Multiple myeloma is one of the most common malignancies of the hematologic system. In recent years, rapid progress has been made in the diagnosis, treatment, and efficacy criteria of multiple myeloma due to the emergence of new drugs that have improved efficacy. In view of this, the Hematologist Branch of the Chinese Medical Association has convened some experts nationwide to develop this guideline.
Multiple myeloma is a malignant proliferative plasma cell disease in which clonal plasma cells in the bone marrow proliferate abnormally and secrete monoclonal immunoglobulins or their fragments (M proteins) and cause related organ or tissue damage (ROTI). Common clinical manifestations are bone pain, anemia, renal insufficiency, and infection.
II. The most common symptoms of multiple myeloma are those associated with anemia, renal insufficiency, infection or bone destruction. Commonly, there are.
1.Skeletal symptoms: bone pain, local masses, pathological fractures, and may be combined with paraplegia.
2, decreased immunity: recurrent bacterial pneumonia and/or urinary tract infections, sepsis; viral infections with herpes zoster are 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 sudden onset of impaired consciousness, finger numbness, insufficient coronary artery blood supply, and chronic heart failure. 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 hypertrophy of tongue, enlarged parotid gland, enlarged heart, diarrhea or constipation, enlarged liver and spleen and peripheral neuropathy; advanced patients may also have bleeding tendency.
Myeloma-related organ or tissue damage (ROTI) increased blood calcium levels corrected serum calcium above the upper limit of normal 0,25 mmol/L [1 mg/dL] or >2,8 mmol/L [11,5 mg/dL]
Renal impairment blood creatinine >176, 8 μmol/L [2mg/dL]
Anemia Hemoglobin <100g/L or more than 20g/L below normal Bone destruction Osteolytic damage or osteoporosis with compression fracture Other symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (≥2 times/year) III. Diagnostic criteria, typing, staging and differential diagnosis (a), diagnosis 1. Main diagnostic criteria.
①Tissue biopsy proves the presence of plasmacytoma or bone marrow smear examination: plasma cells > 30%, often accompanied by morphological changes.
② Monoclonal immunoglobulin (M protein): IgG>35g/L, IgA>20g/L, IgM>15g/L, IgD>2g/L, IgE>2g/L, monoclonal K or λ light chain>1g/24 hours in urine, and exclude amyloidosis.
Secondary criteria.
①Bone marrow examination: 10%-30% plasma cells.
② Presence of monoclonal immunoglobulin or its fragments, but below the above criteria.
③ X-ray examination with osteolytic damage and/or extensive osteoporosis.
④Decreased amount of normal immunoglobulins: IgM <0,5g/L, IgA <1,0g/L, IgG <6,0g/L.
MM can be diagnosed when any of the following conditions are met.
Major criterion No. 1 + No. 2; or No. 1 major criterion + one of the secondary criteria ② ③ ④; or No. 2 major criterion + one of the secondary criteria ① ③ ④; or one of the secondary criteria ① ② + secondary criteria ③ ④.
2, minimum diagnostic criteria (meet two of the following) ① bone marrow malignant plasma cells ≥10% or <10% but confirmed clonal and/or biopsy for plasmacytoma and serum and/or urine with monoclonal M protein; if M protein is not detected, then bone marrow malignant plasma cells ≥30% and/or biopsy for plasmacytoma ② myeloma-related organ function impairment (at least one, see Table 1 for details) [other types of end-organ damage may also occasionally occur and require treatment. If the damage to these organs is confirmed to be related to myeloma, it can also be used for the diagnosis of myeloma]
3. Diagnostic criteria for symptomatic MM.
①Meet the diagnostic criteria of MM.
②The presence of any ROTI.
4. Diagnostic criteria for asymptomatic MM.
①Meet the diagnostic criteria of MM.
②No signs and symptoms of ROTI.
(II), typing according to the increase of abnormal immunoglobulin types can be divided into the following eight types.
IgG type, IgA type, IgD type, IgM type, IgE type, light chain type, biclonal type and non-secretory type. According to the light chain type, they are divided into κ and λ types.
(C), staging Durie-Salmon staging system and the International Staging System (ISS) are available.
ISS staging system staging ISS staging criteria median survival (months) I β2-MG <3, 5 mg/L, albumin ≥35 g/L; 62II does not meet the stage I and III of all patients 45III β2-MG ≥5, 5 mg/L.
