附錄一 International Myeloma Working Group 治療反應共識標準[25]
Standard IMWG response criteria||
Stringent complete response
Complete response as defined below plus normal FLC ratio** and absence of clonal cells in bone marrow biopsy by immunohistochemistry (κ/λ ratio ≤4:1 or ≥1:2 for κ and λ patients, respectively, after counting .100 plasma cells)‡‡
Complete response Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5%
plasma cells in bone marrow aspirates Very good partial
response
Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 h
Partial response ≥50% reduction of serum M-protein plus reduction in 24 h urinary M-protein by ≥90% or to <200 mg per 24 h;
If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria;
If serum and urine M-protein are unmeasurable, and serum-free light assay is also unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma-cell percentage was ≥30%. In addition to these criteria, if present at baseline, a ≥50% reduction in the size (SPD)§§ of soft tissue plasmacytomas is also required
Minimal response ≥25% but ≤49% reduction of serum M-protein and reduction in 24-h urine M-protein by 50 to 89%. In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size (SPD)§§ of soft tissue plasmacytomas is also required
Stable disease Not recommended for use as an indicator of response; stability of disease is best described by providing the time-to-progression estimates. Not meeting criteria for complete response, very good partial response, partial response, minimal response, or progressive disease
Progressive disease¶¶,|||| Any one or more of the following criteria:
Increase of 25% from lowest confirmed response value in one or more of the following criteria:
Serum M-protein (absolute increase must be ≥0.5 g/dL);
Serum M-protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL;
Urine M-protein (absolute increase must be ≥200 mg/24 h);
In patients without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg/dL);
In patients without measurable serum and urine M-protein levels and without measurable involved FLC levels, bone marrow plasma-cell percentage irrespective of baseline status (absolute increase must be
≥10%);
Appearance of a new lesion(s), ≥50% increase from nadir in SPD§§ of >1 lesion, or ≥50% increase in the longest diameter of a previous lesion >1 cm in short axis;
≥50% increase in circulating plasma cells (minimum of 200 cells per µL) if this is the only measure of disease
Clinical relapse Clinical relapse requires one or more of the following criteria:
Direct indicators of increasing disease and/or end organ dysfunction (CRAB features) related to the underlying clonal plasma-cell proliferative disorder. It is not used in calculation of time to progression or progression-free survival but is listed as something that can be reported optionally or for use in clinical practice;
Development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures do not constitute progression);
Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50%
(and ≥1 cm) increase as measured serially by the SPD§§ of the measurable lesion;
Hypercalcemia (>11 mg/dL);
Decrease in hemoglobin of ≥2 g/dL not related to therapy or other non-myeloma-related conditions;
Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and attributable to myeloma;
Hyperviscosity related to serum paraprotein.
Relapse from complete response (to be used only if the end point is
disease-free survival)
Any one or more of the following criteria:
Reappearance of serum or urine M-protein by immunofixation or electrophoresis;
Development of ≥5% plasma cells in the bone marrow;
Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcemia [refer to 'clinical relapse' above]).
Relapse from MRD negative (to be used only if the end point is
disease-free survival)
Any one or more of the following criteria:
Loss of MRD negative state (evidence of clonal plasma cells on NGF or NGS, or positive imaging study for recurrence of myeloma);
Reappearance of serum or urine M-protein by immunofixation or electrophoresis;
Development of ≥5% clonal plasma cells in the bone marrow;
Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcemia).
IMWG: International Myeloma Working Group; MRD: minimal residual disease; NGF: next-generation flow; NGS: next-generation sequencing;
PET: positron emission tomography; CT: computed tomography; SUV: standardized uptake value; FLC: free light chain; M-protein: myeloma protein; SPD: sum of the products of the maximal perpendicular diameters of measured lesions; CRAB features: calcium elevation, renal failure, anemia, lytic bone lesions; FCM: flow cytometry; SUVmax: maximum standardized uptake value; MFC: multiparameter flow cytometry;
18F-FDG PET: 18F-fluorodeoxyglucose PET; ASCT: autologous stem cell transplantation.
is κ/λ of >4:1 or <1:2.
||Derived from international uniform response criteria for multiple myeloma.11 Minor response defi nition and clarifi cations derived from Rajkumar and colleagues.14 When the only method to measure disease is by serum FLC levels: complete response can be defined as a normal FLC ratio of 0·26 to 1·65 in addition to the complete response criteria listed previously. Very good partial response in such patients requires a
≥90% decrease in the difference between involved and uninvolved FLC levels. All response categories require two consecutive assessments made at any time before the institution of any new therapy; all categories also require no known evidence of progressive or new bone lesions or extramedullary plasmacytomas if radiographic studies were performed. Radiographic studies are not required to satisfy these response
requirements. Bone marrow assessments do not need to be confirmed. Each category, except for stable disease, will be considered unconfirmed until the confirmatory test is performed. The date of the initial test is considered as the date of response for evaluation of time dependent outcomes such as duration of response.
