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As a precursor disease of multiple myeloma, smoke-emitting multiple myeloma may progress to symptomatic multiple myeloma, and this article introduces the diagnosis and treatment of smoke-emitting multiple myeloma.
I. Definition of smoke-emitting multiple myeloma
Multiple myeloma (MM) is a malignant plasma cell tumor whose precursors are monoclonal gamma globulin disease (MGUS) of unknown significance and smoldering multiple myeloma (SMM).
Smoke-emitting multiple myeloma, which is somewhere between MGUS and MM, is a multiple myeloma that meets the diagnostic criteria for multiple myeloma but progresses slowly and has no clinical symptoms, also known as asymptomatic multiple myeloma. As early as 1980, Kyle and Gripp, who found cases of the disease, based on the characteristics of the disease, described it as "smoke-emitting type".
Smoke-emitting multiple myeloma accounts for 8% to 14% of multiple myeloma, and the median age of onset of patients is 67 years old, with an annual incidence of 0.4 cases per 100,000 people.
The vast majority of patients with smoking multiple myeloma eventually progress to symptomatic multiple myeloma, a highly heterogeneous disease with varying clinical processes, with a probability of progressing to multiple myeloma each year within 5 to 10 years after diagnosis, and a reduced risk of progression to about 1% after 10 years.
Second, the diagnostic criteria for smoke-emitting multiple myeloma
Combining the guidelines of the National Comprehensive Cancer Network (NCCN) and the International Myeloma Task Force (IMWG), the diagnostic criteria for smoke-emitting multiple myeloma are as follows:
1. Serum M protein (IgG or IgA) > 3 g/dL, or urine M protein > 500mg/24 hours
2. The proportion of bone marrow monoclonal plasma cells ≧ 10% and
3. There is no damage to related organs and tissues, such as terminal organ damage (CRAB) or other malignant biomarkers (SLiM-) or amyloidosis
CRAB: serum calcium above the upper limit of normal> 1 mg/dL or > 11 mg/dL; renal insufficiency: serum creatinine > 2 mg/dL or creatinine clearance 2 g/dL or
SLiM: bone marrow monoclonal plasma cells ≥60%; serum affected/non-affected free light chain ratio >100; MRI shows > focal bone destruction above 5 mm.
3. Stratification of smoke-emitting multiple myeloma
There is still a lack of an ideal risk stratification system, which divides patients into three stages according to the three risk factors of disease progression: low-risk (no risk factor), medium risk (1 risk factor), and high-risk (≥ 2 risk factors), with a 2-year progression risk of 9.7%, 26.3%, and 47.4%, respectively.
Fourth, the treatment of smoke-emitting multiple myeloma
Because smoke-emitting multiple myeloma is not accompanied by organ dysfunction and there are few drugs used to treat multiple myeloma, treatment was previously considered unnecessary, and the standard model is observation and monitoring every 3 to 6 months until symptoms appear after disease progression.
Recent advances in research on the disease suggest that regular follow-up observation is still recommended for medium- and low-risk patients, which helps doctors grasp disease changes and, if progression occurs, patients can be treated in a timely manner. For high-risk patients, due to the easy progression to multiple myeloma, early intervention is advocated in the clinic, and the current drug intervention is still in the clinical trial stage.
(1) Clinical trial 1:
The first large-scale Phase 3 trial for early treatment of smoke-emitting multiple myeloma was conducted in Spain, with the trial group receiving 9-week induction therapy with dexamethasone plus lenalidomide followed by maintenance therapy for 2 years or until disease progression, while the control group received no treatment until disease progression.
The results showed that the median to disease progression time in the treatment group was not reached, and the median to disease progression time in the untreated group was 21 months. 23% of patients in the treated and untreated groups progressed to symptomatic multiple myeloma in the treatment group and 76% of patients, respectively. During induction therapy, 79% of patients achieved partial or better response, including 7% of remissions in the strict sense, 7% of complete responses, and 11% of very good partial responses. The 3-year and 5-year survival rates were 98% and 94% in the treatment group and 80% and 78% in the untreated group, respectively.
Overall, the trial showed that early intervention in patients with high-risk smoke-emitting multiple myeloma in the lenalidomide plus dexamethasone regimen significantly delayed progression to symptomatic multiple myeloma and enabled oss to benefit from such patients.
(2) Clinical trial 2:
A recent open-label, Phase III clinical trial (E3A06) evaluated the efficacy of oral lenalidomide monotherapy in patients with smoke-emitting multiple myeloma.
Results showed that 50% of patients receiving oral lenalidomide achieved partial or better response, with a median to 5-month response time and no response in the untreated group. At the same time, the progression-free survival of the treatment group was significantly higher than that of the untreated group, and the cumulative incidence of disease progression after 3 years was significantly lower than that of the untreated group.
Overall, oral lenalidomide therapy in patients with smokey multiple myeloma can significantly delay disease progression.
(3) Clinical trial 3:
A Phase II study evaluated the efficacy of a combination of carfizomib, lenalidomide, and dexamethasone (CRd) in patients with smoke-emitting multiple myeloma.
The results showed that after 2 cycles of treatment with this regimen, all 12 patients participating in the study achieved partial remission, of which 6 patients achieved very good partial remission. In addition to this, in terms of safety, the combined regimen also has a good safety profile, and the common adverse reactions are gastrointestinal diseases and lymphopenia with hypopulmonary function.
V. Follow-up of smoke-emitting multiple myeloma
Monitoring of patients with smoke-emitting multiple myeloma should be performed every 2-3 months after initial diagnosis for 6-12 months. The relevant indicators mainly include: blood creatinine, albumin, lactate dehydrogenase, serum calcium, β2 microglobulin, serum immunoglobulin quantification, serum protein electrophoresis and hemoimmobilization electrophoresis, 24 h total urine protein, urine protein electrophoresis and urine immunosetting electrophoresis. In addition, serum FLC is helpful in judging disease progression; bone tests can be done once a year or when clinical symptoms are present.
If follow-up monitoring is stable, follow-up may be done every 4-6 months for another year and every 6-12 months thereafter. In addition, individualized follow-up should be performed based on the patient's risk of progression.
6. Summary
With regard to smoke-emitting multiple myeloma, while following up and monitoring low- and intermediate-risk patients, the focus is on identifying high-risk patients who require early therapeutic intervention. A variety of clinical trials are also underway to control the disease and delay its progression.