I. Definition
MM is a malignant proliferative disease of plasma cells in which clonal plasma cells in the bone marrow proliferate abnormally and secrete monoclonal immunoglobulins or their fragments (M proteins) and cause associated organ or tissue damage (ROTI). Common clinical manifestations are bone pain, anemia, renal insufficiency, and infection.
II. Clinical manifestations
The most common symptoms of MM are those associated with anemia, renal insufficiency, infection or bone destruction.
1, skeletal symptoms: bone pain, local masses, pathological fractures, and may be combined with paraplegia.
2, immune deficiency: recurrent fine shade pneumonia and/or urinary tract infection, sepsis; viral infection with herpes zoster is common.
3, anemia: orthocytic orthochromic anemia; a few combined with leukopenia and/or thrombocytopenia.
4, hypercalcemia: vomiting, weakness, confusion, polyuria or constipation.
5, renal impairment: light chain tubular nephropathy is the most common cause of renal failure.
6, hyperviscosity syndrome: there may be dizziness, vertigo, blurred vision, tinnitus, and may be sudden onset of impaired consciousness, finger numbness, insufficient coronary blood supply, chronic heart failure and other symptoms. In addition, the M component of some patients is cold globulin, which causes microcirculatory disorders and Raynaud’s phenomenon.
7. Others: Those with amyloidosis lesions may show tongue hypertrophy, parotid enlargement, heart enlargement, diarrhea or constipation, liver, spleen enlargement and peripheral neuropathy; advanced patients may also have bleeding tendency.
III. Diagnostic criteria, typology, staging and differential diagnosis
(I) Diagnosis
1.Diagnostic criteria
Main criteria
(1) Tissue biopsy proves the presence of plasmacytoma or bone marrow smear examination: plasma cells >0.30, often accompanied by morphological changes.
(2) monoclonal immunoglobulin (M protein): IgG>35 g/L, IgA>20 g/L, IgM>15 g/L, IgD>2 g/L, IgE>2 g/L, monoclonal K or into light chain>1 g/24 h in urine, and exclude amyloidosis.
Secondary criteria.
(1) Bone marrow examination: plasma cells 0.10-0.30.
(2) Presence of monoclonal immunoglobulin or its fragments, but below the above criteria.
(3) Osteolytic damage and/or extensive osteoporosis on x-ray.
(4) Decreased amount of normal immunoglobulins: IgM < 0.5 g/L, XgA < 1.0 g/L, IgG < 6.0 g/L.
MM can be diagnosed when any of the following conditions are met.
Primary criteria (1) + (2).
or one of the main criteria (1) + secondary criteria (2), (3), (4).
or one of the main criteria (2) + secondary criteria (1), (3), (4)
or secondary criteria (1), (2) + one of the secondary criteria (3), (4).
2. Minimum diagnostic criteria (2 of the following are met).
(1) bone marrow malignant plasma cells ≥0.10 or although <0.10, confirmed clonal and/or biopsy for plasmacytoma and the presence of monoclonal M protein in serum and/or urine; if no M protein is detected, bone marrow malignant plasma cells t>0.30 and/or biopsy for plasmacytoma are required.
(2) Myeloma-associated impairment of organ function (at least 1), and other types of end-organ damage may occasionally occur and require treatment. If these organ damages are confirmed to be related to myeloma, they can also be used for the diagnosis of myeloma.
3. Diagnostic criteria for symptomatic MM.
(1) Meeting the diagnostic criteria for MM.
(2) The presence of any ROTI.
4. Diagnostic criteria for asymptomatic MM.
(1) Meet the diagnostic criteria of MM.
(2) no signs and symptoms of R0 smash.
(II) Typing
According to the increased abnormal immunoglobulin type can be divided into the following 8 types: IgG type, IgA type, IgD type, IgM type, IgG type, light chain type, biclonal type and non-secretory type. According to the light chain type, it is divided into K and entry type.
