【ダラキューロ配合皮下注】に関する費用対効果評価[第 1.0 版]【ヤンセンファーマ株式会社】【提出日】2022 年 2 月 10 日

【目次】

0. 要旨 .................................................................................................................................. 5
1. 対象となる医薬品･医療機器の性質 ................................................................................. 8
1.1 名称 ............................................................................................................................. 8
1.2 保険償還価格 .............................................................................................................. 8
1.3 治療効果のメカニズム................................................................................................ 8
1.3.1 ダラツムマブ ....................................................................................................... 8
1.3.2 ボルヒアルロニダーゼ アルファ ......................................................................... 8
1.4 対象疾患 ..................................................................................................................... 8
1.5 使用方法等 ................................................................................................................. 9
1.6 対象疾患の治療における当該医薬品･の位置づけ .................................................... 10
1.6.1 国内ガイドライン（日本血液学会）.................................................................. 10
1.6.2 国内ガイドライン（日本骨髄腫学会） .............................................................. 12
1.6.3 海外ガイドライン（NCCN） ............................................................................ 12
1.7 主な有害事象 ............................................................................................................ 14
1.8 他国の医療技術評価機関における評価結果 ............................................................. 15
2. 費用効果分析における分析条件の設定 .......................................................................... 18
2.1 分析対象とする集団 ................................................................................................. 18
2.2 比較対照 ................................................................................................................... 18
2.3 分析の立場と費用の範囲 .......................................................................................... 19
2.4 効果指標 ................................................................................................................... 19
2.5 分析期間 ................................................................................................................... 19
2.6 割引率....................................................................................................................... 19
2.7 分析条件の設定の要約.............................................................................................. 20
3. Additional Benefits ........................................................................................................ 22
3.1 Clinical Questions .................................................................................................... 22
3.2 Systematic Review ................................................................................................... 23
3.2.1 Implementation flow ......................................................................................... 23
3.2.2 Inclusion and exclusion criteria........................................................................ 24
3.2.3 Database ............................................................................................................ 24
3.2.4 Conference search ............................................................................................. 29
3.2.5 Search results .................................................................................................... 31
3.2.6 Listing of clinical studies identified ................................................................. 332

3.2.7 Summary of additional benefit assessment ..................................................... 36
3.2.8 Detailed table of clinical trials.......................................................................... 42
3.3 Evaluation of Additional Benefit............................................................................. 75
3.3.1 Results of additional benefit assessment ......................................................... 75
4. Details of Analytical Methods ....................................................................................... 86
4.1 Analytical Methods .................................................................................................. 86
4.1.1 Calculation of cost-effectiveness ....................................................................... 86
4.1.2 Assumptions used in the model ........................................................................ 90
4.2 Parameters Used in the Analysis ............................................................................ 92
4.2.1 Details of parameters such as efficacy and safety ........................................... 94
4.2.2 Details of QOL values ....................................................................................... 97
4.2.3 Details of Cost Parameters ............................................................................... 98
5. Analytical Results ....................................................................................................... 109
5.1 Results of the Analysis .......................................................................................... 109
5.1.1 Incremental cost, effect, and ratio of cost-effectiveness in the base analysis.................................................................................................................................. 109
5.1.2 Sensitivity analyses ........................................................................................ 110
5.1.3 Assessing the validity of the analysis............................................................. 111
5.1.4 Interpretation of Analysis Results ................................................................. 113
5.1.5 Price Adjustment Rate Weight ....................................................................... 113
5.1.6 Price increases ................................................................................................. 113
5.2 Analysis Including Public Nursing Care Expenses and Productivity loss [only if
applicable] .................................................................................................................... 114
5.3 Other Analyses ....................................................................................................... 114
5.3.1 Other analysis: cost difference from HCP time perspective. ......................... 114
5.3.2 Other analysis: CUA (Scenario analysis) ....................................................... 115
6. 再分析用のデータ ........................................................................................................ 120
7. 実施体制....................................................................................................................... 121
8. 参考文献....................................................................................................................... 122
Appendix A: Parameters Used in the Analysis (DVd [SC] vs Vd, Cost Utility Analysis).......................................................................................................................................... 129
Appendix B: Parameters Used in the Analysis (DRd [SC] vs Rd, Cost Utility Analysis).......................................................................................................................................... 143
Appendix C: Time-to-Event Analysis for Progression-Free Survival (PFS) ................. 157
Appendix D: Time-to-Event Analysis for Overall Survival (OS) ................................... 159
3

Appendix E: Time-to-Event Analysis for Time-To-Treatment Discontinuation (TTD). 161
Appendix F: Details of QOL Values (Disutility Inputs) ................................................. 163
Appendix G: Subsequent Treatment Costs in RRMM Models ...................................... 165
Appendix H: Medical Resource Utilization .................................................................... 167
Appendix I: Progression-Free Survival Distribution Parameters (Cost Utility Analysis).......................................................................................................................................... 169
Appendix J: Overall Survival Distribution Parameters (Cost Utility Analysis) .......... 171
Appendix K: Time-to-Treatment Discontinuation Distribution Parameters (Cost Utility
Analysis) .......................................................................................................................... 173
Appendix L: MDV database analysis ............................................................................. 175
Appendix M: Cost per the administration from the perspective of HCP workload ...... 177
Appendix N: Literature of Asian and Japanese-only population .................................. 179
Appendix O: One-Way Sensitivity Analysis ................................................................... 192

4

0. 要旨In the table below, include the content for the 主要分析. For other analysis
performed, details can be found in the report section 5.3.
分析対象技術名 [1.1 節]

ダラキューロ配合皮下注 （ダラツムマブ・ボルヒアルロニダーゼ
アルファ） (Dara SC)
イギリス（NICE）：その他*
イギリス（SMC）：推奨 (Reimbursed in previously
recommended regimens for Dara IV）
フランス（HAS）：SMR-important、ASMR-V（効率性評価:

他国の医療技術評価機関における評価結果 [1.8 節]

不要）
ドイツ（IQWiG）：その他*
カナダ（CADTH）：その他*
オーストラリア（PBAC）：推奨 （Based on a cost
minimization basis with Dara IV.）*NO HTA EVALUATION required for formulation
changes. Reimbursement based on Dara IV

対象とする疾患･集団 [2.1 節]造血幹細胞移植の適応とならない未治療の多発性骨髄腫及び再発又は難治性の多発性骨髄腫

比較対照技術名 [2.2 節]

ダラザレックス点滴静注 (Dara IV)

分析の立場と費用の範囲 [2.3

公的医療の立場節]

公的医療費

使用する効果指標 [2.4 節]

費用最小化分析：なし（費用のみ）設定した分析期間 [2.5 節]

費用最小化分析：32 週間（主要評価）および 1 年（感度分析）

割引率 [2.6 節]

費用最小化分析：なし (分析期間 ≤ 1 年)

P: 造血幹細胞移植の適応とならない未治療の多発性骨髄腫

システマティックレビューのクリニ
カルクエスチョン [3.1/3.3 節]

及び再発又は難治性の多発性骨髄腫
I: Dara SC
C: Dara IV
O: 有効性（ORR、PFS、OS）、安全性、HRQoL

システマティックレビュー結果のシステマティックレビューの結果、組み入れ対象となる臨床試験概要 [3.2/3.4 節]

等は 1 件であった。

間接比較の結果 [3.7 節]

該当せず

5

□ 追加的有用性あり ■ 「追加的有用性なし」あるいは「あるとは判断できない」
有効性（ORR 及び PFS）に関して Dara SC は Dara IV に対して非劣性であることが示された。また Dara SC と Dara IVの間で Infusion related reaction（AE）率及び治療満足度に差があることが確認されているが、これらのベネフィットを費
追加的有用性の有無[3.8 節]用効用分析の枠組みに組み込むことは困難である。治療満足度が高いことに加えて、薬物投与期間が短く、患者の拘束時間は短い。さらに、Dara SC は医療従事者による医療行為に要する時間を大幅に短縮し、患者管理全体の効率を改善する可能性がある。よって、その他の分析として、薬剤投与のための来院時に HCP に要する時間とそれを金銭的価値に換算した値の分析を実施した。: [その他：HCP の時間的観点からの費用
差]
Based on the additional benefit assessment result,
Janssen determined to take a conservative
approach and performed a cost minimization
analysis as below.
An Excel model was built to calculate weekly direct
medical cost including drug, drug administration,
hospitalization and IRR (AE) management. Threedaratumumab regimens were included, DVMP, DRd
and DVd. For each of the regimen, we compare the

費用対効果の分析方法の概要[4.1.1 項、4.2 節等]

accumulative direct medical cost between Dara SC(intervention) and DARA IV (comparator). Final
results were pooled by the percentage of usage ofeach regimen in actual clinical practice based on
MDV data.
The duration comparison is set to be 32 weeks
based on average daratumumab treatment durationin Japan as base case. A sensitivity analysis was
performed with the duration of 52 weeks[Sensitivity analysis 1]. Another sensitivity analysis
was performed assumingof patients receiving

DARA SC regimen (due to the improved
6

administration and safety) will not require
hospitalization for regimen initiation [Sensitivity
analysis 2].
Dara SC results in lower total cost compared with
Dara IV. Compared with Dara IV, Dara SC reduced
total direct medical costs by ¥546,091 in the basecase. The cost saving ranged from ¥443,078 to結果の概要 [5.1 節]¥721,951 among different regimens. The sensitivity
analysis showed consistent results. In Sensitivity
analysis 1 and 2, Dara SC reduced total direct
medical costs by ¥550,036 and ¥481,985,
respectively.
In the base case analysis and sensitivity analysis of
the main analysis, the result all demonstrated costsaving.
Two other analysis results provided the additional

ICER の所属する確率が最も高

evaluation on HCP time/cost saving that contribute

いと考える区間

to overall health care system efficiency and the ICER
result in a subset of Multiple Myeloma patients(RRMM) comparing to different comparators. As it isagreed that the main evaluation focuses on different
population, comparator, and/or perspective, theanalyses only served as supplementary analyses.

7

1. 対象となる医薬品･医療機器の性質
1.1 名称•

製品名
ダラキューロ配合皮下注•

一般名
ダラツムマブ（遺伝子組換え）1800mg、ボルヒアルロニダーゼ アルファ（遺伝子組換え）
30000 単位（1 バイアル 15mL 中）

1.2 保険償還価格
保険償還価格：15mL 1 バイアル 434,209 円

算定方式：

類似薬効比較方式(I)

算定上の最類似技術

ダラザレックス点滴静注 400mg

有用性系加算有用性加算 II

加算率

5%1.3 治療効果のメカニズム
1.3.1 ダラツムマブ
ダラツムマブは，骨髄腫細胞に高発現する CD38 に特異的に結合し，直接的な作用及び免疫調節作用により高い抗腫瘍効果を示す。
1.3.2 ボルヒアルロニダーゼ アルファボルヒアルロニダーゼ アルファは，皮下間隙における細胞外マトリックスの構成成分の一つであるヒアルロン酸を加水分解することでヒアルロン酸を脱重合し、細胞外マトリックスの粘性を一過性に低下させる。これにより、治療薬の拡散と吸収を促進する。
1.4 対象疾患•

保険適用となる疾患
多発性骨髄腫 (本分析の対象とする疾患)
全身性 AL アミロイドーシス•

分析対象とする疾患の疫学的性質(有病率、新規発症者数、好発年齢等)
日本における多発性骨髄腫(MM)の年間の発症率は 10 万人あたり約 6 人と推定され、2018

年の罹患推定値は 7,765 人である[1]。日本骨髄腫学会（旧 日本骨髄腫研究会）に属する施設を対象にした調査研究によると，2001～2012 年に診療された MM の初診時年齢の中央値
は 67 歳である[2]。
CancerMpact により予測される将来の MM の 5 年有病者数の推移は以下のとおりである。
5 年有病者数は過去 5 年以内に MM と診断された患者数のうち，推計対象年に生存している患8

者数を示しており，5 年有病者数の推移から MM 全体における患者数の増減が予測される。MM
有病者数は今後も高齢人口の増加とともに緩徐に増加していくと考えられるものの，MM 患者は毎年一定の患者が亡くなってしまうため，急激な増加は予測されていない[3]。
•表 1-1 MM*の 5 年有病者数
2021

2022

2023

2024

2025

2026

2027

2028

2029

2030

*ICD10のC90（多発性骨髄腫及び悪性形質細胞性新生物）のみ•

分析対象とする疾患における当該医薬品･医療機器の使用(見込)者数
保険償還時の使用見込み数は、ピーク時市場規模予測で 6900 名である。

•

当該医薬品･医療機器を使用する患者の主な年齢(層)や性別等
国内の MM 患者集団は初診時年齢の中央値は 67 歳と比較的高齢者が多く、男性の割合がやや高いことが知られており[2]、ダラキューロ配合皮下注(Dara SC)の投与対象として想定される集団も国内の MM 患者集団と年齢層および性別において同様である。
実際に、再発又は難治性の多発性骨髄腫(RRMM)患者を対象としたダラザレックス点滴静注(Dara IV)の製造販売後特定使用成績調査[4]によると、安全性解析対象症例の患者背景は、
男性が

%（

歳、平均値

例）、女性が歳（範囲:%（例）であった。年齢の中央値は歳）であり、65 歳未満が

%（

例）で

あった。

1.5 使用方法等
本剤の使用方法を以下の表に示す。
•

表 1-2 本剤の使用方法
投与経路

皮下投与

投与方法

他の抗悪性腫瘍剤との併用
ダラツムマブ（遺伝子組換え）として 1,800mg 及びボルヒアルロニ

1 回あたりの投与量

ダーゼ アルファ（遺伝子組換え）30,000 単位（2,000 単位/mL））
以下の A 法又は B 法の投与間隔で皮下投与する。

投与頻度

A 法：1 週間間隔、2 週間間隔及び 4 週間間隔の順で投与する。
B 法：1 週間間隔、3 週間間隔及び 4 週間間隔の順で投与する。

平均的な投与期間
9

疾患増悪まで継続的に使用

1.6 対象疾患の治療における当該医薬品･の位置づけ
ダラツムマブは MM 治療における有用な薬剤であり、造血幹細胞移植の適応とならない未治療の MM(TIE NDMM)患者及び RRMM 患者に対して，国内外の診療ガイドラインで推奨されている。特に国内の日本血液学会及び日本骨髄腫学会の診療ガイドラインにおいて，ダラツムマブ
は TIE NDMM 患者に対する推奨治療レジメンすべてに含まれている唯一の薬剤である。
また NCCN ガイドラインでは，本剤は，すべてのダラツムマブ治療レジメンにおいて Dara IVと併記されている。国内ガイドラインにおいても，有効性を維持しつつ利便性と安全性を大きく改善する本剤は Dara IV と同様に推奨されることが想定される。
TIE NDMM 患者及び RRMM 患者の治療における国内及び海外のガイドラインの推奨は以下のとおりである。
1.6.1 国内ガイドライン（日本血液学会）


造血器腫瘍ガイドライン 2018 年版補訂版 第 Ⅲ 章 骨 髄 腫 より抜 粋

移 植 非 適 応 の初 発 MM の治 療 アルゴリズム【移植非適応の初発多発性骨髄腫（症候性）】
CQ1 移植非適応の多発性骨髄腫（症候性）に対する推奨治療レジメンは何か

推奨グレード：カテゴリー1

10新規薬剤を用いた D-MPB 療法（ダラツムマブ，メルファラン，プレドニゾロン，ボルテゾミブ）
もしくは，D-Ld 療法（ダラツムマブ，レナリドミド，少量デキサメタゾン）が推奨される。

RRMM の治療アルゴリズム【再発・難治性骨髄腫】
CQ1 再発・難治性骨髄腫患者に対する新規薬剤療法は大量デキサメタゾン療法に比べて生存期間を延長させるか推奨グレード：カテゴリー1
再発・難治性骨髄腫患者に対する新規薬剤療法は，大量デキサメタゾン療法と比較し，無増悪
生存期間や生存期間を延長させるので推奨される。

11

1.6.2 国内ガイドライン（日本骨髄腫学会）


多発性骨髄腫の診療指針 第 5 版より抜粋

1.6.3 海外ガイドライン（NCCN）•

National Comprehensive Cancer Network (NCCN) guidelines Multiple
Myeloma, Version 3.2021

12本剤は新たな薬理作用を有するボルヒアルロニダーゼ アルファを配合することにより，Dara
IV（Dara IV：500～1000mL）と比較して投与時の液量を減らす（本剤：15mL）ことが可能となった。これにより，本剤は短時間の皮下投与が可能となり，Dara IV と比較して投与時の容量負荷リスク軽減が期待されるとともに，IRR 発現率が低減されることが示されている。
本剤の臨床試験では、国内外で実施された 4 試験において有効性・安全性、治療満足度スコ
ア、投与時間及び IRR の発現率が評価された。第Ⅲ相試験の結果から本剤と Dara IV は有効性において非劣性が検証された。また、安全性（特に IRR 発現率）の改善、治療満足度スコアの改善において有用性が認められた。
IRR 発現率の臨床試験結果



MMY3012 試験ではダラツムマブ投与に伴う IRR の発現率が主要な副次評価項目で評価されており，IRR 発現率は Dara IV 群（34.5%）と比較して本剤群（12.7%）で有意に低かった［オッズ比=0.28 (95% CI: 0.18,0.44)，p<0.0001］。


治療満足度スコアの臨床試験結果
MMY3012 試験では，がん治療満足度質問票改変版（改変 CTSQ）を用いて被験者の治療満

足度を患者報告アウトカムで評価した。改変 CTSQ を用いた評価では，がん治療（静脈内投与／皮下投与）に関する被験者満足度及び考えを調査した。がん治療の満足度に関する質問 7 項目の総合的な平均スコアは，評価期間を通して Dara IV 群と比較して本剤群で良好であった。
加えて、Dara IV による治療は大量の輸液を用いて長時間の投与が必要であることから，初回
約 7 時間，2 回目以降約 3～4 時間と長時間の投与時間が必要であり，長時間の拘束による患者に与える身体的負担は大きい。また，投与時間の長さから入院を要することも課題とされてきた。
ダラツムマブによる MM 治療は疾患増悪まで継続し，患者によっては長期間にわたる投与が必要
13

