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 from across China to develop this guideline.
I. Definition
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 include bone pain, anemia, renal insufficiency, and infection. Xu Songfeng, Department of Orthopedics, General Hospital of Jinan Military Region
II. Clinical manifestations
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. immune deficiency: recurrent bacterial pneumonia and/or urinary tract infections, sepsis; viral infections with herpes zoster are common.
3. Anemia: orthocytic orthochromic anemia; rarely 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 the tongue, enlargement of the parotid gland, enlarged heart, diarrhea or constipation, enlarged liver and spleen and peripheral neuropathy; advanced patients may also have bleeding tendency.
Table 1 Myeloma-related organ or tissue damage (ROTI)
Elevated blood calcium levels
Calibrated serum calcium above the upper limit of normal of 0.25 mmol/L [1 mg/dL] or >2.8 mmol/L [11.5 mg/dL]
Impaired renal function
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, typology, staging and differential diagnosis
(I) Diagnosis
1.Diagnostic criteria
Main 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 in urine>1g/24 hours, and exclude amyloidosis.
Secondary criteria.
①Bone marrow examination: 10% to 30% plasma cells.
② Presence of monoclonal immunoglobulin or its fragments, but below the above criteria.
③Osteolytic damage and/or extensive osteoporosis on x-ray.
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 (meeting two of the following)
① bone marrow malignant plasma cells ≥ 10% or although < 10% but confirmed clonal and/or biopsy for plasmacytoma and the presence of monoclonal M protein in serum and/or urine; if M protein is not detected, then bone marrow malignant plasma cells ≥ 30% and/or biopsy for plasmacytoma
② Myeloma-associated impairment of organ function (at least one, see Table 1 for details) [Other types of end-organ damage may 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.
(iii) Staging
The Durie-Salmon staging system and the International Staging System (ISS) are both available.
ISS staging system
Staging
ISS staging criteria
Median survival (months)
I
β2-MG <3.5mg/L.
Albumin ≥35g/L.
62
II
All patients not eligible for stages I and III
45
III
β2-MG ≥ 5.5 mg/L.
29
Durie-Salmon staging system
Staging
Durie-Salmon staging criteria
I
Hemoglobin > l00g/L
Serum calcium level ≤3.0mmol/L [12mg/dL]
Bone X-ray: normal bone structure or isolated bone plasmacytoma
Low serum myeloma protein production rate
IgG <50g/L
IgA <30g/L
Benign periostin <4g/24h
Tumor cell count ＜0.6×1012/m2 body surface area
II
All patients not meeting stage I and III
Tumor cell count 0.6-1.2×1012/m2 body surface area
III
Hemoglobin <85g/L
Serum calcium >3.0 mmol/L [12 mg/dL]
Very high serum or urinary myeloma protein production rate
IgG > 70g/L
IgA＞50g/L
Benzedrine > 12g/24h
Osteolytic lesions >3 in skeletal examination
Tumor cell count >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 [2mg/dL])
(IV), differential diagnosis
Differentiate from 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, liver 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.
(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.
⑥IgH gene clonal rearrangement negative.
2, primary macroglobulinemia (Waldenstr?m “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 more common in the bone marrow. Biopsies of lymph nodes, liver and spleen suggest diffuse 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.
(3) Osteogenic manifestations are mostly accompanied by increased bone density around the osteolytic defect.
④heaps of cancer cells can be seen on bone marrow smear or biopsy.
⑤ Most 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 or other light chain, heavy chain or immunoglobulin-related tissue damage.
5. Diagnostic criteria for isolated plasmacytoma (bone or extramedullary) (meeting 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 urine M protein levels.
(ii) 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.
③No myeloma-related organ function impairment, etc.
III. Criteria for judging the efficacy: see Annex I for details
IV. Treatment
(I) Treatment principles
1. Patients with asymptomatic myeloma or D-S stage I can be observed and reviewed once every 3 months.
2. Patients with symptomatic MM or myeloma without symptoms but who have developed myeloma-related 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.