29Durie-Salmon staging system staging Durie-Salmon staging criteria I hemoglobin >l00g/L serum calcium level ≤3, 0mmol/L [12mg/dL]
Skeletal X-ray: normal skeletal structure or isolated bone plasmacytoma Low serum myeloma protein production IgG <50g/L IgA <30g/L Benzedrine <4g/24h Tumor cell count <0, 6x1012/m2 body surface area II All patients not meeting stages I and III Tumor cell count 0, 6-1, 2x1012/m2 body surface area III Hemoglobin <85 g/L serum calcium >3, 0 mmol/L [12 mg/dL]
Very high rate of serum or urinary myeloma protein production IgG > 70 g/L IgA > 50 g/L Benzedrine > 12 g/24h Number of osteolytic lesions in skeletal examination > 3 tumor cells > 1, 2×1012/m2 body surface area Subtype criteria A normal renal function (serum creatinine level < 176, 8 mol/L [2 mg/dL]) B abnormal renal function (serum creatinine level ≥ 176, 8 mol/L [2 mg/dL]) (d) Differential diagnosis with the following conditions: reactive plasmacytosis (RP), primary macroglobulinemia (WM) and osteolytic lesions of metastatic carcinoma, and other diseases that can present with M protein such as monoclonal gammopathy of undetermined significance (MGUS), light chain amyloidosis, isolated plasmacytoma (bone or extramedullary) , non-Hodgkin's lymphoma, chronic lymphocytic leukemia.
1, reactive plasmacytosis (reactive plasmacytosis).
(i) presence of primary disease: e.g. chronic inflammation, typhoid fever, systemic lupus erythematosus, cirrhosis, metastatic carcinoma, etc.; (ii) plasma cells ≤ 30% and no morphological abnormalities; (iii) immunophenotype: reactive plasma cells have an immunophenotype of CD38+CD56-, whereas MM is CD38+CD56+; (iv) M protein identification: no monoclonal immunoglobulins or their fragments; (v) cytochemical staining: plasma cell acid phosphatase and 5’nucleotidase reactions were mostly negative or weakly positive, while all MM patients were positive; (6) IgH gene clonality rearrangement was negative.
2, primary macroglobulinemia (Waldenström “s macroglobulinemia, WM).
①IgM-type immunoglobulin in blood is monoclonal increased, while other immunoglobulins are normal or mildly suppressed.
②Imaging: osteoporosis is less commonly seen on X-ray, and osteolytic lesions are extremely rare.
③Plasma cell morphology: lymphocytes and plasma cell-like lymphocytes are prevalent in the bone marrow. Biopsies of lymph nodes, liver and spleen suggest diffusely well-differentiated or plasma-like lymphocytic lymphoma.
Immunophenotype: mostly IgM+, IgD-, CD19+, CD20+, CD22+, CD5-, CD10- and CD23-.
3.Osteolytic lesions of metastatic cancer.
①Bone pain is obvious at rest and at night; ②Serum alkaline phosphatase is often elevated; ③Most of them are accompanied by osteogenic manifestations, with increased bone density around the osteolytic defect; ④Stacks of cancer cells can be seen on bone marrow smear or biopsy; ⑤Most patients can find the primary foci, but some patients can not find the primary foci.
4, monoclonal gammopathy of undetermined significance (MGUS) diagnostic criteria (meet the following three) ① blood M protein <30g/L; ② bone marrow clonal plasma cells <10%; ③ no ROTI, no other B cell proliferative disorders or light chain-related amyloidosis and other light chain, heavy chain or immune (3) no ROTI, no other B-cell proliferative disorders or light chain-related amyloidosis, and no other light chain, heavy chain or immune protein-related tissue damage.
5. Diagnostic criteria for isolated plasmacytoma (bone or extramedullary) (meet three of the following) ① Biopsy confirmed monoclonal plasmacytoma at a single site with no positive findings on X-ray, MRI and/or FDG PET except for the primary site and low serum and/or urinary M protein levels; ② Normal plasma cell count on multi-site bone marrow aspiration smear or bone biopsy with no evidence of clonal proliferation by flow cytometry or PCR; ③ No evidence of clonal proliferation by flow cytometry or PCR. No evidence of hyperplasia; ③ No myeloma-related organ function impairment, etc.
III. Criteria for judging efficacy: see Annex I for details.
Treatment (a) Principles of treatment 1. Patients with asymptomatic myeloma or D-S stage I can be observed and reviewed every 3 months.
2. Patients with symptomatic MM or myeloma without symptoms but with myeloma-associated sexual organ failure should be treated early.
3. Those aged ≤65 years who are suitable for autologous stem cell transplantation should avoid alkylating agents and nitrosoureas.
4. Those who are suitable for clinical trials should be considered to enter clinical trials.
(B) Treatment of patients with symptomatic MM or D-S stage II or above (see Annex II for details of chemotherapy regimen) 1. Induction therapy: serum immunoglobulin quantification and M protein quantification, blood cell count, BUN, creatinine, blood calcium, bone marrow aspiration (bone marrow biopsy can be repeated if clinically necessary) are reviewed once a month during induction therapy; detection of serum free light chain is recommended (if no new site of bone pain occurs (if no new site of bone pain occurs or the degree of bone pain worsens, then X-ray skeletal photos, MRI, PET/CT can be reviewed more than six months). In general, chemotherapy regimens are required to evaluate the efficacy of the disease at 3~4 courses (including new drug regimens can be advanced), and when the efficacy reaches MR or above (those who do not reach MR or above are considered to have primary drug resistance or NC and need to change the treatment regimen), the original regimen can be continued until the disease turns into the plateau stage.