であることから，実臨床上ではより簡便な治療が望まれていた。
本剤の投与時間は約 3～5 分となり，Dara IV と比べて大幅な投与時間の短縮が可能となる。
臨床試験では本剤と Dara IV の投与時間が評価され，本剤は Dara IV と比較して投与時間が大幅に短縮できることが示された。また，Dara IV では輸液ポンプを用いて点滴速度を管理し，さらに投与中に初回投与及び 2 回目の投与では少なくとも 3 回，その後の投与では少なくとも 2 回点滴速度を変更する必要があり，その対応とモニタリングは医療従事者にとって負担となる。また
投与速度調整ミスによる，不適切な点滴速度での投与リスクも生じる。一方，本剤ではそれらの必要がなく，医療従事者の負担軽減と投与速度調整ミスによる不適切な点滴速度での投与リスクが軽減できる。このように，本剤は Dara IV と比較して投与の利便性を高めることで，医療従事者の薬剤調製負担の軽減・医療過誤の低減，医療従事者の患者ケアにかかる負担の軽減が期待できる。
本剤が医療従事者にもたらす負担軽減は，投与に関連する医療行為の時間短縮を確認した調査結果[5]からも示されている。本剤の国際共同第Ⅲ相試験（MMY3012 試験）に患者の組み入れを実施した施設のうち本剤の投与経験があり、かつ本調査への参加に合意が得られた施設を対象に、医療行為に要する時間の調査結果を実施した。その結果、医療従事者による医療行為に要する時間に要する時間は初回投与では 63.8%，2 回目以降では 49.5%、それぞれ短縮された。患者の拘束時間は Dara IV と比較して 97%減少した。
以上より，本剤はダラツムマブの皮下投与による簡便な治療を可能とし，投与における利便性を著しく向上させ，患者と医療従事者の双方に高い医療上の有用性をもたらすと考えられる。また，
ダラツムマブ投与のための入院によるベッドを開放できる事は，大きな医療上の有用性と考えられる。
1.7 主な有害事象
本剤の重大な副作用として以下の副作用が該当する。
・Infusion related reaction (IRR)
・骨髄抑制
・感染症
・腫瘍崩壊症候群(TLS)・間質性肺疾患
各事象につき、推奨されている対応方法は以下の通りである。
Infusion related reaction
・

Infusion related reaction の管理を適切に実施できる体制下で本剤を投与する。

・

発現した場合は、必要に応じて、本剤の中止等を含めた適切な治療を行う。

・

Infusion related reaction を軽減させるため、副腎皮質ホルモン剤、解熱鎮痛剤、抗ヒスタミン剤による前投与を実施する。

14

・

遅発性の infusion related reaction(本剤投与開始から 24 時間以降に発現)を軽減させるため、必要に応じて副腎皮質ホルモン剤等による投与後処置を実施する。

・

本剤投与中及び投与後は infusion related reaction の症状がないか十分に観察す
る。



骨髄抑制
・

関連検査値のモニタリングを実施し、好中球減少が発現した場合は、必要に応じて、本剤の中止、併用薬剤の休薬及び減量、G-CSF 治療等を考慮する。

・

関連検査値のモニタリングを実施し、血小板減少が発現した場合は、必要に応じて、本剤の中止、併用薬剤の休薬及び減量、血小板輸血等を考慮する。



感染症
・



異常が認められた場合は、必要に応じて、本剤の中止等を含めた適切な治療を行う。

腫瘍崩壊症候群(TLS)・

高腫瘍量等のハイリスク患者では適切な予防措置及び注意深いモニタリングを実施する。



間質性肺疾患・間質性肺疾患の初期症状（息切れ、呼吸困難、咳嗽、発熱等）が発現した場合には、必要に応じて、胸部 X 線検査、胸部 CT 検査、血清マーカー等の検査を実施し、適切な処置を行う。

1.8 他国の医療技術評価機関における評価結果
医療技術評価機関における評価結果を以下に要約した。
•

表 1-3 医療技術評価機関における評価結果
国名評価結果 (記載例)

機関名

リスト価格
(現地通貨建)

NICE

その他 (

(TA)

)

GBP

推奨 (Based on Abbreviated

イギリス
SMC

submission. Reimbursed in previously
recommended regimen for Dara IV)･ SMR: Important

フランス

HAS

･ ASMR: V (vs DARA IV)

EUR･ 効率性評価:不要
ドイツ

15

IQWiG
(早期有

その他 (
)

EUR

国名

評価結果 (記載例)

機関名

リスト価格
(現地通貨建)

用性評
価)
CADTH

その他 (

(CDR/p

カナダ

CAD

CODR)
オーストラリア

PBAC

推奨（Based on a cost minimizationbasis with Dara IV）

AUD

また各国における医療経済評価の詳細は以下の通りであった。
•

表 1-4 医療技術評価機関における評価結果の有無
国名

機関名

評価結果の有無

イギリス

NICE

なし

SMC

あり（Based on Abbreviated submission.
Reimbursed in previously recommended regimen
for Dara IV）（効率性評価：不要）

フランス

HAS

あり（効率性評価：不要）

ドイツ

IQWiG

なし

カナダ

CADTH

なし

オーストラリア

PBACあり（費用最小化分析）

また評価結果の詳細は以下の通りであった。
•

表 1-5 医療技術評価機関における評価結果
国名オーストラリア

機関名

PBAC

評価結果の URL など

https://www.pbs.gov.au/industry/listing/elements/pbacmeetings/psd/2021-07/files/daratumumab-psd-july2021.pdf

評価対象技術評価結果
条件付き推奨の場合は、

16Dara SC
推奨
PBAC は、Dara SC が Dara IV に対して確立されている既存の構

その条件の詳細

成に追加されることが妥当であると判断した。

評価対象疾患RRMM

多発性骨髄腫; 1 種類以上の前治療ののちに再発又は難治性となった患者（すなわち、2nd line の MM 患者）。
使用方法 (※)

Dara IV が使用されているすべての適応症のレジメンに対して;･ 1 種類以上の前治療歴を有する MM 患者の治療を目的としたRd 併用療法又は Vd 併用療法
･ プロテアソーム阻害薬（PI）及び免疫調節薬を含む 3 レジメン以上の前治療歴を有する、又は PI 及び免疫調節薬の両方に難治性の MM 患者への単剤療法･ VMP との併用で、新規に MM と診断され、自家幹細胞移植（ASCT）に不適格な患者の治療

比較対照

Dara IV

主要な増分費用効果比のDara IV を比較対照とした費用最小化分析の結果に基づき薬価が値算定された。申請者は年間コストをベースとした費用最小化分析を実施し、PBAC はそれを合理的であるとみなした。分析の中で Dara
SC の平均投与期間は、Dara IV の平均投与期間は、と設定された。PBAC はスケジュール間のマークアップの違い
により若干の違いはあるものの、Dara SC は Dara IV と比較して本質的にコスト中立であるとした。この勧告を行うにあたり、PBAC
は Dara SC が生活の質の改善及び利便性において Dara IV と比較して優れているという消費者の意見に同意した。

17

2. 費用効果分析における分析条件の設定
2.1 分析対象とする集団[主要分析]
造血幹細胞移植の適応とならない未治療の多発性骨髄腫及び再発又は難治性の多発性骨髄腫[その他：HCP の時間的観点からの費用差]: 主要分析と同じ[その他：シナリオ分析]
再発・難治の 2 次治療以降の患者**ダラキューロ（MM）の費用対効果評価に関わる分析枠組み決定の際に、費用対効果評価専門組織において感度分析の位置づけとして本集団に対するシナリオ分析の実施が決定した。

2.2 比較対照
[主要分析]
Dara IV•

選定理由

Dara SC と Dara IV の添付文書上の効能または効果、投与間隔は同一であることから、Dara
IV が比較対象技術として適切である。また NCCN ガイドラインにおいても、Dara SC はすべてのダラツムマブ投与レジメンにおいて Dara SC と区別されていない。
1) Dara IV は、本剤が分析対象集団の治療に導入される時点以降で、大部分患者が本剤により置き換えられると予想される。
2) Dara IV は、本剤の国際共同第Ⅲ相ランダム化比較試験における対照薬であり、薬理作用は同一である。また薬価算定における最類似薬である。
3) ダラツムマブは MM 治療における有用な薬剤であり、 TIE NDMM 患者及び RRMM 患者に対して、国内外の診療ガイドラインで推奨されている。 TIE NDMM 患者に対して、ダラツムマブ
は、日本血液学会及び日本骨髄腫学会の診療ガイドラインにおいて推奨治療レジメンすべてに含まれている唯一の薬剤である。RRMM 患者に対してダラツムマブは、日本血液学会の診療ガイド
ラインにおいて、より良好な転機をもたらすとして、カテゴリー1 のエビデンスで裏付けられた推奨レジメンである。また、NCCN ガイドラインでは、ダラツムマブは、NCCN ガイドラインのカテゴリー
1 のエビデンスで裏付けられた推奨レジメンとして臨床現場で使用されている。本剤は、すべてのダラツムマブ治療レジメンにおいて Dara IV と併記されている。国内ガイドラインにおいても、有効性を維持しつつ利便性と安全性を大きく改善する本剤は Dara IV と同様に推奨されることが想定される。
[その他：HCP の時間的観点からの費用差]: 主要分析と同じ[その他：シナリオ分析]
費用対効果評価専門組織において「最も費用対効果のよい治療法」を選択し RRMM 患者における分析の比較対照とすることが決定された。本決定について弊社と C2H による議論の上、Vd お18よび Rd を比較対照とすることが合意された。
•

選定理由

弊社が実施した MDV データベースを使用した MM の治療パターン分析（一部の結果を第４６回
日本骨髄腫学会学術集会において発表した[6]）において、RRMM における 2 次治療の各治療法の頻度と割合を集計し、Vd および Rd の 2 つの治療法は広く一般的に使用されていると考えられた。またこの 2 つの治療法は他の HTA 評価国で広く償還されており、その費用対効果は十分に確立されていると考えられる。
2.3 分析の立場と費用の範囲
ガイドラインの原則に基づき、分析の立場は公的医療の立場、費用の範囲は公的医療費とした。
その他の分析における除外：HCP の時間的観点からの費用差の分析は、HCP の時間的観点か
ら費用差を検討するために実施した。
2.4 効果指標[主要分析]
費用最小化分析：有効性が同等であると仮定して、費用による比較を行った。
[その他：HCP の時間的観点からの費用差] なし（費用のみ）[その他：シナリオ分析]
費用効用分析：ガイドラインの原則に基づき、効果指標は QALY とした。
2.5 分析期間
[主要分析]
費用最小化分析：弊社が実施し第４６回日本骨髄腫学会学術集会において発表した MDV データ
ベース(2019 年 8 月データ)を使用した MM の治療パターン分析と同様の解析を MDV データベース(2021 年 5 月データ)に対して行い、Dara IV の平均投与期間を集計したところ、TIE
NDMM と RRMM においてそれぞれ 32 週間であった。Dara SC の実際の投与期間はデータから得られなかったため、Dara SC と Dara IV の投与期間は同じであると仮定した。以上より、分析期間は 32 週間、また感度分析として分析期間を 52 週間(1 年)とした分析を実施した。
[その他：HCP の時間的観点からの費用差]
患者あたりの薬剤投与のための来院[その他：シナリオ分析]
費用効用分析：生涯 (30 年)
2.6 割引率[主要分析]
19

費用最小化分析：32 週間および 1 年間の分析であるため割引を行わなかった。
[その他：HCP の時間的観点からの費用差]なし(分析期間≤ 1 年)
[その他：シナリオ分析]
費用効用分析：ガイドラインの原則に基づき、割引率は、費用、効果共に年率 2%とした。
2.7 分析条件の設定の要約
主要分析

その他：HCP の時間的観点からの費用差分析対象とする集造血幹細胞移植の適応とならない

造血幹細胞移植の適応とならない未団

未治療の多発性骨髄腫及び再発治療の多発性骨髄腫及び再発又は又は難治性の多発性骨髄腫(TIE

難治性の多発性骨髄腫(TIE

NDMM & RRMM)

NDMM & RRMM)

比較対照

Dara IV

Dara IV

比較対照を選定しDara SC と Dara IV の添付文書

Dara SC と Dara IV の添付文書

た理由

上の効能または効果、投与間隔は上の効能または効果、投与間隔は同一であることから、Dara IV が同一であることから、Dara IV が比比較対照技術として適切である。

較対照技術として適切である。また

また NCCN ガイドラインにおいてNCCN ガイドラインにおいても、も、Dara SC はすべてのダラツム

Dara SC はすべてのダラツムマブ

マブ投与レジメンにおいて Dara

投与レジメンにおいて Dara SC と

SC と区別されていない。

区別されていない。

分析の立場と費

公的医療の立場

HCP の時間的観点

用の範囲

公的医療費のみ

効果指標

公的医療費

なし（時間および費用のみ）

分析期間

主要分析:32 週間

患者あたりの薬剤投与のための来感度分析:52 週間

院

なし

なし

割引率

その他：シナリオ分析
分析対象とする集再発又は難治性の多発性骨髄腫(RRMM)

団
比較対照

20

Vd 及び Rd

その他：シナリオ分析
比較対照を選定し費用対効果評価専門組織において「最も費用対効果のよい治療法」を選た理由

択し RRMM 患者における分析の比較対照とすることが決定された。本決定について弊社と C2H による議論の上、Vd および Rd を比較対照とす
ることが合意された。
この 2 つの治療法は広く一般的に使用されていると考えられた。またこの
2 つの治療法は他の HTA 評価国で広く償還されており、その費用対効果
は十分に確立されていると考えられる。

分析の立場と費

公的医療の立場

用の範囲

公的医療費のみ

効果指標

QALY、生存年

分析期間

生涯 （30 年）

割引率

費用･効果ともに年率 2%

21

3. Additional Benefits
3.1 Clinical Questions
A systematic literature review (SLR) of randomized clinical trials (RCTs) to
examine additional benefit of daratumumab subcutaneous injection (Dara SC)
among multiple myeloma patients with transplant ineligible newly diagnosed
multiple myeloma (TIE NDMM) and relapsed or refractory multiple myeloma(RRMM) was conducted based on the research questions.
As agreed by expert committee meeting (on 27th August, 2021), the main
analysis will focus on the target population of patients with multiple myeloma(including TIE NDMM and RRMM). The intervention is Dara SC and the comparator
is daratumumab intravenous infusion (Dara IV).
Separately, other analysis was requested to focusing on RRMM patients and thecomparator are set to be bortezomib in combination with dexamethasone (Vd)and lenalidomide in combination with dexamethasone (Rd). After initial search,a study was identified to directly comparing DARA SC and DARA IV, however,there were no study identified directly comparing Dara SC with other selectedcomparators. The search was therefore broadened to include Dara IV assuming
similar efficacy between Dara IV and SC based on the main analysis.
For each of the two research questions, a search strategy was developed using
the designated databases. The outcomes were efficacy, safety and patientreported outcome (PRO). The time frame of the systematic literature search wasfrom 1st January 2011 to 31st October 2021 for the main analysis and scenario
analysis as presented in Table 3-1 and Table 3-2.
•

Table 3-1 Research questions of systematic review – main analysis
Item
Population

Description
Multiple myeloma (including transplant ineligible
NDMM and RRMM)

Intervention

Daratumumab SC

Comparator

Daratumumab IV

Outcome• Efficacy (ORR, PFS, OS)• Safety• HRQoL

Study design

Randomized controlled trial

Literature search period

1st January 2011 to 31st October 2021

HRQoL: health-related quality of life; IV: intravenous; NDMM: newly diagnosed multiple

22

myeloma; ORR: overall response rate; OS: overall survival; PFS: progression-free survival;
Rd: Revlimid (Lenalidomide) + Dexamethasone; RRMM: relapsed refractory multiple
myeloma; SC: subcutaneous; Vd: Velcade (Bortezomib) + Dexamethasone•

Table 3-2 Research questions of systematic review – scenario analysis
Item

Description

Population

RRMM (1L+)

Intervention

Daratumumab (SC and IV*)

Comparator

Vd and Rd

Outcome• Efficacy (ORR, PFS, OS)• Safety• HRQoL

Study design

Randomized controlled trial

Literature search period

1st January 2011 to 31st October 2021

1L: first line of treatment; HRQoL: health-related quality of life; IV: intravenous; ORR:
overall response rate; OS: overall survival; PFS: progression-free survival; Rd: Revlimid(Lenalidomide) + Dexamethasone; RRMM: relapsed refractory multiple myeloma; SC:
subcutaneous; Vd: Velcade (Bortezomib) + Dexamethasone* As there were no study identified comparing Dara SC with the comparator. The search wastherefore broadened to include Dara IV assuming similar efficacy between Dara IV and SC.

3.2 Systematic Review
3.2.1 Implementation flow
In the literature search process, an expert of literature search developed thesearch formula by combining conditions for disease name, drug name, study
design, and search period. Screening based on publication abstracts and thefollowing operation to identify relevant RCTs for the evaluation of additional
benefit were performed with blinding by two independent reviewers. Inclusion or
exclusion of publications was determined based on the prespecified criteria.
Those eligible for inclusion were selected for full text screening and independent
review. Discrepancies were resolved by involving a third investigator andreaching consensus. Articles meeting criteria at the full-text stage were includedin the analysis. Publications and conference abstracts were selected for extracting
the relevant data including the post hoc, updated and subgroup analyses. The
RCTs identified were summarized in a table form with a summary of results.
23

3.2.2 Inclusion and exclusion criteria
The key inclusion and exclusion criteria for the SLR are presented as follows.
3.2.2.1 Inclusion criteria•

The target disease is patients with transplant ineligible NDMM or RRMM forthe main analysis and RRMM patients for the scenario analysis.

•

The intervention is Dara SC (for scenario analysis, at the initial search, we
set the intervention as Dara SC; since, no study was found initially, thesearch was broadened to include Dara IV assuming similar efficacy
between Dara IV and SC).