(C) Staging
Durie-Salmon staging system and international staging system (ISS) (IV) Differential diagnosis
Differentiate from the following conditions: reactive plasmacytosis (RP), primary macroglobulinemia (WM) and osteolytic lesions of metastatic carcinoma, and other diseases in which M protein can be present, such as monoclonal gammopathy of undetermined significance (MGUS), light chain amyloidosis, isolated plasmacytoma (bone or extramedullary), non-Hodgkin’s lymphoma, and chronic lymphocytic leukemia.
1, RP.
(1) Presence of primary disease: such as chronic inflammation, typhoid fever, systemic lupus erythematosus, cirrhosis, metastatic carcinoma, etc.
(2) Plasma cells ≤ 0.30 and no morphological abnormalities.
(3) Immunophenotype: reactive plasma cells have an immunophenotype of CD Ang cD V, whereas MM are CD38+CD56+.
(4) M protein identification: no monoclonal immunoglobulin or its fragments.
(5) Cytochemical staining: plasma cell acid phosphatase as well as 5’nucleotidase reactions were mostly negative or weakly positive, while all MM patients were positive.
(6) negative for clonal rearrangement of lgH gene.
2.WM.
(1) monoclonal increase of IgM type immunoglobulins in blood, with normal or mildly suppressed other immunoglobulins.
(2) Imaging: osteoporosis is less commonly seen on X-ray, and osteolytic lesions are extremely rare.
(3) Plasma cell morphology: lymphocytes and plasma cell-like lymphocytes are prevalent in the bone marrow. Biopsies of lymph nodes, liver and spleen suggest diffuse well-differentiated or plasma-like lymphocytic lymphoma.
(4) Immunophenotype: mostly IgM+, IgD-, CD19+, CD20+, CD22+, CD5-, CD10- and CD23-.
3.Osteolytic lesions of metastatic carcinoma.
(1) Bone pain is obvious at rest and at night.
(2) Serum alkaline phosphatase is often elevated.
(3) Osteogenic manifestations are mostly accompanied by increased bone density around the osteolytic defect.
(4) Bone marrow smear or biopsy reveals piles of cancer cells.
(5) Most patients can find the primary foci, but some patients can not find the primary foci.
4. Diagnostic criteria for monoclonal gammopathy of undetermined significance (MGUS) (3 of the following are met).
(1) M protein <30 g/L in blood.
(2) Bone marrow clonal plasma cells <0.10.
(3) No ROTI, no other B-cell proliferative disorders or light chain-associated amyloidosis or other light chain, heavy chain or immunoglobulin-associated tissue damage.
5. Diagnostic criteria for isolated plasmacytoma (bone or extramedullary) (meeting 3 of the following).
(1) Biopsy-confirmed monoclonal plasmacytoma at a single site, with no positive findings on x-ray, MRI and/or fluorodeoxyglucose positron emission tomography (FDGPET) except for the primary site, and low serum and/or urine M protein levels.
(2) Normal plasma cell count on multi-site bone marrow aspiration smear or bone biopsy, with no evidence of clonal proliferation in the specimen by flow cytometry or PCR.
(3) No myeloma-related organ function impairment, etc.
IV. Criteria for judging efficacy
V. Treatment
(A) Treatment principles
1. Patients with asymptomatic myeloma or Durie-Salmon stage I can be observed and reviewed once every 3 months.
2. Patients with symptomatic MM or asymptomatic myeloma who have developed myeloma-related sexual organ failure should be treated early.
3.Those who are ≤65 years old and suitable for autologous stem cell transplantation should avoid alkylating agents and nitrosoureas.
4. Those who are suitable for clinical trials should be considered for entry into clinical trials.
(B) Treatment of patients with symptomatic MM or DulJe-Salmon stage II or above (see Annex 2 for chemotherapy regimen)
1. Induction therapy: serum immunoglobulin quantification and M protein quantification, blood cell count, BUN, creatinine, blood calcium, bone marrow aspiration (if clinically necessary, bone marrow biopsy can be repeated) are reviewed once a month during induction therapy; serum free light chain testing is recommended (if no new site of bone pain occurs or the degree of bone pain worsens, x-ray skeletal photos, MPI, PET/CT can be reviewed for more than six months). The general chemotherapy regimen is required to evaluate the efficacy of the disease at 3-4 courses (including new drug regimen can be earlier), and when the efficacy reaches micro-remission (MR) or above (those who do not reach MR or above are considered as primary drug resistance or no change, and need to change the treatment regimen) the original regimen can be used to continue the treatment until the disease turns into plateau stage.