(II), 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 reviewed if clinically necessary) are reviewed once a month during induction therapy; serum free light chain detection is recommended (X-ray skeletal photos, MRI, PET/CT can be reviewed for more than six months if no new site of bone pain occurs or the degree of bone pain worsens). In general, chemotherapy regimens need to be evaluated for disease efficacy 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 primary drug resistance or NC and need to change treatment regimens) the original regimen can be used to continue treatment until the disease turns into 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 therapy may be used prophylactically in high-risk patients.
? VAD±T (vincristine + adriamycin + dexamethasone ± thalidomide)
? TD (thalidomide + dexamethasone)
? BD (bortezomib + dexamethasone)
? PAD (bortezomib + adriamycin + dexamethasone)
? DVD (liposomal adriamycin + vincristine + dexamethasone)
? BTD (bortezomib + thalidomide + dexamethasone)
Age >65 years or not suitable for autologous stem cell transplantation with blood Cr ≥176 mmol/L: one of the following regimens can be chosen until PR and above is achieved.
? VAD (adriamycin + dexamethasone ± vincristine)
? TD (thalidomide + dexamethasone)
? PAD (bortezomib + adriamycin + dexamethasone)
? DVD (liposomal adriamycin + vincristine + dexamethasone)
Age > 65 years or those who are not suitable for autologous stem cell transplantation, blood Cr ≤ 176 mmol/L: In addition to the above regimens, one of the following regimens can be chosen until PR and above is achieved.
? MP (Marfalan + prednisone)
? M2 (cyclophosphamide + vincristine + capsaicin + mafran + prednisone)
? MPV (mafran + prednisone + bortezomib)
? MPT (mafran + dexamethasone + 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 should be performed as soon as possible if conditions are suitable.
② Enter clinical trials if they are eligible.
3.Treatment of MM relapse
Relapse after chemotherapy
① Relapse within six months after remission, switch to a new regimen that has not been used before.
②For relapse more than six months after remission, the original regimen for inducing remission can be tried; if it is ineffective, switch to a new regimen not used before.
(iii) Stem cell transplantation (autologous, allogeneic) if conditions are suitable.
Relapse after transplantation
(i) relapse after allogeneic transplantation: donor lymphocyte infusion with a previously unused regimen containing a new drug.
② Relapse after autologous stem cell transplantation: allogeneic hematopoietic stem cell transplantation using previously unused, new drug-containing regimens may be considered.
4.Maintenance therapy
The significance of maintenance therapy is unclear. The timing of maintenance therapy is carried out in patients who do not undergo transplantation after achieving optimal efficacy and then consolidating 2 courses of therapy; patients who undergo autologous HSCT after achieving VGPR and above. Response arrest 50-200 mg/d, QN, combined with prednisone 50 mg/d, QOD, and interferon 3MU, QOD 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
①Autologous HSCT is often performed after 3-4 courses of effective chemotherapy; avoid alkylating agents and nitrosoureas in patients who are likely to undergo autologous HSCT.
(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 obtained efficacy above VGPR after the first autologous stem cell transplantation can undergo observation or maintenance treatment, or can be tested for the second autologous stem cell transplantation, 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 patients with multiple myeloma; 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: on the basis of chemotherapy
Treatment of bone disease
① Use 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. (i) Disodium pamidronate or zoledronic acid may cause osteonecrosis of the jaw and aggravate renal function impairment.
(ii) 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.
③In 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: daily rehydration of 2000-3000 ml; maintain urine volume >1500 ml/day.
② use of bisphosphonates.
③Glucocorticoids and/or calcitonin.
Anemia: erythropoietin treatment can be considered.
Renal insufficiency
① hydration diuresis; reduce uric acid formation and promote uric acid excretion.
(ii) Active dialysis in the presence of renal failure.
③Cautious use of non-steroidal anti-inflammatory and analgesic drugs.
④Avoid intravenous pyelogram.
Infection: actively treat various infections and treat according to the principles of immune depression.
Hyperviscosity: plasma exchange can be used in patients with symptomatic hyperviscosity syndrome.
V. 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. 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.