•The comparator is Dara IV for the main analysis and Rd and Vd for the
scenario analyses.

•

The study design is randomized controlled trial.

•

Published during the designated period (1st January 2011 to 31st October2021).

3.2.2.2 Exclusion criteria•

Meeting minutes or conference details•

Not written in English or Japanese

3.2.3 Database
PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL),
Ichushi-Web, J-stage and ClinicalTrials.gov were used for collection of the target
studies.
3.2.3.1 Search formula
Main analysis
The search formulas for the SLR for main analysis are presented as follows, which
compared Dara SC and Dara IV.
Search formula for PubMed
Date of search: November 02, 2021
#1. (((multiple myelomas[MeSH Terms]) OR ("multiple myeloma")) OR(myeloma-multiple)) OR ("myeloma multiple")#2. (#1) NOT ("transplant-eligible" OR "AL amyloidosis" OR "before and after
autologous stem-cell transplantation " OR "triple-class refractory multiple
24

myeloma" OR "smoldering multiple myeloma")#3. ((Daratumumab[Title/Abstract]) AND (subcutaneous[Title/Abstract])) OR(DARA-SC OR "DARA SC" OR DARZQURO)#4. ((Daratumumab[Title/Abstract]) AND (intravenous[Title/Abstract])) OR(DARA-IV[Title/Abstract] OR "DARA IV"[Title/Abstract] OR
DARZALEX[Title/Abstract])#5. ((Randomized Controlled Trial[Publication Type]) OR ((randomized[Title]
OR randomised)[Title] AND (trial[Title] OR trials)[Title])) OR (randomized
controlled trials as topic[MeSH Terms])#6. #2 AND #3 AND #4 AND #5#7. #2 AND #3 AND #4 AND #5: Filter 2011 to 2021
Number of publications: 05
Search formula for Embase and Cochrane
Date of search: November 02, 2021
#1. ("multiple myelomas" or "multiple myeloma" or myeloma-multiple or"myeloma multiple").mp.
#2. ("transplant-eligible" or "AL amyloidosis" or "before and after autologous
stem-cell transplantation " or "triple-class refractory multiple myeloma" or"smoldering multiple myeloma").mp.
#3. 1 not 2#4. ((Daratumumab and subcutaneous) or (DARA-SC or "DARA SC" orDARZQURO)).ti,ab.
#5. ((Daratumumab and intravenous) or (DARA-IV or "DARA IV" orDARZALEX)).ti,ab.
#6. ("Randomized Controlled Trial" or ((randomized or randomized) and (trial
or trials)) or randomized controlled trials).ti,ab.

25

#7. 3 and 4 and 5 and 6#8. remove duplicates from 7
Number of publications: 14

Search formula for Ichushi Web, J-stage and Clinical trials.gov
Date of search: November 02, 2021
Used keyword: “Daratumumab”
Number of publications•

Ichushi Web: 302•

J-stage: 122•

Clinical Trials.gov: 184

Scenario analysis – initial search
The search formulas for the SR for scenario analysis comparing Dara SC with Rd
and Vd are presented as follows.
Search formula for PubMed
Date of search: November 02, 2021
#1. (((multiple myelomas[MeSH Terms]) OR ("multiple myeloma")) OR(myeloma-multiple)) OR ("myeloma multiple")#2. (#1) NOT ("transplant-eligible" OR "AL amyloidosis" OR "before and after
autologous stem-cell transplantation " OR "triple-class refractory multiple
myeloma" OR "smoldering multiple myeloma")#3. ((Daratumumab[Title/Abstract]) AND (subcutaneous[Title/Abstract])) OR(DARA-SC OR "DARA SC" OR DARZQURO)#4. ((Bortezomib OR Velcade) AND Dexamethasone) OR ((Lenalidomide OR
Revlimid) AND Dexamethasone)#5. ((Randomized Controlled Trial[Publication Type]) OR ((randomized[Title]
OR randomised)[Title] AND (trial[Title] OR trials)[Title])) OR (randomized
controlled trials as topic[MeSH Terms])

26

#6. #2 AND #3 AND #4 AND #5
Number of publications: 0
Search formula for Embase and Cochrane
Date of search: November 02, 2021
#1. ("multiple myelomas" or "multiple myeloma" or myeloma-multiple or"myeloma multiple").mp.
#2. ("transplant-eligible" or "AL amyloidosis" or "before and after autologous
stem-cell transplantation " or "triple-class refractory multiple myeloma" or"smoldering multiple myeloma").mp.
#3. 1 not 2#4. ((Daratumumab and subcutaneous) or (DARA-SC or "DARA SC" orDARZQURO)).ti,ab.
#5. ((Bortezomib or Velcade) and Dexamethasone).mp. or ((Lenalidomide or
Revlimid) and Dexamethasone).ti,ab.
#6. ("Randomized Controlled Trial" or ((randomized or randomized) and (trial
or trials)) or randomized controlled trials).ti,ab.
#7. 3 and 4 and 5 and 6#8. remove duplicates from 7
Number of publications: 9 (NONE of the records are relevant to inclusion criteria
after checking)Search formula for Ichushi Web, J-stage and Clinical trials.gov
Date of search: November 02, 2021
Used keyword: “Daratumumab”
Number of publications:

27•

Ichushi Web: 302•

J-stage: 122

•Clinical Trials.gov: 184(NONE of the records are relevant to inclusion criteria after checking)Since no studies met the inclusion criteria comparing Dara SC with thecomparators (Rd and Vd), the search was extended to include Dara IV.

Scenario analysis – the extended search
The search formulas for the SR for scenario analysis comparing Dara IV with Rd
and Vd are presented below.
Search formula for PubMed
Date of search: November 02, 2021
#1. (((multiple myelomas[MeSH Terms]) OR ("multiple myeloma")) OR(myeloma-multiple)) OR ("myeloma multiple")#2. (#1) NOT ("transplant-eligible" OR "AL amyloidosis" OR "before and after
autologous stem-cell transplantation " OR "triple-class refractory multiple
myeloma" OR "smoldering multiple myeloma")#3. Daratumumab[Title/Abstract]#4. ((Bortezomib OR Velcade) AND Dexamethasone) OR ((Lenalidomide OR
Revlimid) AND Dexamethasone)#5. ((Randomized Controlled Trial[Publication Type]) OR ((randomized[Title]
OR randomised)[Title] AND (trial[Title] OR trials)[Title])) OR (randomized
controlled trials as topic[MeSH Terms])#6. #2 AND #3 AND #4 AND #5#7. #2 AND #3 AND #4 AND #5: Filter 2011 to 2021
Number of publications: 47

Search formula for Embase and Cochrane
Date of search: November 02, 2021
#1. ("multiple myelomas" or "multiple myeloma" or myeloma-multiple or28

"myeloma multiple").mp.
#2. ("transplant-eligible" or "AL amyloidosis" or "before and after autologous
stem-cell transplantation " or "triple-class refractory multiple myeloma" or"smoldering multiple myeloma").mp.
#3. 1 not 2#4. Daratumumab.ti,ab.
#5. ((Bortezomib or Velcade) and Dexamethasone).mp. or ((Lenalidomide or
Revlimid) and Dexamethasone).ti,ab.
#6. ("Randomized Controlled Trial" or ((randomized or randomized) and (trial
or trials)) or randomized controlled trials).ti,ab.
#7. 3 and 4 and 5 and 6#8. Remove duplicates from 7
Number of publications: 131

Search formula for Ichushi Web, J-stage and Clinical trials.gov
Date of search: November 02, 2021
Used keyword: “Daratumumab”
Number of publications: two records were found to be relevant as per
inclusion criteria•

Ichushi Web: 302•

J-stage: 122•

Clinical Trials.gov: 184

3.2.4 Conference search
The search also included the following conference proceedings:

29•

American Society for Clinical Oncology (ASCO);•

American Association for Cancer Research (AACR);•

European Society of Medical Oncology (ESMO);

30•

European Hematology Association (EHA);•

Japanese Society of Hematology (JSH) and•Japanese Society of Medical Oncology (JSMO).

3.2.5 Search results
The results of the SLR were summarized as shown in Figure 3-1 and Figure 3-2
with reference to the flow chart recommended by PRISMA Statement.
•

Figure 3-1 PRISMA statement for the main analysis
Identification of studies via Hand search

Identification of studies via databases

Records identified from
Conferences: (n=54)
ASCO (n=8)
AACR (n=22)
ESMO (n=0)
EHA (n=10)
JSH (n=4)
JSMO (n=1)
IMS (n=9)

Records identified fromdatabases (n = 627)
[PubMed (n=5),
Embase & Cochrane (n=14),
Ichushi (n=302),
J-Stage (n=122), CT.gov(n=184)]
Duplicaterecords
removed (n=3)
Records screened(n=624)

Reports assessed for
eligibility(n=7)

Records excluded(n=617)
Population (n=45)Intervention (n=309)
Study type (n=263)

Reports assessed for
eligibility(n=1)

Reports excluded(n=53)
Duplicate with
databases (n=7)
Population (n=11)Intervention (n=26)
Study type (n=9)

Grey literature search(n=1)

Reports of included studies(n=9)

Clinical trial (n=1)
COLUMBAAACR: American Association for Cancer Research; ASCO: American Society of ClinicalOncology; EHA: European Hematology Association; ESMO: European Society for Medical
Oncology; IMS: International Myeloma Society; JSH: Japanese Society of Hematology;
JSMO: Japanese Society of Medical Oncology

31•Figure 3-2 PRISMA statement for the scenario analysis

Identification of studies via databases

Records identified fromdatabases (n=786)[PubMed (n=47),
Embase & Cochrane(n=131),
Ichushi Web (n=302),
J-Stage (n=122),
CT.gov (n=184)]

Records screened(n=783)

Duplicaterecords
removed(n=3)

Identification of studies via Hand search

Records identified from
Conferences (n=54)
ASCO (n=8)
AACR (n=22)
ESMO (n=0)
EHA (n=10)
JSH (n=4)
JSMO (n=1)
IMS (n=9)

Reports excluded(n=50)
Duplicate with
databases (n=7)
Population (n=11)Intervention (n=23)
Study type (n=9)

Records excluded(n=770)Population (n=53)Intervention (n=338)
Study type (n=379)

Reports assessed for
eligibility(n=13)

Reports assessed
for eligibility(n=4)

Reports of included studies(n=17)CASTOR (n=7), LEPUS (n=1), POLLUX (n=9)

Clinical trial (n=3)
CASTOR, LEPUS, POLLUXAACR: American Association for Cancer Research; ASCO: American Society of ClinicalOncology; EHA: European Hematology Association; ESMO: European Society for Medical
Oncology; IMS: International Myeloma Society; JSH: Japanese Society of Hematology;
JSMO: Japanese Society of Medical Oncology

323.2.6 Listing of clinical studies identified•

Table 3-3 List of identified clinical studies – Main analysis: COLUMBA; scenario analysis: CASTOR, LEPUS and POLLUXClinicalIntervention

Comparator

Sample size

Statistics

study

Primary
analysispublication

Main analysis
COLUMBA

Dara SC

Dara IV• Dara SC: n=263• The Kaplan-Meier method was used to• Dara IV: n=259

estimate time-to-event distributions.

Mateos et. al.
2020[7]• Hazard ratios and 95% CIs were
estimated using a stratified Cox
proportional hazards regression model.
Scenario analysis*
CASTOR

Dara IV + Vd

Vd

• Dara IV + Vd:
n=251• Vd: n=247• The log-rank test method was used tocompared both groups.
• Hazard ratios and 95% CIs were
estimated using a stratified Cox
proportional hazards regression model.
• The Kaplan–Meier method was used toestimate the distributions.
• A stratified Cochran–Mantel–Haenszel
chi-square test was used to test
between-group differences in the

Palumbo et. al.
2016[8]

Clinical

Intervention

Comparator

Sample size

Statistics

study

Primary
analysispublication

overall response rate.
LEPUS

Dara IV+ Vd

Vd• Dara IV + Vd:
n=141• Vd: n=70

• The Kaplan–Meier method was used toestimate the distributions.

Lu et. al.
2021[9]• A stratified Cox regression model withtreatment as the sole explanatory
variable was used to estimate HRs and
95% confidence intervals.
• A stratified Cochran–Mantel–Haenszel
chi-square test was used to measuretreatment differences in the overall
response rate, ≥very good partial
response rate, and ≥CR rate.

POLLUX

Dara IV + Rd

Rd

• Dara IV + Rd:• Stratified log-rank test method was

Dimopoulos et.

n=286

used to compared both groups.

al. 2016[10]• Rd: n=283• Hazard ratios and 95% confidence
intervals were estimated with the useof a Cox regression model, withtreatment as the sole explanatory
variable.

34

Clinical

Intervention

Comparator

Sample size

Statistics

Primary

study

analysispublication• Cochran–Mantel–Haenszel tests wereused to compare overall response rates,
rates of very good partial response or
better, and other binary end points.

Dara: daratumumab; IV: intravenous; Rd: Revlimid + dexamethasone; SC: subcutaneous; Vd: Velcade + dexamethasone* As there were no study identified comparing Dara SC with the comparator. The search was broadened to include Dara IV assuming similar
efficacy between Dara IV and SC.

35

3.2.7 Summary of additional benefit assessment
3.2.7.1 Main analysis
COLUMBA clinical trial
The methodology of the systematic review performed to examine additional
benefit of daratumumab was generally appropriate. Through the systematic
review, following publications related to the RCTs to evaluate the efficacy andsafety of daratumumab were identified. Publications (1), (2) and (3) were originalarticles identified from databases and were associated with COLUMBA trial.
Publication (4) was identified through grey literature search. Publications (5) to(9) were records of presentation at scientific meetings.

(1) Mateos MV, Nahi H, Legiec W, et. al. Subcutaneous versus intravenous

daratumumab in patients with relapsed or refractory multiple myeloma(COLUMBA): a multicentre, open-label, non-inferiority, randomised,phase 3 trial. Lancet Haematol. 2020 May;7(5):e370-e380. doi:
10.1016/S2352-3026(20)30070-3.[7](2) Usmani SZ, Mateos MV, Hungria V, et. al. Greater treatment satisfaction

in patients receiving daratumumab subcutaneous vs. intravenous forrelapsed or refractory multiple myeloma: COLUMBA clinical trial results.
J

CancerRes

Clin

Oncol.

2021

Feb;147(2):619-631.

doi:

10.1007/s00432-020-03365-w.[11](3) Iida S, Ishikawa T, Min CK, et. al. Subcutaneous daratumumab in Asianpatients with heavily pretreated multiple myeloma: subgroup analysesof the noninferiority, phase 3 COLUMBA study. Ann Hematol. 2021
Apr;100(4):1065-1077. doi: 10.1007/s00277-021-04405-2.[12](4) Slavcev M, Spinelli A, Absalon E, Masterson T, Heuck C, Lam A, De Cock

E. Results of a Time and Motion Survey Regarding Subcutaneous versus
Intravenous Administration of Daratumumab in Patients with Relapsed
or Refractory Multiple Myeloma. Clinicoecon Outcomes Res. 2021 Jun
8;13:465-473. doi: 10.2147/CEOR.S302682.[5](5) Mateos MV, Usmani SZ, Grosicki S, et. al. Randomized, Open-Label,

Non-Inferiority,

Phase

3

Study

of

Subcutaneous(SC)

VersusIntravenous (IV) Daratumumab (DARA) Administration in Patients(Pts) with Relapsed or Refractory Multiple Myeloma (RRMM): Body
Weight Subgroup Analysis of Columba. Abstract presented at 61st ASH
Annual Meeting. Orlando United States. 134(Supplement 1) (pp 1906),
2019.[13](6) Usmani SZ, Mateos MV, Nahi H, et. al. Randomized, Open-Label, Non-

Inferiority, Phase 3 Study of Subcutaneous (SC) Versus Intravenous(IV) Daratumumab (DARA) Administration in Patients with Relapsed or
Refractory Multiple Myeloma: Columba Update. Abstract presented at
61st ASH Annual Meeting. Orlando United States. 134(Supplement 1)(pp 1865), 2019. [14](7) Kaiser M, Mateos MV, Usmani SZ, Phase 3, open-label, non-inferiority

study of subcutaneous versus intravenous daratumumab in patientswith relapsed or refractory multiple myeloma: Body weight subgroup
analysis of Columba. Abstract presented at 60th Annual Scientific
Meeting of the British Society for Haematology. Birmingham United
Kingdom. 189(Supplement 1) (pp 22), 2020.[15](8) Mateos

MV, Nahi H, Legiec W, et. al. Efficacy and safety of therandomized,

open-label,

non-inferiority,

phase

3

study

of

subcutaneous (SC) versus intravenous (IV) daratumumab (DARA)
administration in patients (pts) with relapsed or refractory multiple
myeloma (RRMM): COLUMBA. Annual Meeting of the American SocietyofClinicalOncology,

ASCO

2019.

Chicago,IL

UnitedStates.

37(Supplement 15) (no pagination), 2019.[16](9) Mateos MV, Nahi H, Legiec W, et. al. Randomized, open-label, non-inferiority, phase 3 study of subcutaneous (SC) versus intravenous (IV)daratumumab (DARA) administration in patients with relapsed or
refractory multiple myeloma: COLUMBA. Presented at European
Hematology Association (EHA), 2019.[17]The following outcome measures were used for the evaluation of additional
benefit:37•

Primary outcomes: Overall response•

Secondary outcomes: PFS, OS, PRO, and IRR

3.2.7.2 Scenario analysis
CASTOR clinical trial
Publications (1) was identified as a primary analysis of CASTOR clinical trial andpublications (2) to (5) were supporting original articles reporting data forextended follow-up, subgroup analyses and quality of life. Publications (6) and(7) were records of abstract presentation at ASH and EHA conferences,respectively.