Those aged ≤ 65 years or suitable for autologous stem cell transplantation: Stem cell mobilization collection can be performed for those who can choose one of the following regimens for induction therapy for 4 courses, or for those who have achieved partial remission (PR) and better outcomes for less than 4 courses. Anticoagulation therapy may be used prophylactically in high-risk patients. Specific protocols.
(1) VAD ±T (vincristine + adriamycin + dexamethasone ± thalidomide).
(2) TD (thalidomide + dexamethasone).
(3) BD (bortezomib + dexamethasone).
(4) PAD (bortezomib + adriamycin + dexamethasone).
(5) DVD (liposomal adriamycin + vincristine + dexamethasone).
(6) BTD (bortezomib + thalidomide + dexamethasone).
Age >65 years or not suitable for autologous stem cell transplantation, and blood creatinine ≥176 μmol/L: one of the following regimens can be chosen until PR or above is achieved. Specific regimens.
(1) VAD (adriamycin + dexamethasone ± vincristine).
(2) TD (thalidomide + dexamethasone).
(3) PAD (bortezomib + adriamycin + dexamethasone).
(4) DVD (liposomal adriamycin + vincristine + dexamethasone).
Age >65 years or not suitable for autologous stem cell transplantation, blood creatinine ≤176μmol/L: In addition to the above regimens, one of the following regimens can be chosen until PR or above is achieved.
Specific regimens.
(1) MP (melphalan + prednisone).
(2) M2 (cyclophosphamide + vincristine + carmustine + melphalan + prednisone).
(3) MPV (melphalan + prednisone + bortezomib).
(4) MPT (melphalan + diphenhydramine + thalidomide).
2. Treatment of primary drug-resistant MM.
(1) switch to a new regimen that has not been used, and if PR or above can be obtained, autologous stem cell transplantation will be performed as soon as possible if conditions are suitable.
(2) Those who are eligible for clinical trials, enter clinical trials.
3.Treatment of MM relapse.
Relapse after chemotherapy.
(1) relapse within six months after remission, switch to a new regimen not previously used.
(2) Relapse more than six months after remission, the original regimen for induction of remission can be tried; if it is ineffective, switch to a new regimen not used before.
(3) Stem cell transplantation (autologous, allogeneic) for those with suitable conditions.
Relapse after transplantation.
(1) Relapse after allogeneic transplantation: donor lymphocyte infusion with a previously unused regimen containing a new drug.
(2) Relapse after autologous stem cell transplantation: use a previously unused, new drug-containing regimen and consider allogeneic hematopoiesis for cell transplantation.
(4) Maintenance therapy: the significance of maintenance therapy is unclear. The timing of maintenance therapy is performed in patients who do not undergo transplantation after achieving optimal efficacy followed by 2 courses of consolidation; in patients who undergo autologous HSCT after achieving very good PR (VGPR) and above. Thalidomide 50-200 mg/d combined with prednisone 50 mg/d every other day and interferon 3 MU every other day are available. If there is no evidence of ROTI in the maintenance phase, the above indexes will be reviewed every 3 months in the first year and every 6 months in the second year.
5.Autologous stem cell transplantation.
(1) Autologous HSCT is often performed after 3-4 courses of effective chemotherapy; avoid alkylating agents and nitrosoureas in patients with potential for autologous HSCT.
(2) Patients who obtained less than VGPR after the first autologous stem cell transplantation may undergo a second autologous stem cell transplantation; the second transplantation is usually performed within 6 months after the first transplantation.