**All recommendations regarding clinical uses relating to serum FLC levels or FLC ratio are based on results obtained with the validated
Freelite test (Binding Site, Birmingham, UK). ††Presence/absence of clonal cells on immunohistochemistry is based upon the κ/λ/L ratio. An abnormal κ/λ ratio by immunohistochemistry requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is κ/λ of >4:1 or <1:2.
‡‡Special attention should be given to the emergence of a different monoclonal protein following treatment, especially in the setting of patients having achieved a conventional complete response, often related to oligoclonal reconstitution of the immune system. These bands typically disappear over time and in some studies have been associated with a better outcome. Also, appearance of monoclonal IgG κ in patients receiving monoclonal antibodies should be differentiated from the therapeutic antibody
§§Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI scans, or dedicated CT scans where applicable. For patients with only skin involvement, skin lesions should be measured with a ruler. Measurement of tumour size will be determined by the SPD.
¶¶Positive immunofixation alone in a patient previously classified as achieving a complete response will not be considered progression. For purposes of calculating time to progression and progression-free survival, patients who have achieved a complete response and are
MRD-negative should be evaluated using criteria listed for progressive disease. Criteria for relapse from a complete response or relapse from MRD should be used only when calculating disease-free survival.
||||In the case where a value is felt to be a spurious result per physician discretion (eg, a possible laboratory error), that value will not be considered when determining the lowest value.
附錄二 療效評估文獻電子資料庫搜尋策略 Pubmed
Search Query Items
found
#1 Search Multiple Myeloma 49,602
#2 Search ixazomib 273
#3 Search (Multiple Myeloma) AND ixazomib 207
selected 0
Embase
No. Query Results
#1 'ixazomib'/exp OR 'ixazomib' 1,197
#2 'multiple myeloma'/exp/mj OR 'multiple myeloma' 81,390
#3 #1 AND #2 897
#4 #1 AND #2 AND ([cochrane review]/lim OR [systematic review]/lim OR [meta analysis]/lim OR [randomized controlled trial]/lim) AND
([article]/lim OR [article in press]/lim OR [review]/lim)
36
selected 0
Cochrane Library
ID Search Hits
#1 MeSH descriptor: [Multiple Myeloma] explode all trees 1,348
#2 (ixazomib):ti,ab,kw OR (Ninlaro):ti,ab,kw OR (MLN9708):ti,ab,kw OR (MLN 9708):ti,ab,kw OR (MLN-9708):ti,ab,kw
142
#3 #1 AND #2 in Cochrane Reviews, Trials (Word variations have been searched)
29
selected 0
附錄三 Ninlaro 納入健保給付財務影響之敏感度分析（單位：億元）
相關參數 第 1 年 第 2 年 第 3 年 第 4 年 第 5 年
Base case 1.89 2.67 2.78 2.89 3.02
二線治療比例（base case = 46%）
60% 2.44 3.46 3.62 3.77 3.93
62% 2.54 3.58 3.74 3.90 4.08
高風險細胞遺傳異常（base case = 43%）
15% 1.06 1.51 1.56 1.62 1.70
20% 1.21 1.69 1.77 1.85 1.92
二線 Rd 治療後達 PR/SD 比例 （base case = 66%）
58% 1.85 2.62 2.72 2.82 2.96
本品市佔率†
高市佔 (+10%) 2.20 3.11 3.22 3.36 3.52
低市佔 (-10%) 1.58 2.23 2.32 2.42 2.54
年度最小值 1.06 1.51 1.56 1.62 1.70
年度最大值 2.54 3.58 3.74 3.90 4.08
†Base case：建議者假設本品市佔率在高風險細胞遺傳異常病人群為 80%，在二
線 Rd 治療後僅達 PR/SD 之病人群為 30%。
免瘤諾 膠囊 (Ninlaro Capsules 4mg、3mg、2.3mg)
4mg: 含 5.7 mg ixazomib citrate，相當於 4 mg ixazomib 3mg: 含 4.3 mg ixazomib citrate，相當於 3 mg ixazomib 2.3mg: 含 3.3 mg ixazomib citrate，相當於 2.3 mg ixazomib 主管機關許可適應症
a
Ninlaro 併用 lenalidomide 及 dexamethasone 適用於接受過至少一 線治療的多發性骨髓瘤患者。
建議療程 NINLARO 併用 lenalidomide 及 dexamethasone
NINLARO 的建議起始劑量為 4 mg，每週一次口服，於 28 天療