(1) Palumbo

A, Chanan-Khan A, Weisel K, et. al. Daratumumab,

Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med.
2016 Aug 25;375(8):754-66. doi: 10.1056/NEJMoa1606038.[8](2) Mateos MV, Sonneveld P, Hungria V, et. al. Daratumumab, Bortezomib,

and Dexamethasone Versus Bortezomib and Dexamethasone inPatients With Previously Treated Multiple Myeloma: Three-year Followup of CASTOR. Clin Lymphoma Myeloma Leuk. 2020 Aug;20(8):509518. doi: 10.1016/j.clml.2019.09.623.[18](3) Spencer A, Lentzsch S, Weisel K, et. al. Daratumumab plus bortezomib

and dexamethasone versus bortezomib and dexamethasone in
relapsed or refractory multiple myeloma: updated analysis of CASTOR.
Haematologica.

2018

Dec;103(12):2079-2087.

doi:

10.3324/haematol.2018.194118.[19](4) Weisel K, Spencer A, Lentzsch S, et. al. Daratumumab, bortezomib,

and dexamethasone in relapsed or refractory multiple myeloma:
subgroup analysis of CASTOR based on cytogenetic risk. J Hematol
Oncol. 2020 Aug 20;13(1):115. doi: 10.1186/s13045-020-009485.[20]38(5) Hungria V, Beksac M, Weisel KC, et. al. Health-related quality of life

maintained over time in patients with relapsed or refractory multiple
myeloma treated with daratumumab in combination with bortezomib
and dexamethasone: results from the phase III CASTOR trial. Br J
Haematol. 2021 May;193(3):561-569. doi: 10.1111/bjh.17321.[21](6) Weisel

KC, Sonneveld P, Mateos MV et. al. Efficacy and Safety of

Daratumumab,

Bortezomib,

andDexamethasone(D-Vd)

VersusBortezomib and Dexamethasone (Vd) in First Relapse Patients (pts)with Multiple Myeloma (MM): Four-Year Update of CASTOR. Presented
at American Society of Hematology (ASH), 2019.[22](7) Weisel

K, Spencer A, Lentzsch S, et. al. Efficacy and safety ofdaratumumab, bortezomib, and dexamethasone (D-Vd) in relapsed or
refractory multiple myeloma (RRMM): Updated subgroup analysis of
CASTOR based on cytogenetic risk. Presented at European Hematology
Association (EHA), 2019.[23]The manufacturer used the following outcome measures for the evaluation of
additional benefit:•

Primary outcomes: PFS•

Secondary outcomes: ORR, OS, safety and HRQoL

LEPUS clinical trial
One publication was identified associated with LEPUS (MMY3009) clinical trial
reporting data for daratumumab plus bortezomib and dexamethasone. LEPUS
study was conducted to confirm that DVd demonstrates similar efficacy andsafety in Chinese patients with RRMM compared with the global phase 3 CASTOR.
(1) Lu J, Fu W, Li W, et. al. Daratumumab, bortezomib, and dexamethasone

versus bortezomib and dexamethasone in Chinese patients withrelapsed or refractory multiple myeloma: Phase 3 LEPUS (MMY3009)
study. Clin Lymphoma Myeloma Leuk. 2021 Sep;21(9):e699-e709.
doi: 10.1016/j.clml.2021.04.012.[9]The manufacturer used the following outcome measures for the evaluation of
additional benefit:39

•Primary outcomes: PFS•

Secondary outcomes: ORR, OS, and safety

POLLUX clinical trial
Publications (1) was identified as a primary analysis of POLLUX clinical trial andpublications (2) to (6) were supporting original articles reporting data forextended follow-up, subgroup analyses and quality of life. Publications (7), (8)and (9) were records of abstract presentation at ASH, 2019 and EHA, 2019conferences.
(1) Dimopoulos MA, Oriol A, Nahi H, et. al. Daratumumab, Lenalidomide,and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016 Oct
6;375(14):1319-1331. doi: 10.1056/NEJMoa1607751.[10](2) Bahlis

NJ, Dimopoulos MA, White DJ, et. al. Daratumumab plus

lenalidomide and dexamethasone in relapsed/refractory multiple
myeloma: extended follow-up of POLLUX, a randomized, open-label,
phase

3

study.

Leukemia.

2020

Jul;34(7):1875-1884.

doi:

10.1038/s41375-020-0711-6.[24](3) Kaufman

JL, Dimopoulos MA, White D, et. al. Daratumumab,

lenalidomide, and dexamethasone in relapsed/refractory myeloma: acytogenetic subgroup analysis of POLLUX. Blood Cancer J. 2020 Nov
3;10(11):111. doi: 10.1038/s41408-020-00375-2.[25](4) Dimopoulos

lenalidomide

MA, San-Miguel J, Belch A, et. al. Daratumumab plus
anddexamethasone

versuslenalidomide

anddexamethasone in relapsed or refractory multiple myeloma: updated
analysis of POLLUX. Haematologica. 2018 Dec;103(12):2088-2096.
doi: 10.3324/haematol.2018.194282.[26]40(5) Suzuki

K, Dimopoulos MA, Takezako N, et. al. Daratumumab,

lenalidomide, and dexamethasone in East Asian patients with relapsed
or refractory multiple myeloma: subgroup analyses of the phase 3
POLLUX

study.

Blood

Cancer

J.

2018

May

1;8(4):41.

doi:

10.1038/s41408-018-0071-x.[27](6) Plesner T, Dimopoulos MA, Oriol A, et al. Health-related quality of life

in patients with relapsed or refractory multiple myeloma: treatment
with daratumumab, lenalidomide, and dexamethasone in the phase 3
POLLUX trial. Br J Haematol . 2021 Jul;194(1):132-139. doi:
10.1111/bjh.17435.[28](7) Kaufman JL, Usmani SZ, San-Miguel J, et. al. Four-Year Follow-up of

the Phase 3 Pollux Study of Daratumumab Plus Lenalidomide andDexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd)
Alone in Relapsed or Refractory Multiple Myeloma (RRMM). Abstract
presented at 61st ASH Annual Meeting. Orlando United States.
134(Supplement 1) (pp 1866), 2019.[29](8) Bahlis N, Dimopoulos MA, White DJ, et al. Three-Year Follow up of thePhase 3 POLLUX Study of Daratumumab Plus Lenalidomide andDexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd)
Alone in Relapsed or Refractory Multiple Myeloma (RRMM). Presented
at American Society of Hematology (ASH), 2019.[30](9) Dimopoulos MA, San-Miguel J, White D, et. al. Efficacy and safety ofdaratumumab, lenalidomide, and dexamethasone (D-Rd) in relapsed
or refractory multiple myeloma (RRMM): updated subgroup analysis of
POLLUX based on cytogenetic risk. Presented at European Hematology
Association (EHA), 2019.[31]The manufacturer used the following outcome measures for the evaluation of
additional benefit:•

Primary outcomes: PFS

Secondary outcomes: ORR, OS and HRQoL

41

3.2.8 Detailed table of clinical trials
A summary of one clinical trial (COLUMBA) that was relevant to the researchquestions for the main analysis is provided in Table 3-4.
For scenario analysis, three clinical trials were identified (CASTOR, LEPUS and
POLLUX) from the searches and the extracted data is reported in Table 3-5.
POLLUX study compared addition of daratumumab with lenalidomide anddexamethasone to lenalidomide and dexamethasone, whereas CASTOR and
LEPUS studies compared addition of daratumumab with bortezomib anddexamethasone to bortezomib and dexamethasone alone.
3.2.8.1 Main analysis•

Table 3-4 List of literature for main analysis – COLUMBA study
Study name

COLUMBA study

Bibliographic

Mateos MV, Nahi H, Legiec W, Grosicki S, Vorobyev

information

V, Spicka I, Hungria V, Korenkova S, Bahlis N,
Flogegard M, Bladé J. Subcutaneous versus
intravenous daratumumab in patients with relapsed
or refractory multiple myeloma (COLUMBA): a
multicentre, open-label, non-inferiority,
randomised, phase 3 trial. The Lancet
Haematology. 2020 May 1;7(5):e370-80.[7]Clinicaltrials.gov

NCT03277105

registry information
Study sites

Multicenter (147 sites in 18 countries)

Study enrollment

October 31, 2017 to December 27, 2018

periodTarget population

Recruited patients with RRMM who had received atleast three previous lines of therapy and had
evidence of response to at least one previous
treatment regimen.

Eligibility criteria•

Eligible patients were aged ≥18 years.

•

Patients had a documented diagnosis ofmultiple myeloma according to theInternational Myeloma Working Group

42

(IMWG) diagnostic criteria.
•

Patients with relapsed or refractory multiple
myeloma had received at least threeprevious lines of therapy, including aproteasome inhibitor and an
immunomodulatory drug, or were double
refractory to both a proteasome inhibitor andan immunomodulatory drug.

•

Patients had evidence of response to at least
one previous treatment regimen.

•

Pretreatment clinical laboratory values
during the screening phase were required toshow adequate bone marrow, liver, andkidney function.

•

Women of childbearing potential had toagree to use two methods of birth control atleast 4 weeks before first treatment doseand had to have a negative pregnancy test 2
weeks before randomization.

Key exclusion•

criteria

Previous treatment with daratumumab orother anti-CD38 therapies.

•

Anti-myeloma treatment within 2 weeks orfive pharmacokinetic half-lives before
randomization.

•

Receipt of an autologous stem cell transplantwithin 12 weeks before randomization.

•

Malignancies other than multiple myeloma,
unless all treatment of that malignancy had
been completed at least 2 years before
consent and the patient had no evidence ofthe disease.

•

Meningeal involvement of the myeloma.

•

Chronic obstructive pulmonary disease with aforced expiratory volume in 1 s of less than43

50% of the predicted normal.
•

Moderate or severe persistent asthma or ahistory of asthma within the last 2 years.

•

Clinically significant cardiac disease.

•

Seropositivity for HIV, hepatitis B, or
hepatitis C.

•

Known allergies to study-relevant
compounds and any other conditions thatmight interfere with the study protocol.

Details of•Dara SC group (n=263)

interventional

Dosing: 1800 mg of daratumumab co-methodformulated with rHuPH20 2000 U/mL.
Patients received daratumumab once weekly (cycles
1 and 2), every 2 weeks (cycles 3–6), and thenevery 4 weeks (28-day cycles).

Details of•comparators

Dara IV group (n=259)
Dosing: 16 mg/kg of daratumumab

Patients received daratumumab once weekly (cycles
1 and 2), every 2 weeks (cycles 3–6), and thenevery 4 weeks (28-day cycles).
Study design

Randomized, phase 3 trial
Randomization was stratified based on baseline
bodyweight, previous therapy lines, and myeloma
type (IgG vs non-IgG).

Blinding method

Open labelPrimary endpoint

Overall response (partial response or better)

Key secondary•

endpoints

Proportion of patients with very good partial
response or better.

•

Proportion of patients with complete
response or better

44•

Time to response•

Duration of response•

Progression-free survival•

Overall survival

Statistical methods•

Time to next therapy•

Patient reported treatment satisfaction•

Incidence of infusion-related reactions•

The Kaplan-Meier method was used toestimate time-to-event distributions.

•Hazard ratios and 95% CIs were estimatedusing a stratified Cox proportional hazards
regression model.

•

The infusion-related reaction rate and rates
of very good partial response or better werecompared between groups using a stratified
Cochran-Mantel-Hansel test.

Sample size•

Dara SC group: n=263•

Dara IV group: n=259

Follow-up period

Median, 7.5 months (IQR 6.5–9.3)

Main background

Dara SC group vs Dara IV groupfactors of subjects•

Male, n (%):136 (52) vs 149 (58)•Median age (range), years: 65 (42–84) vs 68(33–92)•

Median weight, kg*: 72.4 (39–130) vs 73(28.6–138)•

Median time since initial diagnosis, years:
6.01 (0.8–21.1) vs 5.36 (0.6–39)•

Efficacy results

Cytogenetic risk, n (%)
Standard risk: 146 (74) vs 167 (83)High risk: 52 (26) vs 35 (17)Overall Response•

An overall response was observed in 41%(n=108/263) patients in the SC group and
37% (n=96/259) in the IV group (RR 1.11,
95% CI 0.89–1.37).

PFS•Median PFS was 5.6 vs 6.1 months for SC
group vs IV group, respectively (HR 0.99,

4595% CI 0.78–1.26, p=0.93).
OS•

Six-month survival was 88% (95% CI, 83–91) with SC daratumumab and 83% (95%CI, 78–87) with IV daratumumab.

•

Follow-up was short and therefore OS data
were not mature.

Patients with very good partial response•

Proportion of patients with very good partial
response or better was similar between the
SC and IV groups (50 [19%] vs 44 [17%]);
OR 1.16, 95% CI 0.73–1.85, p=0.53).

Safety results

IRRs•

IRR was significantly lower for SC group vsIV group•

Dara SC group: 13%, n=33/260

Dara IV group: 34%, n=89/258



OR 0.28, 95% CI 0.18–0.44, p<0.0001

The most common IRR were chills (5% vs
12% patients), pyrexia (5% vs 3%) anddyspnea (1% vs 7%) in SC group vs IV
group, respectively.

•

With IV group, IRR led to dose interruptionsfor 79 (31%) patients, one instance of aterminated infusion, decreases in infusion
rate in 26 (10%) patients and two treatment
discontinuations.

•

Whereas, with Dara SC, there was notreatment discontinuation, dose interruption
or incomplete dose administration.

•Median time to onset for IRRs afteradministration of first dose was longer in the
SC group (3.4 h, IQR 1.5–4.4, range 1–47.8)
than IV group (1.5 h, 1–1.8, 0–24.5).

46

SAEs
•

Serious adverse events occurred in 26% vs
29% patients in the SC vs IV group•

The most common adverse events leading todiscontinuation were thrombocytopenia (2patients in SC group vs 5 in IV group),
anemia (2 vs 3) and septic shock (2 vs 3).

Patient-reported

Satisfaction with therapy [1, 5]: Cancer Therapy

outcomeSatisfaction Questionnaire (CTSQ)
Patients in the SC group responded more positively
to individual components of following parameters vsIV group:•

Satisfied with form of cancer therapy•

Taking cancer therapy as difficult as
expected•

Were side effects as expected

The Time and Motion survey[5] observed that
reduced treatment time which may resulted inincreased satisfaction and improved HRQoL.
HCP-reported•

outcomes[7]Time savings for Dara SC compared with
Dara IV:•First treatment: 63.8%

Subsequent treatments: 49.5%

Drug preparation time stayed consistent
between first and subsequentadministrations and was also relatively
consistent between the Dara SC and Dara IV
formulations.

•

Drug administration duration was reduced
for Dara SC versus Dara IV for primary
analysis by:

•

47



First treatment: 99%

Subsequent treatments: 98%

Active HCP involvement was reduced forDara SC versus Dara IV for primary analysis
by:

•



First treatment: 96%

Subsequent treatments: 91%

Estimated active HCP time per patient was
reduced for Dara SC compared with Dara IV
by 50% each for year 1 and year 2.

•

Estimated patient chair time was reduced forDara SC compared with Dara IV for primary
analysis by 97% each for first andsubsequent treatments.

Limitations•

Patients and physicians were not masked totreatment.

•

Bias cannot be excluded in adverse-event
reporting or responses to the modified CTSQ.

Conclusion•

Dara SC was non-inferior to Dara IV in termsof efficacy and had an improved safety
profile, especially in IRR.

•

The time and motion survey showed that
Dara SC is associated with substantial
reduction in active HCP time, duration of
drug administration and patient chair usage
compared with Dara IV.

48

3.2.8.2 Scenario analysis•

Table 3-5 List of literature for scenario analysis
Study nameCASTOR study

LEPUS (MMY3009) study

POLLUX study

Bibliographic

Palumbo A, Chanan-Khan A,

Jin Lu, Weijun Fu, Wei Li,

Dimopoulos MA, Oriol A, Nahi

information

Weisel K, Nooka AK, Masszi

Jianda Hu, Gang An, Yafei

H, San-Miguel J, Bahlis NJ,

T, Beksac M, Spicka I,

Wang, Chengcheng Fu, Lijuan

Usmani SZ, Rabin N, Orlowski

Hungria V, Munder M, Mateos

Chen, Jie Jin, Xinan Cen, Zheng

RZ, Komarnicki M, Suzuki K,

MV, Mark TM, Qi M, Schecter

Ge, Zhen Cai, Ting Niu, Ming

Plesner T, Yoon SS, Ben

J, Amin H, Qin X, Deraedt W,

Qi, Steven Sun, Xue Gai,

Yehuda D, Richardson PG,

Ahmadi T, Spencer A,

Weiping Liu, Wenyu Liu, Xue

Goldschmidt H, Reece D, Lisby

Sonneveld P; CASTOR

Yang, Xiaojun Huang.

S, Khokhar NZ, O'Rourke L,

Investigators: Daratumumab,

Daratumumab, Bortezomib,

Chiu C, Qin X, Guckert M,

Bortezomib, andand Dexamethasone Versus

Ahmadi T, Moreau P; POLLUX

Dexamethasone for Multiple

Bortezomib andInvestigators. Daratumumab,

Myelom, N Engl J Med

Dexamethasone in Chinese

Lenalidomide, and2016;375(8):754-66.[8]Patients with Relapsed or

Dexamethasone for Multiple

Refractory Multiple Myeloma:

Myeloma. N Engl J Med

Phase 3 LEPUS (MMY3009)

2016;375:1319-31.[10]Study. Clin Lymphoma
Myeloma Leuk. 2021
Sep;21(9):e699-e709. doi:
10.1016/j.clml.2021.04.012.[9]Study nameCASTOR study

LEPUS (MMY3009) study

POLLUX study

Clinicaltrials.gov

NCT02136134

NCT03234972

NCT02076009

Multicenter (115 centers in

Multicenter (27 sites in China

Multicenter (135 sites in 18

16 countries across Europe,and Taiwan)

countries across Northregistry information
Study sites

North America, SouthAmerica, Europe, and the Asia

America, and the Asia-PacificPacific region)

region)Study enrollment

September 2014 toDecember 24, 2017 to August

periodSeptember 2015

6, 2019

Target population

Patients had relapsed orPatients had received at least 1

Patients had relapsed or

refractory multiple myeloma

prior line of therapy forrefractory multiple myeloma

and received one or more

multiple myeloma, had at leastand received one or more lines

lines of previous therapy.

a partial response to at least 1of previous therapy.

