at which point they, too, were treated with melphalan and prednisone).

Median overall survival in this trial was actually higher for the patients who received deferred treatment (71 months) compared to those who received treatment immediately (64 months).

Dr. Mateos noted during her presentation, however, that these older trials did not distinguish between standard-risk and high-risk smol­dering multiple myeloma patients. She explained that standard-risk smol­dering patients might not benefit from treatment, whereas high-risk patients might.

Current Research In High-Risk Smoldering Myeloma

Due to the possibility that high-risk smoldering myeloma patients might benefit from early treatment, Dr. Mateos and her colleagues initiated a trial that included only high-risk patients.

In the trial, half the 125 patients were randomly selected to receive an initial nine cycles of treatment with Revlimid plus dexamethasone, followed by Revlimid maintenance therapy, while the other half received no treatment until their disease progressed to active myeloma (see related Beacon [8] news).

The updated results of this study continue to show that the high-risk smoldering patients who received treatment im­medi­ately had better outcomes than the patients who did not receive treatment until disease progression.

Time to disease progression is longer for the actively treated patients (not yet reached at a median follow-up time of 40 months, versus 21 months), as is overall survival at five years after diagnosis (94 percent versus 78 percent).

Dr. Mateos added that there are currently numerous trials being carried out in high-risk smoldering myeloma patients that include treatment with approved drugs such as Revlimid and Kyprolis [9] (carfilzomib) as well as investigational treatments such as elotuzumab [10], siltuximab [11], BHQ880 [12], and ixazomib [13] (MLN9708 [14]).

She pointed, in particular, to a Phase 2 trial that is investigating the efficacy and safety of Kyprolis, Revlimid, and dexamethasone in high-risk smoldering myeloma patients. Initial results of the trial, which look very promising, were also presented at the IMW earlier this month. In particular, all patients included in the trial have responded to treatment (see related Beacon [15] news).  Time to progression and overall survival results for this study, however, are not yet available.

For further details of Dr. Mateos's presentation and the study she and her colleagues have been conducting, see the slide deck [16] (PDF) of her IMW presentation, which she has made available as a courtesy to the Beacon's readers.


Article printed from The Myeloma Beacon: https://myelomabeacon.org

URL to article: https://myelomabeacon.org/news/2013/04/26/early-treatment-for-high-risk-smoldering-myeloma-imw-2013/

URLs in this post:

[1] smoldering myeloma: https://myelomabeacon.org/tag/smoldering-multiple-myeloma/

[2] Revlimid: https://myelomabeacon.org/resources/2008/10/15/revlimid/

[3] dexamethasone: https://myelomabeacon.org/resources/2008/10/15/dexamethasone/

[4] melphalan: https://myelomabeacon.org/resources/2008/10/15/melphalan/

[5] prednisone: https://myelomabeacon.org/resources/2008/10/15/prednisone/

[6] thalidomide: https://myelomabeacon.org/resources/2008/10/15/thalomid/

[7] Italian trial: http://www.nature.com/bjc/journal/v82/n7/pdf/6691087a.pdf

[8] Beacon: https://myelomabeacon.org/news/2012/01/09/revlimid-lenalidomide-dexamethasone-combination-delays-disease-progression-in-patients-with-smoldering-multiple-myeloma-ash-2011/

[9] Kyprolis: https://myelomabeacon.org/tag/kyprolis/

[10] elotuzumab: https://myelomabeacon.org/tag/elotuzumab

[11] siltuximab: https://myelomabeacon.org/tag/siltuximab

[12] BHQ880: https://myelomabeacon.org/tag/BHQ880

[13] ixazomib: https://myelomabeacon.org/tag/ixazomib/

[14] MLN9708: https://myelomabeacon.org/tag/mln9708/

[15] Beacon: https://myelomabeacon.org/news/2013/04/09/kyprolis-revlimid-dexamethasone-high-risk-smoldering-myeloma-imw-2013/

[16] slide deck: https://myelomabeacon.org/docs/imw2013/slides/Mateos-ShouldWeTreatSmolderingMyeloma.pdf

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