(3) Patients who obtained efficacy above VGPR after the first autologous stem cell transplantation can undergo observation or maintenance treatment, or a second autologous stem cell transplantation can be tested, but the patient does not necessarily benefit.
6.Allogeneic stem cell transplantation: Allogeneic stem cell transplantation with autologous-reduced pretreatment regimen can be performed for MM patients; allogeneic stem cell transplantation with reduced pretreatment regimen is usually performed within six months after autologous stem cell transplantation. Clear marrow allogeneic stem cell transplantation, transplantation can be performed in young patients and is often used in patients with refractory relapse.
7.Supportive therapy: supportive therapy on the basis of chemotherapy
Bone disease.
(1) Use oral or intravenous bisphosphonate drugs: including disodium clodronate, disodium pamidronate, zoledronic acid, ibandronate. When using intravenous preparations, strictly control the infusion time, pay attention to monitoring renal function before and after use, and do not use them for more than 2 years in total; if there is still active bone damage after 2 years, they can be used intermittently. Disodium pamidronate or zoledronic acid may cause osteonecrosis of the jaw and aggravate renal impairment.
(2) In the presence of pathological fractures of long bones or spinal fractures compressing the spinal cord feasible surgical treatment, symptomatic spinal compression fractures feasible kyphoplasty.
(3) In severe pain with poor pain relief, local low-dose radiotherapy can be used, and systemic radiotherapy can be avoided before stem cell collection.
Hypercalcemia: (1) hydration and diuresis: 2000-3000 ml of fluid daily; maintain urine volume >1500 ml/d; (2) use of bisphosphonates; (3) glucocorticoids and/or calcitonin.
Anemia: erythropoietin treatment can be considered.
Renal insufficiency.
(1) hydration diuresis: reduce uric acid formation and promote uric acid excretion.
(2) Active dialysis in the presence of renal failure.
(3) Use non-steroidal anti-inflammatory and analgesic drugs with caution.
(4) Avoid intravenous pyelogram.
Infections: treat all kinds of infections aggressively and according to the principles of immune depression.
Hyperviscosity: plasma exchange can be used in patients with symptomatic hyperviscosity syndrome.
VI. Prognosis
The natural course of MM is highly heterogeneous, with a median survival of about 3-4 years, and some patients can survive for more than 10 years. The prognostic factors affecting MM are: age, c-reactive protein (CRP) level, degree of bone marrow plasma cell infiltration and Durie-Salmon clinical stage (including renal function), and ISS stage. Cytogenetic alterations are important factors in determining the efficacy response and survival of MM. Fluorescence in situ hybridization (FISH) detected high-risk MM with t(4;14), t(14;16), and del(17p), and interphase cytogenetic detection of 13q- is also a high-risk factor. In addition, the degree of plasma cell differentiation, circulating plasma cell count, and serum lactate dehydrogenase (LDH) levels are all unique prognostic factors for MM survival; performance status (PS) is likely to have a strong predictive power for MM survival.
Annex 1 Chinese MM outcome criteria
They are complete remission (CR), strictly complete remission (sCR), near complete remission (nCR), very good partial remission (VGPR), partial remission (PR), minimal remission (MR), no change (NC), plateau, disease progression (PD), and relapse after CR.
1. CR: All of the following conditions must be met.
(1) Negative immunofixation electrophoresis for both serum and urinary M protein.
(2) Disappearance of soft tissue plasmacytoma.
(3) no increase in the extent or number of osteolytic lesions; bone marrow plasma cells <0.05 (e.g. for non-secretory plasma myeloma, at least 2 bone marrow examinations at least 6 weeks apart or more are required, both of which have plasma cells <0.05).
2, sCR: On the basis of CR, serum free light chain ratio is normal and no clonal plasma cells are found in bone marrow (immunohistochemistry or immunofluorescence method).
3, nCR: all indicators met the criteria of CR except for positive immunofixation electrophoresis.
4, VGPR: blood M protein decreased ≥ 90% and urine light chain < 100 mg/24 h but did not meet the CR criteria.
5, PR: all of the following conditions must be met.