June 16, 2014 to July 14, 2015prior multiple myeloma
regimen.
Eligibility criteria•

Patients who had

50

Patients were ≥18 years of•Patients had documented

received at least one

age and had documented

multiple myeloma andprevious line of therapy

multiple myeloma.

measurable disease at

Received at least 1 priorscreening according toPatients had at least aline of therapy for multiple

serum or urinary M-

partial response to one

myeloma.

protein levels or serum

for multiple myeloma•••

Study nameCASTOR study
or more of their previous•

LEPUS (MMY3009) study
Had at least a partial

free light-chain levels andtherapies, and had

response to at least 1 priorabnormal serum

documented progressive

multiple myeloma

immunoglobulin free light-

diseaseregimen; had documented

chain ratios (kappa:

At screening, all patients

progressive disease

lambda light chains).

were required to haveaccording to International

measurable disease

Myeloma Working Groupdisease according tobased on assessments of(IMWG) criteria on or afterInternational Myeloma

the serum, urine, or

their last regimen.

Working Group (IMWG)••

Patients had progressive

both or to have•

ECOG PS score of ≤2.

criteria during or after themeasurable disease as•

Had measurable disease atreceipt of their lastassessed by the serum

screening based on serum

regimen, received and had

free light-chain assay

M-protein level (≥1 g/dL

a response to one or more

or 0.5 g/dL for patientslines of previous therapy.

with IgA, IgD, IgE, or IgM
multiple myeloma), urine
M-protein level (≥200
mg/24 hours), or serum Ig
free light chain ≥10 mg/dL
with abnormal serum Ig
kappa lambda free light
51

POLLUX study

Study nameCASTOR study

LEPUS (MMY3009) study

POLLUX study

chain ratio (for patients
without measurable Mprotein in serum andurine).
•And had any toxicities
from prior therapy
resolved or stabilized to≤grade 1.

Key exclusion•

criteria

Neutrophil count of 1000

52•

Key exclusion criteria wererefractory to a proteasome

lenalidomide-refractory

millimeter, a hemoglobin

inhibitor or were intolerant

diseaselevel of 7.5 g or less per

to bortezomib.

•

The discontinuation ofPatients who received

previous Lenalidomide

prior anti-CD38 therapies.

treatment owing toPatients who received

adverse events, amillimeter, a creatinine

anti-myeloma treatment

neutrophil count ofclearance of 20 ml orwithin 2 weeks or 5

1.0×109 or less per liter, aless per minute per 1.73

pharmacokinetic half-lives

hemoglobin level of 7.5 g

m2 of body-surface areaof treatment, whicheveror less per deciliter, a

An alanine

was longer, before

platelet count of less thanaminotransferase or

randomization.

75×109 per liter•

Platelet count of lessthan 75,000 per cubic•

Patients who had diseaseor less per cubic

deciliter•••Study nameCASTOR study
aspartate•••

Patients who planned to

POLLUX study•

An alanine

aminotransferase level

undergo a stem cellaminotransferase orof ≥2.5 times the uppertransplantation prior toaspartate amino

limit of the normal

progression of disease ontransferase level of 2.5 orrange, and a bilirubin

this study.

more times the upper limit

Patients who hadof the normal range,level of ≥1.5 times the•

LEPUS (MMY3009) study•

upper limit of the normal

meningeal involvement ofrange

multiple myeloma; gradelevel of 2.5 or more times

Patient refractory to≥2 peripheral neuropathy

the upper limit of thebortezomib that wasor neuropathic pain;

normal range

refractory to anotherchronic obstructive

proteasome inhibitor

pulmonary disease with amore times the upper limit

Patients had

forced expiratory volumeof the normal range, and a

unacceptable side effects

in 1 second <50% of

creatinine clearance of lessfrom bortezomib

predicted normal;

than 30 ml per minute.

Grade ≥2 peripheral

uncontrolled asthma;

neuropathy ormoderate or severe

neuropathic pain

persistent asthma within••

An alkaline phosphatase

A bilirubin level of 1.5 or

the previous 2 years.
Details ofDaratumumab group:

Daratumumab group:

Daratumumab group:interventional

Daratumumab + Bortezomib

Daratumumab + Bortezomib

Daratumumab + Lenalidomide

53

Study nameCASTOR study

LEPUS (MMY3009) study

POLLUX study

method+ Dexamethasone (DVd)and dexamethasone (DVd)+ Dexamethasone (DRd)Dosing:
•

•

•

•

54

Dosage:Daratumumab at a dose

Dosing: Daratumumab 16

of 16 mg per kilogram

mg/kg IV was administeredkilogram IV administeredadministeredweekly during cycles 1 throughweeklyintravenously once per

3, every 3 weeks during cycles

week

4 through 8, and every 4

Bortezomib administeredweeks and received up to eightsubcutaneously at 1.3

21-day cycles of bortezomib

mg per square meter

1.3 mg/m 2 subcutaneously on

Patients received daratumumab

Dexamethasone at adays 1, 4, 8, and 11 of eachon days 1, 8, 15, and 22 for 8

dose of 20 mg per cycle

cycle and dexamethasone 20

weeks during cycles 1 and 2,(Orally or intravenously)

mg orally or IV on days 1, 2, 4,

every 2 weeks (on days 1 andPatients received

5, 8, 9, 11, and 12 of each15) for 16 weeks (cycles 3

daratumumab

cycle. A reduced dose ofthrough 6), and every 4 weeks.

intravenously once per

dexamethasone (20 mg

Lenalidomide administeredweek (days 1, 8, and 15)

weekly).

orally on days 1 to 21 of each••

Daratumumab: 16 mg per

Lenalidomide: 25 mg
orally•Dexamethasone: 40 mg
weeklyduring cycles 1 to 3,

cycle if the creatinine clearance

once every 3 weeks (onwas more than 60 ml per

day 1) during cycles 4 tominute.

8, and once every 4

The dose of dexamethasone

Study nameCASTOR study

LEPUS (MMY3009) study

POLLUX study

weeks until the patient

was administered at a dose ofwithdrew consent, the20 mg before infusion as

disease progressed, or

prophylaxis for infusion-related

unacceptable toxic

reactions and 20 mg was

effects developed.

administered the next day.

Patients received
Bortezomib on days 1, 4,
8, and 11 of cycles 1 to
8. Dexamethasone
administered on days 1,
2, 4, 5, 8, 9, 11, and 12.
Details ofControl group: Bortezomib +Control group: Bortezomib +Control group: Lenalidomide +comparators

Dexamethasone (Vd)

Dexamethasone (Vd)

Dexamethasone (Rd)

Dosing:Dosing: Patients received up to

Dosing:••Bortezomib administeredeight 21-day cycles ofsubcutaneously at 1.3

bortezomib 1.3 mg/m 2

mg per square metersubcutaneously on days 1, 4,

Dexamethasone at a8, and 11 of each cycle anddose of 20 mg per cycle

dexamethasone 20 mg orally or(orally or intravenously)

IV on days 1, 2, 4, 5, 8, 9, 11,
and 12 of each cycle. A

55•

Lenalidomide: 25 mg
orally•Dexamethasone: 40 mg
weeklyStudy nameCASTOR study

LEPUS (MMY3009) study

POLLUX study

reduced dose of
dexamethasone (20 mg
weekly)Study design

Randomized, phase 3 trial

Randomized, phase 3 trial

Randomized, phase 3 trial

Randomization was assigned

Randomization was assigned in

Randomization was assigned inin a 1:1 ratio.

a 2:1 ratio.

a 1:1 ratio

Blinding method

Open label

Open label

Open labelPrimary endpoint

Progression-free survival

Progression-free survival

Progression-free survival

Key secondary•

endpoints

Time to disease•progression•

Overall response rate•

Proportion of patients
who achieved very good

•

56

•

response or better)••partial response or
betterOverall response (partial•

Very good partial response

Time to diseaseprogression•

Overall response rate, rate

or betterof very good partial

Median duration of

response or better

response(comprising very goodTime to response

partial, complete, andDuration of response,

stringent complete

the time to response

responses)•

Overall survival•

The time to subsequentor better (comprising

antimyeloma treatmentcomplete and stringent

was an exploratorycomplete responses)•

Rate of complete responseStudy nameCASTOR study

LEPUS (MMY3009) study

efficacy end point.

POLLUX study•

Percentages of patientswith results below thethreshold for minimal
residual disease, time toresponse, duration of
response, and overall
survival

Statistical analysis

•

•

•

The log-rank test

57

The Kaplan–Meier method•

Stratified log-rank test

method was used to

was used to estimate themethod was used tocompared both groups.

distributions.

compared both groups.

Hazard ratios and 95%•

A stratified Cox regression•

Hazard ratios and 95%

CIs were estimatedmodel with treatment asconfidence intervals wereusing a stratified Cox

the sole explanatory

estimated with the use of

proportional hazards

variable was used toa Cox regression model,

regression model.

estimate HRs and 95%

with treatment as the sole

The Kaplan–Meierconfidence intervals.

explanatory variable.

method was used to

•

•

•

A stratified Cochran–•Cochran–Mantel–Haenszel

estimate theMantel–Haenszel chi-tests were used to

distributions.

square test was used tocompare overall response

A stratified Cochran–measure treatment

rates, rates of very good

Mantel–Haenszel chi-differences in the overall

partial response or better,

Study nameCASTOR study

LEPUS (MMY3009) study

POLLUX studysquare test was used toresponse rate, ≥very goodand other binary end

test between-group

partial response rate, andpoints. Duration ofdifferences in the overall≥CR rate.

response was assessed byresponse rate.

means of the Kaplan–
Meier method.

Sample size•

Daratumumab group:

•

n=251
•
Follow-up period

Control group: n=247

Primary analysis, median: 7.4

Daratumumab group:

•

n=141
•

Control group: n=70

Median, 8.2 months

Daratumumab group:
n=286

•

Control group: n=283

Primary analysis, median: 13.5

monthsmonthsUpdated analysis, median: 40

Updated analysis, median: 44.3

monthsmonthsMain background

Daratumumab group vs

Daratumumab group vs control

Daratumumab group vs control

factors of subjects

control group

group

group

•

Median age (range),•

years: 64 (30–88) vs 64(33–85)••Median age (range),

42 (60.0)

years: 65 (34–89) vs 65

Median age (range),(42–87)

Median time since initial

years: 61.0 (28-79) vsdiagnosis, years: 3.87

61.0 (43-82)

diagnosis, years: 3.5 (0.4–Median time since initial

27.0) vs 4.0 (0.4–21.7)(0.7–20.7) vs 3.72 (0.6–
18.6)
58

•

Male, n (%): 85 (60.3) vs•diagnosis, years: 3.53••

Median time since initial

Cytogenetic risk, n/n (%)

Study nameCASTOR study•(0.6-11.5) vs 3.45 (0.8-lines of therapy (range):

14.1)

193/228 (84.6) vsMedian no. of previous

176/211 (83.4)•

Cytogenetic risk, n (%)


•

137/174 (78.7)
Standard risk:

High risk: 35/228(1-11) vs 2 (1-7)(15.4) vs 35/211

Cytogenetic risk, n (%)(16.6)

High risk: 41/181

Standard risk: 92(66.7) vs 41 (60.3)(22.7) vs 37/174

(21.3)High risk: 46 (33.3)
vs 27 (39.7)

Primary analysis[2]Primary analysis [3]Primary analysis[4]Overall response

Overall Response

Overall Response•

The overall response

An overall response wasrate was 82.9% in theobserved in 82.5%

was 92.9% in

daratumumab group and(n=113/137) patients in the D-

Daratumumab group vs.

63.2% in the control

Vd and 65.1% (n=41/63) in Vd

76.4% in the control

group (p<0.001).

(p= 0.00527).

group (p<0.001).

PFS
•

•

The overall response rate

>CR or better 32.8%

PFS

The 12-month rate of(n=45/137) vs 11.1%•

PFS rate was 60.7%(n=7/63); p=000.79.

reached in Daratumumab

VGPR or bettergroup compared with 18.4•

(95% CI, 51.2-69.0) in
59

lines of therapy (range): 2

Standard risk:
140/181 (77.3) vsEfficacy results

POLLUX study

Median no. of previous
2 (1–9) vs 2 (1–10)•

LEPUS (MMY3009) study•

Median PFS was notStudy nameCASTOR study

LEPUS (MMY3009) study

the daratumumab group

65%(n=89/137) vs 33.3%

months in the control

as compared with 26.9%(n=21/63); p=0.0002

group (HR 0.41; 95% CI(95% CI, 17.1-37.5) inthe control group.

Subgroup analysis•

OS

Patients with 1 prior line of

0.26-0.66; p<0.001).
•

The Kaplan–Meier PFS ratetherapy: 90.2% vs.

at 12 months was 83.2%

Remained immature at

66.7%; OR, 4.63; 95% CI,(95% CI, 78.3-87.2) inthe time of primary

1.11-19.19.

the daratumumab group

Patients with priorand 60.1% (95% CI, 54.0-

Partial and complete

bortezomib treatment:

65.7) in the control group.

response

81.1% vs. 62.0%; OR,•analysis.

••

Partial response or
better n=142 (59.2% vs.

2.64; 95% CI, 1.24-5.58.

OS•

Kaplan–Meier rate of

The ORR was higher withoverall survival at 12

29.1%, and complete

DVd versus Vd in themonths was 92.1% (95%

response or better n=68

standard-risk cytogenetic

CI, 88.2-94.7) in the(19.2% vs. 9.0%,

abnormalities subgroup

daratumumab group and

p<0.001)(85.6% vs. 57.9%; OR,

86.8% (95% CI, 82.2-

Exploratory, post hoc,

4.31; 95% CI, 1.80-

90.3) in the control groupsecondary analysis[16]10.30).

Patients with very good partial

The ORRs were similar

response

Median follow-up: 19.4

60

POLLUX study••

monthswith DVd and Vd in thePFShigh-risk cytogenetic•

Partial response or better
response (43.1% vs.

Study nameCASTOR study•

LEPUS (MMY3009) study

Daratumumab groupabnormality’s subgroup19.2%, p<0.001).

significantly prolonged(75.0% for both groups;

Updated exploratory, post

PFS as compared toOR, 1.00; 95% CI, 0.32-

hoc, secondary subgroupcontrol group (16.7 vs3.15).

analyses[11]7.1 months; HR, 0.31;

PFS

95% CI, 0.24-0.39;

ITT population•

PFS: Daratumumab group
improved PFS comparedmonths; HR 0.28; 95% CI,with control group

ORR was significantly

0.17-0.47; p<0.00001 for(median not reached vs.

improved with DVd

DVd vs Vd, respectively.

17.5 months; HR, 0.41;

The estimated 12-month

95% CI, 0.31-0.53;

versus 63.2%;

PFS rate was 62.4% with

p<0.0001).

p<0.0001), including

DVd versus 24.2% withhigher rates of stringent

Vd.

rate was 92.9% vs 76.4%,

The median time toand 51.2% vs 21.0%(8.8% vs 2.6%), CR or

disease progression wasachieved a complete

better (28.8% vs 9.8%;

significantly prolonged

response or better,

p<0.0001), and very

with DVd versus Vd

respectively (bothgood partial response or(median, NR vs. 6.5

p<0.0001) and deeper

better (62.1% vsmonths; HR, 0.26; 95%

responses, including

29.1%; p<0.0001).

CI, 0.15-0.46; p<0.00001.

complete response or•ORR

versus Vd (83.8%

complete response

61

Median follow-up: 25.4 months
Median PFS was NR vs 6.3

p<0.0001)•

POLLUX study

•

•

•

ORR: The overall responseStudy nameCASTOR study

LEPUS (MMY3009) study

OS

Subgroup analysis[9]•Remained immature atbetter (56.6 vs 23.2%;

Patients with 1 prior line of

p<0.0001).

the time of secondary

therapy: Median PFS was•

OS: Data was immature

analysis.

NR vs 6.3 months; HR•

Subgroup analyses

Updated three-year

0.16; 95% CI, 0.06-0.47

determined that thefollow-up data[18]for DVd vs Vd,

clinical benefit ofMedian follow-up: 40 months

respectively.

daratumumab wasWith prior bortezomib

maintained in patients

prolonged for patientstreatment: Median PFS

regardless of cytogenetic

receiving daratumumab

was NR vs 5.0 months; HRrisk status prior lines ofversus control group0.31; 95% CI, 0.19-0.51

therapy received, prior(median, 16.7 months

for DVd vs Vd,

treatment exposurevs. 7.1 months; HR,

respectively.

(thalidomide orHigh cytogenetic risk:

lenalidomide), or time

0.40; p<0.0001). PFSMedian PFS was 10.9

since last therapy.

benefit was maintainedmonths vs 6.3 months;

Extended follow-up[24]across patient

HR, 0.36; 95% CI, 0.18-

Median follow-up: 44.3 months

subgroups, including

0.75 for DVd vs Vd,

patient age andrespectively.

•

PFS was significantly

0.31; 95% CI, 0.25-

•
62

•

POLLUX study••

cytogenetic risk status.

OS

ORR was significantly••

PFS: Daratumumab group
significantly prolonged PFS
compared with control

The estimated 12-monthgroup (median, 44.5 vsStudy nameCASTOR study

OS rate was 87.8% with

17.5 months; HR, 0.44;

daratumumab group vs

DVd versus 68.2% with

95% CI, 0.35–0.55;

control group (85% vsVd.

p<0.0001).
•

OS was not reached.

ORR: Significant
improvement was

Subgroup analysis based

observed in Daratumumabon cytogenetic risk

group compared withstatus[20]control group (92.9 vsMedian follow-up: 40 months

76.4%; p<0.0001).