Those aged ≤ 65 years or suitable for autologous stem cell transplantation: one of the following regimens can be selected for induction therapy for 4 courses, or those with less than 4 courses but have achieved PR and better efficacy can undergo stem cell mobilization collection. Anticoagulation may be used prophylactically in high-risk patients.
Ø VAD±T (vincristine + adriamycin + dexamethasone ± thalidomide) Ø TD (thalidomide + dexamethasone) Ø BD (bortezomib + dexamethasone) Ø PAD (bortezomib + adriamycin + dexamethasone) Ø DVD (liposomal adriamycin + vincristine + dexamethasone) Ø BTD (bortezomib + thalidomide + dexamethasone) Age >65 years or not suitable for autologous stem cell transplantation with concomitant blood Cr ≥176 mmol/L: one of the following regimens may be chosen until PR and above is achieved.
Ø VAD (adriamycin + dexamethasone ± vincristine) Ø TD (thalidomide + dexamethasone) Ø PAD (bortezomib + adriamycin + dexamethasone) Ø DVD (liposomal adriamycin + vincristine + dexamethasone) Those aged >65 years or unsuitable for autologous stem cell transplantation with blood Cr ≤176mmol/L: In addition to the above regimens One of the following regimens may also be chosen until PR and above is achieved
Ø MP (mafran + prednisone) Ø M2 (cyclophosphamide + vincristine + carazepam + mafran + prednisone) Ø MPV (mafran + prednisone + bortezomib) Ø MPT (mafran + dexamethasone + thalidomide) 2. Treatment of primary drug-resistant MM ① Switch to a new regimen that has not been used, if PR and above can be obtained If the conditions are suitable, autologous stem cell transplantation will be performed as soon as possible; ② those who are eligible for clinical trials, enter clinical trials; 3, treatment of MM relapse after chemotherapy ① relapse within six months after remission, switch to a new regimen that has not been used before; ② relapse more than six months after remission, the original regimen to induce remission can be tried; if it is not effective, switch to a new regimen that has not been used before; ③ those with suitable conditions for stem cell transplantation (autologous, allogeneic The timing of maintenance therapy is to be carried out in patients who do not undergo transplantation after achieving the best efficacy and then consolidating for 2 courses of treatment; in patients who undergo autologous HSCT after achieving VGPR and above. Patients with autologous HSCT will be treated after achieving VGPR and above. 50-200 mg/d QN, combined with prednisone 50 mg/d, QOD, and interferon 3MU, QOD can be used.
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 ①Autologous HSCT is often performed after 3-4 courses of effective chemotherapy; patients who are likely to undergo autologous HSCT avoid alkylating agents and nitrosoureas.
(ii) Patients who obtained less than VGPR after the first autologous stem cell transplantation may undergo a second autologous stem cell transplantation, and the second transplantation is usually performed within 6 months after the first transplantation.
③Patients who have obtained efficacy above VGPR after the first autologous stem cell transplantation can undergo observation or maintenance treatment, or can be tested for second autologous stem cell transplantation, but the patient may not necessarily benefit.
6. Allogeneic stem cell transplantation can be performed for patients with multiple myeloma with autologous-reduced pretreatment regimen; allogeneic stem cell transplantation with reduced pretreatment regimen is usually performed within six months after autologous stem cell transplantation.
Clear myeloid allogeneic stem cell transplantation can be performed in young patients and is commonly used in patients with refractory relapse.
7.Supportive therapy: treatment of bone disease on the basis of chemotherapy ① Use of oral or intravenous bisphosphonate drugs: including disodium clodronate, disodium pamidronate, zoledronic acid, ibandronate. Strictly control the infusion time when using intravenous preparations, 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. Pamidronate disodium or zoledronic acid may cause osteonecrosis of the jaw as well as aggravate renal function 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 severe pain, when pain relief is not effective, can be localized low-dose radiotherapy, before stem cell collection, avoid systemic radiotherapy.
Hypercalcemia ① hydration, diuresis: daily rehydration 2000-3000ml; maintain urine volume >1500ml/day; 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 cautious use of non-steroidal anti-inflammatory analgesics; ④ avoid intravenous pyelogram.
Infection: actively treat various infections and treat according to the principles of immune depression.
Hyperviscosity: plasma replacement can be used for patients with symptomatic hyperviscosity syndrome.
V. Prognosis The natural course of MM is highly heterogeneous, with a median survival period 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. Fluorescent in-situ hybridization (FISH) detected high-risk MM with t(4;14), t(14;16), del(17p), and interphase cytogenetic detection of 13q- are also among the high-risk factors. In addition, the degree of plasma cell differentiation, circulating plasma cell count and serum lactate dehydrogenase (LDH) levels were all independent prognostic factors for MM survival; performance status (PS) was most likely a strong predictor of MM survival.