(1) Serum M protein decrease ≥ 50% (for non-secretory myeloma, a decrease in bone marrow plasma cells ≥ 0.50 is required).
(2) 24-h decrease in urinary light chain ≥ 90% or < 200 mg/24 h.
(3) Soft tissue plasmacytoma shrinkage ≥ 50%.
(4) no increase in the extent or number of osteolytic lesions.
6, MR: All of the following conditions must be met.
(1) 25% to 49% decrease in serum M protein level (o.25 to O.49 decrease in bone marrow plasma cells in non-secretory myeloma).
(2) A 50% to 89% decrease in 24 h urinary light chain but >200 mg/24 h.
(3) Soft tissue plasmacytomas shrink by 25% to 49%.
(4) no increase in the extent or number of osteolytic lesions.
7, NC: between MR and PD.
8.Plateau stage: no evidence of progressive myeloma-related damage to sexual organs or functions and changes in M protein and 24-h urinary light chain secretion levels <25% and lasting for more than 3 months.
9. PD: reappearance of 1 or more of the following during the course of therapy or during the plateau phase.
(1) Increase in serum M protein level > 25% of baseline level and/or increase in absolute value > 5 g/L.
(2) Increased 24-h urinary light chain secretion >25% of baseline levels and/or an absolute increase of 200 mg
(3) Increased bone marrow plasma cell ratio >25% of baseline levels and 10% absolute increase.
(4) Pre-existing osteolytic damage or soft tissue plasmacytoma of greater volume than before.
(5) The appearance of a new osteolytic lesion or soft tissue plasmacytoma.
(6) The presence of otherwise unexplained hypercalcemia (corrected serum calcium > 2.8 mmol/L i.e. 11.5 mg/d1).
10. Relapse after CR: The presence of 1 or more of the following in a patient with previous CR.
(1) Rediscovery of M protein by serum immunofixation electrophoresis or protein electrophoresis.
(2) bone marrow plasma cell ratio ≥ 0.05.
(3) The presence of a new osteolytic lesion.
(4) soft tissue plasmacytoma; hypercalcemia (corrected serum calcium >2.8 mmol/L) that cannot be explained by other causes.
MM disease progression and prognostic statistics were defined as.
(1) Progression-free survival (PSF): the time from the start of treatment to disease progression or death.
(2) Event-free survival (EFS): The 2006 International Myeloma Working Group did not recommend EFS as a routine study endpoint. This is because the definition of “event” varies among clinical studies and may cause confusion.
(3) Time to disease progression (TTP): This refers to the time between the start of treatment and disease progression. If a patient dies before PD and the cause of death is not PD but something else, this should be treated as a truncated data. This index helps to assess the duration of therapeutic benefit.
(4) Disease-free survival (DFS): applies to patients with CR. It refers to the time from the start of achieving CR to relapse (this index is currently of little value for evaluating the efficacy of myeloma).
(5) Duration of remission (DOR): applies to patients who have reached at least Pil. It refers to the time from the achievement of PR or better efficacy (meaning that the efficacy was first observed and not confirmed by re-examination) to disease progression. DOR should be treated as truncated data if the patient did not die because of disease progression. This is an important study endpoint for assessing the efficacy of new drugs and/or new treatment strategies. DOR and TTP are recommended as study endpoints for evaluating the duration of maintenance of efficacy.
(6) Overall survival (OS): It is the period from the entry of the subject into the clinical study until death caused by various original gangs.OS is the most reliable oncology endpoint indicator and it is the best endpoint indicator when the study can adequately evaluate survival. Improvement in survival undoubtedly reflects clinical benefit. Once time to death is recorded, this endpoint indicator is precise and easy to observe. The greatest advantage is that it is objective and less prone to measurement bias. The disadvantage is that the observation time must be long enough and the number of trial participants must be large enough to observe sufficient mortality events and to have sufficient power of validation.
(7) Time to treatment failure (TTF): is a composite endpoint indicator, i.e., a randomly selected time until termination of this treatment for whatever reason (including due to disease progression, treatment toxicity, and death).