PFS

Cytogenetic subgroup

Daratumumab group

analysis[25]prolonged median PFSMedian follow-up: 44.3 months

compared with control groupin patients with:
•

•

63

POLLUX study

improved with

63%).
•

LEPUS (MMY3009) study•

PFS: Daratumumab groupprolonged PFS vs control

Standard cytogenetic

group in patients withrisk (16.6 months vs 6.6

standard cytogenetic riskmonths; HR, 0.26; 95%(median, not estimable vsCI, 0.19–0.37;

18.6 months; HR, 0.43;

p=0.0001)

95% CI, 0.32–0.57; p<

High cytogenetic risk

0.0001) and high(12.6 vs 6.2 months;

cytogenetic risk (median,Study nameCASTOR study

LEPUS (MMY3009) study

POLLUX study

HR, 0.41; 95% CI, 0.21–

26.8 months vs 8.3

0.83; p=0.0106)

months; HR, 0.34; 95%

ORR

CI, 0.16–0.72; p=0.0035).

Higher overall response rate•

was achieved withof VGPR or better and CR

Daratumumab group vsor better were higher with

control group:

daratumumab group••

Standard risk: 84% vscompared with control

62%, p<0.0001

group, regardless ofHigh risk: 85% vs 56%,

cytogenetic risk status.

p=0.051
Safety results

Primary analysis[8]
•

•

64

ORR: The ORR and rates

Daratumumab group and•Primary analysis[9]•Patients reported at least

OS: Data was immature.

Primary analysis[10]•The rate of infection of

the control group had at

1 TEAE, and grade 3/4

grade 3/4 was slightly

least one adverse event

TEAEs were reported inhigher in theafter the start of

89.3% of patients in thedaratumumab group thantreatment (98.8% and

DVd group and 75.0% of

in the control group95.4%, respectively).

patients in the Vd group.

(28.3% and 22.8%,

The incidence ofrespectively).

Hematologic adverse•

events were observed

treatment-emergent

higher rates in thecytopenias was high with•

The most common
adverse events leading toStudy nameCASTOR study

DVd (any grade, 97.1%;

death were acute kidney

than in the control group

grade 3/4, 72.1%) and Vd

injury (in 0.4% of theof any grade of(any grade, 91.2%; grade

patients in thethrombocytopenia

3/4, 58.8%).

daratumumab group andThrombocytopenia (DVd,in 1.1% in the control

neutropenia (17.7% vs.

51.4%; Vd, 36.8%) andgroup), septic shock (in9.3%), and lymphopenia

lymphopenia (DVd,1.1% and 0.4%,(13.2% vs. 3.8%)

43.6%; Vd, 29.4%) wererespectively), andNon-hematologic

the two most commonly

pneumonia (in 0.7% inadverse events, the ratereported grade 3/4 TEAEs

each group).

of peripheral sensory

in both treatment groups.

neuropathy was higher•

65

POLLUX study

daratumumab group(58.8% vs. 43.9%),•

LEPUS (MMY3009) study••

The percentage of patients

A higher incidence ofwith adverse eventsin the daratumumab

infections was reported

leading to thegroup than in the control

with DVd versus Vd (anydiscontinuation ofgroup (47.3% vs.

grade, 81.4% vs. 63.2%,

treatment was similar in

37.6%).

respectively; grade 3/4,

the two groups: 6.7% in

The rates of grade 3/4

54.3% vs. 41.2%),the daratumumab groupinfections andprimarily attributed to aand 7.8% in the control

infestations were similar

higher incidence of anygroup.

in the two groups

grade and grade 3/4 upper

SAEs(21.4% and 19.0%,

respiratory tract infection••

Serious adverse events

Study nameCASTOR study

LEPUS (MMY3009) study

POLLUX study

respectively), and the(any grade, 37.9% vs.

were reported in 48.8% ofrates of bleeding events

22.1%; grade 3/4, 13.6%

the patients in theof any grade were 7.0%

vs. 4.4%) and lungdaratumumab group andin the daratumumab

infection (any grade,

42.0% in the control

group and 3.8% in the

37.1%; vs. 27.9%; gradegroup.

control group.

3/4, 30.0% vs. 22.1%).

•

IRRs
•

common SAE (in 8.1% in
Any grade infusion-

daratumumab group andrelated reactions

8.5% in control group).

associated withdaratumumab were

•

IRRs
•

The incidence ofreported in 45.3% of thedaratumumab IRRs of any

patients.

grade was 47.7%, with

Infusion-related

92% of the reactions

reactions were mostly

occurring during the firstlimited to grade 1 or 2

infusion. These reactions

events; at least one

were mostly of grade 1 orgrade 3 event was2.

reported in 21 patients

66

Pneumonia was the most•

The most common(8.6%), and no grade 4

infusion-related reactions

events were reported.

were cough (8.5% of theStudy nameCASTOR study•

LEPUS (MMY3009) study

POLLUX study

The most common

patients), dyspnea

adverse event were

(8.5%), and vomiting

dyspnea (10.7%),(5.7%).

bronchospasm (9.1%),•

and cough (7.0%).

(5.3%) had grade 3

Exploratory, post hoc,

infusion reactions, and nosecondary analysis[19]patient had an event ofMedian follow-up: 19.4

grade 4 or 5.

months•Updated exploratory, post

The safety profile ofhoc, secondary subgroup

daratumumab group

analyses[26]remained consistent withMedian follow-up: 25.4 months

longer follow up.

•

Safety profile remained

Subgroup analysis based

unchanged from theon cytogenetic risk

primary analysis.

status[18]Median follow-up: 40 months•

67

A total of 15 patients•

The most common
treatment-emergent

Safety profile ofadverse events of any

daratumumab ingrade included

standard and highneutropenia, anemia,

cytogenetic risk

thrombocytopenia,

Study nameCASTOR study

LEPUS (MMY3009) study

POLLUX study

subgroups was

diarrhea, fatigue, upperconsistent with therespiratory tract infection,

overall population of

cough, constipation,

CASTOR.

muscle spasms,

Updated three-year

nasopharyngitis, andfollow-up data[20]nausea.

Median follow-up: 40 months•••

The most common

No new safety concerns

adverse events (≥1%)

were observed comparedleading to treatment

with previous analyses.

discontinuation in

Most common grade 3/4

daratumumab group

TEAEs in thecompared with control

daratumumab vs control

group included pneumonia

group were

(1.4%vs. 0.7%),

thrombocytopenia (46%pulmonary embolism (0%vs. 33%), anemia (16%vs. 1.1%), generalvs. 16%), andphysical healthpneumonia (10% vs.

deterioration (1.1% vs.

10%).

0%), and renal failure(0.4% vs. 1.1%),
respectively.

68

Study nameCASTOR study

LEPUS (MMY3009) study

POLLUX study
Extended follow-up[24]Median follow-up: 44.3 months•

No new safety concerns
were reported in either
treatment group withlonger follow-up.

Cytogenetic subgroup
analysis[25]Median follow-up: 44.3 months•

The safety profile ofdaratumumab group bycytogenetic risk wasconsistent with the overall
population.

Patient-reported

Primary analysis[8, 21]

outcomes

EORTC QLQ-C30(Daratumumab group n=227
vs control group n=219)•

69

Not reported

Primary analysis[28]
EORTC QLQ-C30•

Mean changes frombaseline were significantly

Mean changes fromgreater in global healthbaseline were generally

status, physicalsimilar between

functioning, and painStudy nameCASTOR study•

scores in the

GHS, functioning andDaratumumab group vssymptoms, and did not

the Control group;

exceed 10 points for

however, magnitude ofeither treatment groupchanges was low,(meaningful change, 5suggesting no meaningfulmonths vs. 5.1 months).

impact on HRQoL.

Subgroup analyses•

For subgroup analysis, inbased on age (<65 years

both treatment groups,

vs. ≥65 years), ECOG

changes from baseline

performance status (0 orwere generally in favour of

1 vs. 2) and depth ofyounger patients versus

response (≥VGPR vs.

older patients for GHS,

≥PR) were consistentemotional, cognitive, andwith the resultssocial functioning scores,

observed in the overall

and pain and fatigue

population.

symptom scores.

group n=225 vs control group
n=216)

70

POLLUX study

treatment groups for

EQ-5D-5L (daratumumab•

LEPUS (MMY3009) study

Median time to a

EQ-5D-5L VAS•

Mean EQ-5D-5L VAS
scores were maintainedwith treatment in bothStudy nameCASTOR study

LEPUS (MMY3009) study

POLLUX study

meaningful change was
5 months for both••

For subgroup analysis,treatment groups (HRirrespective of treatment

1.03; 95% CI: 0.79–

group, changes from

1.35; p=0.8072).

baseline in VAS scores

For subgroup analysis,

generally favoured

Subgroup analyses

younger patients, thosedemonstrated stability ofwith an ECOG

baseline EQ-5D-5L VAS

performance status of 0 orscores regardless of age

1, and those with ≥VGPR.

(<65 years vs. ≥65

Updated exploratory, post

years) or depth ofhoc, secondary subgroupresponse (≥VGPR vs.

analyses[26]≥PR).

Median follow-up: 25.4 months

Exploratory, post hoc,•

No decline in HRQoL

secondary analysis[19]measures were observed

Median follow-up: 19.4

with the addition ofmonthsdaratumumab.

•

No significant differences
in EORTC QLQ-C30
global health status and71

DRd and Rd groups.

Study nameCASTOR study

LEPUS (MMY3009) study

POLLUX study

EQ-5D-5L Utility Score
and VAS score wereobserved.
Limitations••

Incomplete cytogenetic

Not reported•

Small sample size withabnormality data.

previous exposure to

Cytogenetic testing was

lenalidomide.

performed locally and no•PROs were evaluated as

per-protocol specific cut-secondary endpoints andoff values were used for

were not powered todefining the presence ofdetect differences between

genetic abnormalities.

treatment groups.
•

Only a subset of patient
samples was collected forcentral cytogenetic
testing.

Conclusion

•

•

72

DVd group resulted in•

LEPUS study confirmed•

DRd was associated with asignificantly longer PFS,

that DVd demonstrated

significant PFS benefit

and overall response

similar efficacy and safety(p<0.001) and higher

than Vd.

in Chinese patients with

rates of overall response

The treatment arm has

RRMM compared with the(p<0.001) compared toslightly higher rate ofglobal phase 3 CASTOR

Rd. After more than 3

Study nameCASTOR study

LEPUS (MMY3009) study

IRRs, ofstudy.

years of follow-up,

In LEPUS study, DVd

daratumumab groupneutropenia than control

demonstrated significant

continued to demonstrategroup.

efficacy benefits versus

improved efficacy versus

For HRQoL, no

Vd.

control group (HR, 0.44;

The safety profile was

95% CI, 0.35–0.55;

group differences for thegenerally consistent with

p<0.0001).

first eight cycles ofthat reported in the global

therapy were observed

CASTOR study.

thrombocytopenia and•significant between-

•

•

•

•

Daratumumab group was
associated with infusion-for both DVd group andrelated reactions and a

Vd group.

higher rate of neutropenia

After long-term follow-

than the control group.

up (8 cycles of therapy),

73

POLLUX study•

The between-groupthe DVd group reported

magnitude of changes

improvements in quality

from baseline in EORTC

of life including GHS,

QLQ-C30 GHS, functional,

pain and VAS scores as

and symptom scores, andcompared to baseline,

EQ-5D-5L VAS scores

whereas patients in thewere low, therefore

Vd group did not receive

suggesting no meaningful

further treatment.

impact on HRQoL.

74

3.3 Evaluation of Additional Benefit
3.3.1 Results of additional benefit assessment
3.3.1.1 Main analysis: Dara SC vs Dara IV based on COLUMBA trial
COLUMBA clinical trial
The results of main evaluation for Dara SC versus Dara IV are presented in Table
3-6 where the reviewer assessed the individual endpoints. Overall survival is notreported as the data was immature.
•

Table 3-6 Additional benefit assessment for COLUMBA study
Study population

Relapsed or refractory multiple myeloma

Intervention

Daratumumab SC

Comparator

Daratumumab IV

Outcomes

ORR, PFS, IRR and treatment satisfaction (PRO)Presence or

No. The evidence showed that Dara SC was non-inferior

absence ofto Dara IV in terms of efficacy (ORR and PFS). Despite

additional

the confirmed difference in IRR (AE) rate and treatment

usefulness

satisfaction between DARA SC and DARA IV, thesebenefits are difficult to incorporate under the costeffectiveness analysis framework. Although lower IRR
may be associated with some utility gain, however, it
was not measured in the clinical trial. Similarly, higher
treatment satisfaction, shorter duration of drug
administration, and shorter patient chair time which
may improve patients’ utilities were not captured. Thereis a limitation within the calculation of ICER toincorporate these additional benefits. Besides, DARA SC
is associated with substantial reduction in active HCPtime which can improve the efficiency of overall patientmanagement.

Data to support□ Meta-analysis of RCTs

judgment■ Single clinical trial (9 associated publications)□ Prospective, controlled, observational study□ Indirect comparison of RCTs
□ Comparison of single-arm studies□ No relevant clinical study data
□ Other
Reason for judging

Overall response rate

the presence or•

COLUMBA study suggested the non-inferiority ofabsence ofDara SC compared with Dara IV for overall

additional

response, despite the ORR is slightly higher in DARA

usefulness

SC group (41% vs 37%). Depth of response (verygood partial response or better) was similar
between the intervention and comparator groups.
•

Similar overall responses were observed acrossprespecified subgroups, including bodyweightcategories, despite the Dara SC group not receiving
a bodyweight-based dose.

•

Key finding from COLUMBA study was that depth
and time to response were not affected by the routeof administration.

•

For Asian and Japanese-only cohorts, similar results
were observed.

Progression-free survival•

For global COLUMBA population, PFS was similar
between Dara SC and Dara IV groups (5.6 months
vs 6.1 months (p=0.93), respectively).

•

For Asian and Japanese-only cohorts, similar results
were observed.

Infusion-related reaction•

Dara SC had significant reduction in IRRs comparedwith Dara IV (12.7% versus 34.5% (p<0.0001),
respectively).

Treatment satisfaction•

Patients in the Dara SC group had more positive
perception and greater satisfaction with treatment
than those in the Dara IV group.

•

Modified Cancer Therapy Satisfaction Questionnairesatisfaction with therapy domain score is higher

76with Dara SC group (76.9) versus Dara IV group(70.5).
•

Regardless of the route of administration, themajority of patients in the Dara SC group (55.7–
81.3%) responded that they would “definitely” taketheir cancer therapy again compared to Dara IV
group (49.8–65.1%)•

However, patients and physicians were not masked
to treatment, performance bias cannot be excluded
in responses to the modified CTSQ.[7]Other:•

Administration time was found to be markedly lessfor Dara SC (5 minutes) versus Dara IV (7 hours in
the first injection and 3-4 hours per injection
afterwards).

•

Dara SC is associated with substantial reduction in
active HCP time, duration of drug administrationand patient chair usage compared with Dara IV,
resulting in increased satisfaction and may result inbetter quality of life.

•

Table 3-7 ORR analysis in COLUMBA study
Subgroup

Dara IV, n/N

Dara SC, n/N

Relative risk

(%)

(%)

(95% CI)<75 years

70/200 (35.0)

89/216 (41.2)

1.18 (0.92->75 years

26/59 (44.1)

19/47 (40.4)

1.51)

Age

0.92 (0.581.43)
Sex
Male

54/149 (36.2)

62/136 (45.6)

1.26 (0.95-

Female42/110 (38.2)

46/127 (36.2)

1.67)
0.95 (0.681.32)

77

Region
Asia/Pacific16/52 (30.8)

18/43 (41.9)

1.36 (0.79-

Other80/207 (38.6)

90/220 (40.9)

2.34)
1.06 (0.841.34)

Weight<65 kg35/92 (38.0)

41/94 (43.6)

1.15 (0.81->65-85 kg

41/105 (39.0)

38/102 (37.3)

1.63)>85 kg20/61 (32.8)

29/66 (43.9)

0.95 (0.671.35)
1.34 (0.862.12)

No of prior lines oftherapy

72/175 (41.1)

78/174 (44.8)

1.09 (0.86-<424/84 (28.6)

30/89 (33.7)

1.39)

>4

1.18 (0.761.85)

Cytogenetic risk
High risk

11/35 (31.4)

20/52 (38.5)

1.22 (0.69-

Standard risk

64/167 (38.3)

66/146 (45.2)

2.27)
1.18 (0.911.53)

ECOG PS score
0

36/88 (40.9)

26/64 (40.6)

0.99 (0.67->160/171 (35.1)

82/199 (41.2)

1.46)
1.17 (0.911.53)

CI: confidence interval; Dara IV: intravenous daratumumab; Dara SC: subcutaneous
daratumumab; ECOG PS: Eastern Cooperative Oncology Group Performance Status; ORR:
overall response rate
Source: Mateos et al. 2020[7]•Figure 3-3 Progression-free survival for global COLUMBA population

78

DARA IV: intravenous daratumumab; DARA SC: subcutaneous daratumumab; HR: hazard
ratio; PFS: progression-free survival
Source: Mateos et al. 2020[7]•Table 3-8 Summary of IRR for global in COLUMBA study
Study group
Global COLUMBA

Any grade IRRs, n (%)

Grade 3 IRRs, n (%)

Dara SC

Dara IV

Dara SC

Dara IV

33 (12.7)

89 (34.5)

4 (1.5)14 (5.4)

population
Dara, daratumumab; IV, intravenous; SC, subcutaneous; IRR, infusion-related reaction
There were no grade4/5 IRR.
Source: Mateos et al. 2020[7]•Figure 3-4 Modified-CTSQ mean scores for global COLUMBA population for (A)‘Satisfied with Form of Cancer Therapy (Intravenous/Subcutaneous)’; (B) ‘Taking
Cancer Therapy as Difficult as Expected’; and (C) ‘Were Side Effects as Expected’79

CTSQ: Cancer Therapy Satisfaction Questionnaire; DARA IV: intravenous daratumumab;
DARA SC: subcutaneous daratumumab
Source: Mateos et al. 2020[7]803.3.1.2 Scenario analysis
As there were no study identified comparing Dara SC with the comparator. The
search was broadened to include Dara IV assuming similar efficacy between Dara
IV and SC.
DVd vs Vd: The additional benefit result comparing DVd and Vd were confirmed
based on two clinical studies (CASTOR and LEPUS). Similar results were observed
from both studies.
CASTOR and LEPUS clinical trial
The additional benefit results for CASTOR studies are presented in Table 3-9
where the reviewer assessed the individual endpoints. Phase 3 LEPUS (MMY3009)
study was conducted to confirm the efficacy and safety of daratumumab plus
bortezomib and dexamethasone in Chinese patients with RRMM compared withthe global phase 3 CASTOR study. The additional benefit results for LEPUS study
are presented in Table 3-9. Overall survival is not reported for both trials as thedata was immature.

•

Table 3-9 Additional benefit assessment for CASTOR and LEPUS study
Study Population

Relapsed and/or refractory multiple myeloma

Intervention

Daratumumab + Bortezomib and Dexamethasone (DVd)Comparative Control

Bortezomib and Dexamethasone (Vd)

Outcomes

PFS, ORR, safety and HRQoL

Presence or absence

Yes, there is additional benefit comparing DVd* and Vdof additional

based on PFS and ORR result in CASTOR and LEPUS

usefulness

study.
*There was no study identified comparing Dara SC withthe comparator. We first assumed similar efficacy
between Dara IV and SC based on COLUMBA study andleverage the result of Dara IV clinical trial.

Data to support□ Meta-analysis of RCTs

judgment■ 2 clinical trials and 8 associated publications□ Prospective, controlled, observational study□ Indirect comparison of RCTs
81□ Comparison of single-arm studies□ No relevant clinical study data
□ Other
Reason for judging

Progression-free survival

the presence or•Both CASTOR and LEPUS study resulted inabsence ofsignificantly longer PFS as compared to Vd alone,

additionalwith a risk of disease progression or death that was

usefulness

61.4% (p<0.001) and 72% (p<0.00001) lower,
respectively, for the daratumumab group versus thecontrol group.[8, 9]•

For CASTOR study, similar PFS results were observedfor exploratory post hoc analysis and extended
follow-up analyses (median PFS, 16.7 months versus
7.1 months, respectively for both).[18, 19]•

Regardless of the cytogenetic risk status subgroup,
DVd showed better PFS compared to Vd alone after amedian follow-up of more than 3 years (standard
risk, 16.6 vs 6.6 months and high risk, 12.6 vs 6.2
months; respectively) in CASTOR study.[20]Overall response rate•

ORR was significantly improved for DVd group ascompared to Vd group for CASTOR study (82.9% vs63.2% (p<0.001), respectively) and LEPUS study(82.5% vs 65.1%, p=0.00527).

•

For CASTOR study, the rates of very good partial
response or better and complete response or betterin the primary analysis, secondary analysis, extended
follow-up analysis and cytogenetic risk subgroup
analysis (regardless of risk status).[8, 18-20]•

For LEPUS study, ORR was higher with DVd as
compared to Vd for standard-risk cytogenetic
abnormalities subgroup (85.6% versus 57.9%,
respectively) and was similar for DVd and Vd in the82high-risk cytogenetic abnormalities subgroup (75.0%
for both groups).
SafetyDVd was associated with a higher incidence of•adverse events in both CASTOR and LEPUS study ascompared to Vd alone.
Any grade IRRs associated with DVd group were•reported in 45.3% and 37.9% of patients for CASTOR
and LEPUS study, respectively.
HRQoL•

For CASTOR study, no significant between-groupdifferences for the first eight cycles of therapy
were observed for both DVd and Vd group.

•

After long-term follow-up (i.e. after 8 cycles oftherapy), DVd group reported improvements inquality of life including GHS, pain and VAS scores
as compared to baseline, whereas patients in theVd group did not receive further treatment.

DRd versus Rd: The additional benefit result comparing D-Rd and Rd wereconfirmed based on POLLUX clinical trial.
POLLUX clinical trial
The additional benefit results for POLLUX studies are presented in Table 3-10,
where the reviewer assessed the individual endpoints. Overall survival is notreported as the data was immature.
•

Table 3-10 Additional benefit assessment for POLLUX study
Study Population

Relapsed or refractory multiple myeloma

Intervention

Daratumumab + Lenalidomide and Dexamethasone (DRd)Comparative Control

Lenalidomide and Dexamethasone (Rd)Outcomes

PFS, ORR, AE and HRQoL

83

Presence or absence

Yes, there is additional benefit comparing DRd* and Rdof additional

based on PFS and ORR result in POLLUX study.

usefulness*There was no study identified comparing Dara SC withthe comparator. We first assumed similar efficacy
between Dara IV and SC based on COLUMBA study andleverage the result of Dara IV clinical trial.

Data to support□ Meta-analysis of RCTs

judgment■ Single clinical trial and 7 associated publications□ Prospective, controlled, observational study□ Indirect comparison of RCTs
□ Comparison of single-arm studies□ No relevant clinical study data
□ Other

Reason for judging

Progression-free survival

the presence or•

DRd group reported a 63% lower risk of diseaseabsence ofprogression or death than Rd group alone (median

additional

PFS, NR versus 18.4 months, respectively).

usefulness•

Similar outcome was observed for primary analysis,
secondary updated analysis (NR versus 17.5 months,
respectively) and long-term follow-up analysis (44.5
vs 17.5 months, respectively) [10, 24, 26] as well as
East-Asian population subgroup analysis (NR versus
13.8 months) and cytogenetic subgroup analysis,
regardless of cytogenetic risk status (standard risk,
NR vs 18.6 months and high risk, 26.8 vs 8.3
months, respectively).[25, 27]

Overall response rate•

DRd was associated with higher rates of overall
response as compared to Rd alone (92.9% vs 76.4%,
respectively).[10]•Similar outcome was observed for East-Asian
population subgroup analysis (90.2% vs 72.1%,

84

respectively) and cytogenetic subgroup analysis,
regardless of cytogenetic risk status. [25, 27]
Infusion-related reaction•

Incidence of daratumumab any grade IRRs was
47.7%, with 92% of the reactions occurring during
the first infusion.

HRQoL
•

HRQoL was evaluated as secondary endpoint and was
not powered to detect differences between treatmentgroups.

•No meaningful improvements from baseline in HRQoL
observed in POLLUX study for both groups.

•

For subgroup analysis, changes from baseline in
HRQoL scores favored younger patients, those with
an ECOG performance status of 0 or 1, and thosewith ≥VGPR, irrespective of treatment group.

85

4. Details of Analytical Methods
4.1 Analytical Methods
4.1.1 Calculation of cost-effectiveness1) CMA (Main analysis)
Based on the additional benefit assessment result in section 3. Janssen
determined to take a conservative approach and performed a cost minimization
analysis as below.
An Excel model was built to calculate weekly direct medical cost including drug,
drug

administration,

hospitalization

and

IRR

(AE)

management.

Threedaratumumab regimens were included, DVMP, DRd and DVd. For each of theregimen, we compare the accumulative direct medical cost between Dara SC(intervention) and DARA IV (comparator). Final results were pooled by thepercentage of usage of each regimen in actual clinical practice based on MDVdata.
In the main analysis, the duration comparison is set to be 32 weeks based on
average daratumumab treatment duration in Japan from MDV data.
A sensitivity analysis was performed with the duration of 52 weeks [Sensitivity
analysis 1]. Another sensitivity analysis was performed assuming% of patients

receiving DARA SC regimen (due to the improved administration and safety) will
not require hospitalization for regimen initiation [Sensitivity analysis 2].
•

Figure 4-1 Treatment durations in the analyses
Treatment initiation
Week 1

Week

cost

cost

2

Week

3

…

cost

Week 32…

cost

Week 52
cost

32-week total cost (Main)
52-week total cost (Sensitivity analysis 1)

Dosing schedule of each regimen (DVMP, DRd for TIE NDMM, DRD for RRMM and
DVd for RRMM) are as following Figure 4-2 to Figure 4-5.
86

•Figure 4-2 Dosing schedule of DVMP regimen•

Figure 4-3 Dosing schedule of DRd regimen for TIE NDMM•

Figure 4-4 Dosing schedule of DRd regimen for RRMM•

Figure 4-5 Dosing schedule of DVd regimen for RRMM

872) Other analysis: Cost difference from HCP time perspective
Based on the result of time in motion survey result [5], the breakdown of thetime required from different types of HCPs in the first and a subsequent drug
administration visit for DARA SC and DARA IV were acquired. Difference inminutes were calculated between DARA SC and DARA IV. The average hourly
wage for the corresponding type of Japan HCP were applied to convert the HCPtime into monetary term. Differences were calculated between DRAR SC and
DARA IV. The result (HCP time and the value of HCP time) is shown per drug
administration patient visit.
3) Other analysis: CUA (Scenario analysis)
At the request of the expert committee, additional other analysis, cost-utility
analyses, were performed for the RRMM indications to assess the costeffectiveness of DARA SC combination regimens versus non-Dara combination
regimens. These cost-utility models were developed in accordance with theInternational Society for Pharmacoeconomics and Outcomes Research (ISPOR)
Task Force on Good Modeling Practices, and Guideline for cost-effectivenessevaluation in Japan (second edition).
The models assess the incremental cost-effectiveness of DARA SC in combination
with Vd or Rd compared with regimen without DARA SC (i.e. DVd vs. Vd and DRd
vs. Rd) for the treatment of RRMM.
An excel-based partitioned survival model (PSM) was developed to estimate timeand proportion of a cohort of patients in each health state which was estimatedusing progression free survival (PFS) and overall survival (OS) curves. PSM is astandard and well-accepted approach for oncology models for HTA/payer
submissions. The model considered three-health states: pre-progression (or88progression free), post-progression (or progressed disease), and death (Figure
4-6).
•

Figure 4-6 Model Structure

Survival was estimated based on the projection of treatment-specific OS curves
from the respective daratumumab (DARA) IV clinical trials (MMY3004 [DVd] andMMY3003 [DRd]). It was assumed that DARA SC had the same clinical efficacy
as DARA IV. Treatment-specific PFS and OS parametric curves were used todetermine health outcomes. To estimate the long-term health outcomes beyond
trial periods, multiple parametric functions were fitted to the Kaplan Meier (KM)
data for PFS and OS from the two DARA trials with the flexibility to explore allreference curves. The recommended reference curves for base-case and key
scenarios were selected based on goodness-of-fit statistics, i.e. Akaike's
Information Criteria (AIC), Bayesian Information Criteria (BIC).
Utility values informing the PFS and post-progression survival (PPS) health states
as well as disutility values associated with adverse events were based on the data
identified in the literature. These were used in the models to derive the qualityadjusted life year (QALY).
The models considered the following cost categories: drug acquisition, drug
administration, adverse events, and medical resource uses (including end of life).
Drug acquisition and administration costs were estimated by fitting parametricfunctions to the time-to-treatment discontinuation (TTD) KM data for thedaratumumab combinations and comparators which were applied to unit drug
costs data informed by Japan standard sources.
89Cost outcomes include total and incremental costs and health outcomes are
expressed as QALYs gained. The model employs a cost-utility analysis (CUA)
calculating incremental cost-utility ratios (ICURs) as incremental costs perincremental QALYs gained.
One way sensitivity analysis (OWSA) is used to test the joint impact of
uncertainty in the model parameters on the results.
4.1.2 Assumptions used in the model
1) CMA (Main analysis)
1. Dara IV is a weight-based dosing treatment. the weight for dose
calculation is

Kg based on Japan post-market surveillance data.

2. Drug administration/Hospitalization fee is based on DPC payment schedule.
(See Section 4.2.3)
3. MM patients that initiate Dara IV regimens are assumed to admitted tohospital fordays (MDV database analysis, data cut-off: 2021-May) for

drug administration and monitoring side effects. MM patients receiving
Dara SC injection are assumed to be hospitalized for

day as the side

effect are less frequent and usually observed in this timeframe.
4. Cost comparison timeframe is set to be 32 weeks based on average
duration of daratumumab regimen in Japan (MDV database analysis). The
duration of treatment of DARA SC and IV is assumed to be the same basedon the non-inferiority result in ORR and PFS from the clinical trial.
5. Since the duration is within 1 year, no discount was applied.
6. Other AE incidence and related costs are assumed to be the same between
Dara IV and Dara SC except IRR (grade 3+). IRR cost was estimated basedon the AE management guide of the Columba study. It is assumed to be
methylprednisolone oral 60 mg per day for an average of
7. In sensitivity analysis 2, we assumed

days.

% of patients receiving DARA SC

regimen (due to the improved administration and safety) will not require
hospitalization for regimen initiation, the rest of patients will follow theoriginal assumptions. All other parameters remain the same with the main
analysis.
2) Other analysis: Time and cost difference from HCP time perspective
1. The assumptions in the main CMA analysis were applied when applicable.
902. The HCP time required per administration visit in the publication isassumed to be representative of clinical practice in Japan.
3. When average wage of a specific HCP type information is not available,
the average wage of the most similar HCP role is applied.
3) Other analysis: CUA (Scenario analysis)
1. The assumptions in the main CMA analysis were applied in the CUA whenapplicable.
2. Relative efficacy and safety inputs from the MMY3004 (DVd vs Vd) andMMY3003 (DRd vs Rd) trials are assumed to be representative of the
RRMM population in Japan.
3. Dara SC is assumed to have the same efficacy as dara IV in combo with
Vd and Rd
4. The cycle length used is 7 days thus, a year is assumed to consist of 52
cycles of 7 days. A half cycle correction was applied.
5. The effect of subsequent treatments is assumed to be implicitly
incorporated in the OS curve, as patients in the MMY3004 and MMY3003
studies were allowed to receive other MM treatments upon progression
from the randomized treatment.
6. In case the extrapolated PFS and OS curves cross, the model assumes
that the percentage of patients who remain on PFS cannot be higher
than the percentage of patients who remain on OS.
7. In case the extrapolated OS and the general population mortality curves
cross, the model assumes that the percentage of patients who remain
alive based on the OS curve cannot be higher than the percentage ofpatients who remain alive based on the general population mortality
curve.
8. Utility values are assumed to be health-state dependent (treatment
independent) and constant over time.
9. Patients are assumed to have subsequent treatment costs from diseaseprogression until death. Subsequent treatment costs were derived from
MDV, a Japanese claims database.

91

10. The cumulative probability of IRR (Grade 3+) for each Dara (SC)combination regimen was assumed to equal 1.5% in the absence of the
IRR data (cumulative probability based on MMY3012 Dara [SC] arm).
11. The cumulative probabilities of non-IRR adverse events for each dara
(SC) combination regimen were assumed to be the same as dara (IV)combination regimen based on MMY3004 (DVd [IV]) and MMY3003 (DRd[SC]) trials.
4.2 Parameters Used in the Analysis
1) CMA (Main analysis)•Table 4-1 Parameters used for the analysis
Parameter

Main

Sensitivity

analysisanalysis1

SourcePatient characteristics &Setting
Body Weightkg

Proportion of hospitalization for

PMS [4]
MDV database

the initial treatment for Dara%regimenanalysis in
Appendix L
MDV database

Hospitalized days for Dara IV

daystreatment initiation

analysis in
Appendix L

Hospitalized days for Dara SC

daytreatment initiation

Assumption
MDV database

Duration of treatment for Dararegimen

32 weeks

52 weeks

analysis in
Appendix L/
assumption

Efficacy and safety parameter4.2.1*
IRR incidence for Dara SC

1.5%

MMY3012 study

IRR incidence for Dara IV

5.4%

MMY3012 study

IRR duration

days

MMY3012 study[data on file]92

Details of QOL values 4.2.2

Not applicable

Cost parameters 4.2.3
Drug cost

IRR cost per day

See Table 4-3 and 44

MHLW list in
November 2021
[32][33]

yen

See Table 4-10
for details

G005 Outpatient chemotherapy
fee 1 (1) Injection ofantineoplastic drugs II. Age ≥ 15

6,000 yen**

200 yen**

980 yen**

490 yen**

680 yen**years
G000 Intradermal, subcutaneous,
intramuscular injection fee (perone injection)
G004: Intravenous infusion 2. topersons other than thosespecified in 1 (when the dailyvolume of injection is 500 mL or
more)
G004 Intravenous infusion (perday) 3 Other cases (Only forpatients other than hospitalized
patients.)
F400 Prescription Fee 3 in thecase of 1 and 2
DPC cost (per day) (Day 1 - Day
4)
DPC cost (per day) (Day 5 - Day
14))
DPC cost (per day) (Day 15 - Day
60)

yen

**

yen

**

yen

**

*Efficacy is assumed to be the same. Grade3/4 IRR events were included as important safety
events in the analysis. The incidence of IRR events and the duration was set following theresult of MMY3012.

93

** For all medical service fees, the revised medical service fees in April 2020, the revised
Diagnosis Procedure Combination (DPC) the electronic score table in November 2021, and the
Functional Assessment Factor II in April 2020 were used [34] [35] [36].

DPC code: 130040xx99x6xx（Disease name as ‘Multiple myeloma, immune system malignant
neoplasm’, Surgery name as ‘None’ and Surgery and Procudure, etc.2 as ‘6’) was used.
For the calculation of DPC cost, the coefficients by medical institution was set as follows:
Basic coefficient:

The DPC cost was calculated by multiplying the coefficient by medical institution by DPC score
which corresponds to the DPC code and the day at the hospitalization, and then converting it
into yen.

2) Other analysis: Cost difference from HCP time perspective
Parameters used in the analysis are summarized and presented in Appendix M.
3) Other analysis: CUA (Scenario analysis)
All parameters used in the base-case cost utility analysis are summarized andpresented in Appendix A (DVd RRRM model) and Appendix B (DRd RRRM model).
4.2.1 Details of parameters such as efficacy and safety
1) CMA (Main analysis)
See section 4.2, Table 4-1.
2) Other analysis: Cost difference from HCP time perspective
Not applicable3) Other analysis: CUA (Scenario analysis)
4.2.1.1 Time-to-Event Analysis
Time-to-event analysis was used to model and extrapolate OS and PFS curves
based on individual patient data from the clinical trials of each treatment
indication.
94

Following recommendations by the National Institute for Health and Care
Excellence (NICE) Decision Support Unit [37] on survival data extrapolation, six
parametric distributions were fit to extrapolate time-to-event data and were
implemented in the model.
1. Weibull
2. Exponential
3. Log-normal
4. Log-logistic
5. Generalized Gamma
6. Gompertz
The exponential distribution is a one-parameter function and is considered thesimplest parametric model. The exponential model is a proportional hazards
model, assuming a constant HR over time. The survival function can be expressed
as below:𝑆𝑆(𝑡𝑡) = 𝑒𝑒 (−𝜆𝜆𝜆𝜆)

The Weibull and Gompertz distributions are functions with two parameters — ashape and scale. Therefore, these two distributions are more flexible than the
exponential distribution. Both distributions are proportional hazards models.
Their survival functions can be expressed as below:
𝜸𝜸

Weibull:𝑺𝑺(𝒕𝒕) = 𝒆𝒆(−𝝀𝝀𝒕𝒕 )Gompertz:

𝑺𝑺(𝒕𝒕) = 𝑒𝑒 𝜃𝜃(1−𝑒𝑒𝜆𝜆(𝜃𝜃𝜃𝜃) )The log-logistic and log-normal distributions share many similarities. They havea hazard function that can be non-monotonic with respect to time. Therefore,
neither of the distributions can be parameterized as a proportional hazards model.
Furthermore, due to their functional forms, the log-logistic and log-normal
models typically produce long tails in the survivor function. As a result, the clinicalvalidity of log-logistic and log-normal survival models must be carefully assessed.
Their survival functions can be expressed as below:
Log-Logistic:
Log-Normal:𝑺𝑺(𝒕𝒕) = (𝟏𝟏 + 𝒆𝒆𝜽𝜽 𝒕𝒕𝜿𝜿 )−𝟏𝟏𝑺𝑺(𝒕𝒕) = 1 −Φ(𝑙𝑙𝑙𝑙𝑙𝑙𝑡𝑡 − 𝜇𝜇)𝜎𝜎95where φ is the standard normal distribution function
The generalized Gamma distribution is a flexible, three-parameter model. The
Weibull, exponential and log-normal distributions are special cases of thegeneralized Gamma distribution. However, due to its flexibility, the long-term
estimations may be influenced by the end of the Kaplan-Meier (KM) curves, which
are based on small sample sizes. Therefore, like the log-normal and log-logistic
distributions, the clinical validity of the projected survival must be assessed. The
survival function can be expressed as below:
Generalized Gamma:

𝑺𝑺(𝒕𝒕) = 𝟏𝟏 − 𝚪𝚪(𝝀𝝀𝝀𝝀)𝜽𝜽 (𝝆𝝆)

where 𝚪𝚪(𝝀𝝀𝝀𝝀)𝜽𝜽 (𝝆𝝆) is known as the incomplete gammafunction

Recommendations regarding the most appropriate parametric distribution havebeen made based on graphical assessment, fit statistics Akaike information
criterion (AIC)/Bayesian information criterion (BIC) and clinical plausibility oflong-term projections. A general rule of thumb is that the distribution with thelowest AIC and BIC values indicate the best fits to the underlying data. Selected
time-to-event parameters may be found in 0 (PFS) and 0 (OS).

4.2.1.2 Adverse Events
The model used cumulative probabilities of AEs (infusion-related reaction [IRR]
and non-IRRs) that occurred during the observed treatment period in the clinical
trials.
In the absence of the IRR data for each Dara (SC) combo regimen, the cumulative
probability of IRR (Grade 3+) for each Dara (SC) combo regimen was assumed
to equal 1.5%. The cumulative probability was based on the Dara (SC) arm in
the MMY3012 study.
For non-IRR AEs, only grade ≥3 AEs occurring in ≥5% of study subjects in any
daratumumab arms in the different daratumumab studies were considered. This
inclusion criterion has been generally considered appropriate and sufficient tocapture AEs that would have a significant impact on resources and costs.
Cumulative probabilities of IRR and non-IRR AEs included in the model during thetreatment period available for each regimen are shown are shown in Table 4-2.
96

•

Table 4-2 Adverse Event Rates
Adverse Event

DVd (SC)

Vd

DRd (SC)

Rd

AnemiaDiarrhea
FatigueFebrile Neutropenia
Hypertension
Infusion-Related
Reactions
Lymphopenia
Neutropenia
Peripheral
Neuropathy
Pneumonia

Source/Rationale

Assumed theAssumed thesame assame asDVd (IV)

DRd (IV)

based on

MMY3004

based on

MMY3004,

MMY3003,

IRR based

IRR basedon MMY3012

on MMY3012

MMY3003Abbreviations: DRd =daratumumab in combination with lenalidomide anddexamethasone; DVd = daratumumab in combination with bortezomib anddexamethasone; IV = intravenous; RRMM = relapsed/refractory multiple myeloma; SC =subcutaneous

4.2.2 Details of QOL values
1) CMA (Main analysis)
Not applicable.

972) Other analysis: Cost difference from HCP time perspective
Not applicable.
3) Other analysis: CUA (Scenario analysis)
Health state utility values in the base-case scenarios were based on van Agthoven
et al. (2004) [38], a commonly cited published study identified in the SLR.

Most

published RRMM CEAs reference the same data source.
QALYs were calculated as the proportion of patients per health state per cycle
multiplied by the utility weights for each health state and proportion of a year
represented by the cycle. Utility values used to inform model health states andevents in the DRd and DVd models were 0.81 (progression-free) and 0.64 (postprogression).
Utility decrements due to AEs were also calculated based on treatment-specific
AE rates and applied as one-time decrements from baseline utility value. Utility
decrements used in the RRMM model were
DVd (SC), andfor DRd (SC) and Rd,forfor Vd.

The following methods were used to calculate utility decrement:
1. Adjusted disutility value: duration of AE multiplied by the disutility value
per AE
2. Adjusted disutility value multiplied by the cumulative incidence rate perAE
3. Sum of all the calculated incidence rates per treatment regimen
4.2.3 Details of Cost Parameters
Unless otherwise noted, cost parameters values presented were used all
analysis.
4.2.3.1 Drug Acquisition Costs•

Table 4-3 Unit Cost of Drug Acquisition
Drug
Product name

IngredientSpecification

price
(yen)

Velcade Injection 3
mg

Bortezomib

1 bottle of 3 mg

134,92398

Darzalex

Daratumumab

Intravenous(Genetical

Infusion 100 mg

Recombination)

Darzalex

Daratumumab

1 bottle of 400

Intravenous(Genetical

mg 20 mL

Infusion 400 mg

Recombination)

solution

1 bottle of 100
mg 5 mL

52,262

187,970

Daratumumab
Darzquro(Genetical

Combination

Recombination)/Borhyal

1 bottle of 15

Subcutaneousuronidase Alfa

mL

Injection(Genetical

434,209

Recombination)
Decadron Tablet 4

Dexamethasone

1 tablet of 4mg

29.90

Prednisolone tablet

Prednisolone

1 tablet of 5mg

9.80

Alkeran Tablet 2 mg

Melphalan

1 tablet of 2mg

159.70mg

Revlimid Capsule 5
mg
Medrol Tablet 4 mg

1 capsule of 5

Lenalidomide Hydrate

8,085.30

mg

Methylprednisolone

1 tablet of 4mg

14.8

Based on the unit cost of drug, the unit cost per administration for MM treatment
was calculated as follows.
[Unit cost per administration] = [Unit cost of drug] x [Number of doses per
administration]•

Table 4-4 Cost per administration used for CMA (MM treatment)
Product name2.02 mg

3 mg(1.3mg×Intravenous
Infusion

Unit cost per

doses peradministration

administration(yen)

DosageVelcade Injection
Darzalex

Number of

884.8 mg
(16mg×*1)*2

1
2×400mg +*3)*2 1×100mg

134,923

428,20299

Darzquro
Combination
Subcutaneous

1800mg1

434,209

10

299

20

598

19

186.2

7

1117.9540426.5

Injection
Decadron Tablet 4

40 mg

mg

(For DRd regimen)

Decadron Tablet 4

80 mg

mg

(For DVd regimen)

Prednisolone

93 mgtablet(60mg×Alkeran Tablet 2

13.95 mg

mg

(9mg×

Revlimid Capsule
5 mg

*1)*2
*1)*2

25mg

1 The body surface area for the analysis was set atand the mean weight of

m2 from the mean height ofm

kg according to the results of the pharmacovigilance plan for

Dara IV.
2 Assumed that vials were not reused due to the situation where drugs are used (unused drugs
will be discarded).
3 The body weight used in the analysis was set at

kg based on the mean body weightaccording to the results of the pharmacovigilance plan for Dara IV.

4.2.3.2 Drug Administration Costs
Administration of IV and SC treatments require an outpatient or inpatient visitthat

may include nursing and pharmacist

preparation

time.

Therefore,

administration costs for IV and SC treatments were included in the model.
The proportion of patients initiating Dara in the hospital setting and duration of
hospital stay are shown in Table 4-5.
•

Table 4-5 Proportion of Patients Initiating Dara in Hospital and Duration of
Hospital Stay
Hospitalization

Daratumumab SC

Source100

Proportion of Patients
Initiating Dara In%

Hospital
Duration of Hospital

MDV database analysis in
Appendix L

Assumption

Stay (Days)

The hospitalization fee (DPC cost) accounts for costs associated with the hospitalbed, care management, and drug acquisition and administration. For the
calculation of DPC cost, the coefficients by medical institution were set as follows:
•

•

•

•

DPC cost was calculated by multiplying the coefficient by medical institution by
DPC score which corresponds to the DPC code and the day at the hospitalization,and then converting it into yen.
Unit costs related to mode of treatment administration are presented in Table 41 cost parameters
Proportion of the regimens in clinical practice is shown in Table 4-6.
•

Table 4-6 Proportion of regimens in clinical practice (Cost Minimization Analysis)
Regimen (population)

Proportion

Source

DVMP(TIE NDMM and RRMM)
DRd(TIE NDMM)

MDV database analysis in
Appendix L

DRd

101

(RRMM)
DVd(RRMM)

Administration costs are based on schedules outlined in Table 4-7. The
administration cost is applied per administration and does not vary by length ofadministration (i.e. an IV administration requiring two hours costs the same as
an IV administration requiring seven hours).

•

Table 4-7 Dosing Schedules
RegimenTreatment

Days

Doses

per

per

Cycles

Cycle

SC/IV

28

4

SC/IV

28

2

SC/IV

28

1

25mg

Oral

28

21

20mg

Oral

28

8

40mg

Oral

28

4

25mg

Oral

28

21

40mg

Oral

28

4

Dose

Admin

per Admin

Route1800 mg
Daratumumab(SC)(Cycles 1-2)

16 mg/kg(IV)
1800 mg

Daratumumab(SC)(Cycles 3-6)

16 mg/kg(IV)

DRd

1800 mg
Daratumumab(SC)(Cycles 7+)

16 mg/kg(IV)

Lenalidomide(Cycles 1+)
Dexamethasone(Cycles 1-2)
Dexamethasone(Cycles 3+)
Lenalidomide
Rd(Cycles 1+)
Dexamethasone(Cycles 1+)

102

Regimen

Treatment

Days

Doses

per

per

Cycles

Cycle

SC/IV

21

3

SC/IV

21

1

SC/IV

28

1

1.3mg/m2

SC/IV

21

4

20mg

Oral

21

8

1.3mg/m2

SC/IV

21

4

20mg

Oral

21

8

IV/SC

42.00

6.00

IV/SC

42.00

2.00

IV/SC

28.00

1.00

Dose

Admin

per Admin

Route1800 mg
Daratumumab(SC)(Cycles 1-3)

16 mg/kg(IV)
1800 mg

Daratumumab(SC)(Cycles 4-8)

16mg/kg(IV)

DVd

1800 mg
Daratumumab(SC)(Cycles 9+)

16mg/kg(IV)

Bortezomib(Cycles 1-8)
Dexamethasone(Cycles 1-8)
Bortezomib
Vd(Cycles 1-8)
Dexamethasone(Cycles 1-8)

1800 mg

Daratumumab(SC)(Cycle 1)

16 mg/kg(IV)
1800 mg

DVMP

Daratumumab(SC)(Cycles 2-9)

16 mg/kg(IV)

Daratumumab(Cycles 10+)1800 mg(SC)
16 mg/kg
103

Regimen

Treatment

Dose

Admin

per Admin

Route

Days

Doses

per

per

Cycles

Cycle

(IV)

Bortezomib(Cycle 1)
Bortezomib(Cycles 2-9)Melphalan(Cycles 1-9)
Prednisone(Cycles 1-9)

1.30mg/m2

IV/SC

42.00

8.00

1.30mg/m2

IV/SC

42.00

4.00

9.00mg/m2

Oral

42.00

4.00

60.00mg/m2

Oral

42.00

3.00

In clinical practice, bortezomib may be administered via an IV or SC. The
proportion of IV administration of bortezomib is reported in Table 4-8.
•

Table 4-8 Percent Bortezomib IV Administration
IV Administration % for Bortezomib%

SourceBased on Japan Market Intelligence

Unit cost per administration for MM treatment was calculated as follows:[𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑝𝑝𝑝𝑝𝑝𝑝 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎] = [𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑] 𝑥𝑥 [𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑝𝑝𝑝𝑝𝑝𝑝 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎]

Unit costs per administration are presented in Table 4-9.
•

Table 4-9 Unit Cost Per Administration
Product
Name

DosageVelcadeInjection 3mg

mg(1.3mg×Darzalex
Intravenous
Infusion(16mg×*1)*2

Number Of

Unit Cost Per

Doses Per

Administration

Administration

(Yen)

1

134,923.00

mg

2×400mg +kg*3)*2

1×100mg428,202.00

104

Product

Number Of

Unit Cost Per

Doses Per

Administration

Administration

(Yen)

1

434,209.00

10

299.0020598.0019

186.207

1,117.90

540,426.50

DosageName
Darzquro
Combination

1800mgSubcutaneous
Injection
Decadron

40 mg

Tablet 4 mg

(For DRd regimen)

Decadron

80 mg

Tablet 4 mg

(For DVd regimen)

Prednisolone
tabletmg(60mg×AlkeranTablet 2 mg

*1)*2
mg

(9mg×

Revlimid

*1)*2

25mg

Capsule 5 mg

[1] The body surface area for the analysis was set atm and the mean weight of

m2 from the mean height ofkg according to the results of the pharmacovigilance

plan for Dara IV.
[2] Assumed that vials were not reused due to the situation where drugs are used (unused
drugs will be discarded).
[3] The body weight used in the analysis was set at

kg based on the mean bodyweight according to the results of the pharmacovigilance plan for Dara IV.

4.2.3.3 Modeling Treatment Duration (Cost Utility Analysis)
Treatment-related costs (drug acquisition and administration) are accrued basedon the predicted number of patients who remain on treatment each week (model
cycle). The number of patients who remain on treatment over time was estimatedbased on time to treatment discontinuation (TTD) data from the clinical trials
MMY3004 (DVd,RRMM) and

MMY3003(DRd,

distribution based on time-to-event analysis.

RRMM) using parametric
Recommended parametric

distributions for the DVd and DRd RRMM models are presented in 0.
Treatment dosing schedules are modelled accurately, using a weekly cycle length105

in the model. If a treatment or set of treatments as part of a daratumumab SC
regimen are recommended only for up to a fixed duration, drug acquisition andadministration costs for those treatments are accrued only up to the maximum
fixed duration, unless treatment discontinuation occurs earlier.

For example, inthe treatment of a patient with RRMM with DVd, the dosing schedule is set suchthat bortezomib (V) and dexamethasone (d) are only administered for a
maximum of up to 24 weeks; hence, their acquisition and administration costs
are only accrued for up to 24 weeks, while the acquisition and administration
costs of daratumumab (D) are accrued for the time patients remain on treatment,
based on the TTD parametric estimator for DVd.
4.2.3.4 Subsequent Treatment Costs (Cost Utility Analysis)
After patients progress on any of the comparators, it is possible to model postprogression treatment costs. Continuing on subsequent treatment after diseaseprogression is a comparator-specific model parameter, the proportion of patients
receiving subsequent treatments was available for the two main comparators in
the MMY 3003 trial (i.e. DRd and Rd) and MMY 3004 trial (i.e. DVd and Vd).
In the base-case analysis, the proportion of patients continuing on subsequent
treatment was 93.3% [39]and 100.0% [39] for DRd (SC) and Rd, respectively,

and 82.2% [40] and 100.0% [40] for DVd (SC) and Vd, respectively.
Subsequent treatment costs were derived using the Japanese MDV database(May 2021 data cut) following the protocol outlined on Table L1 (Appendix L). It
was assumed that patients would incur the cost for as long as they are in the
post-progression survival health state. Annualized drug and administration costs
were converted to weekly cost in the model analysis based on the method
outlined on Table G1 (Appendix G) and are presented on Table G2 (Appendix G).

4.2.3.5 Adverse Event Costs
The model allows the user to enter individual unit costs of managing infusionrelated reaction (IRR) and non-IRR adverse events (AEs). Adverse events related
to IRR were based on a micro costing approach derived from the literature [41]and AEs related to non-IRR were obtained from the MDV data base (2021-May
cut).

106

4.2.3.5.1 Infusion-Related Reactions (IRR)
The unit cost for the treatment of IRR as AE was calculated based on theinformation presented in Table 4-10.
•

Table 4-10 Unit Cost Per Administration for IRR Treatment
Product Name

Medrol Tablet 4 mg

DosageNumber Of Doses
Per Administration

60 mg/day for

15 tablets/day

4 days

× 4 days

Unit Cost Per
Administration
(Yen)
888

4.2.3.5.2 All Adverse Events (Cost Utility Analysis)
All AE unit costs used in the model are presented in Table 4-11.
•

Table 4-11 RRMM Adverse Event Unit Cost
Adverse Event

Cost Per Event (yen)SourceAnemiaDiarrhea
FatigueFebrile Neutropenia
Hypertension
Infusion-Related

MDV data (2021-May

Reactionscut)

Lymphopenia
Neutropenia
Peripheral Neuropathy
Pneumonia
Thrombocytopenia
An AE cost was applied as a one-time cost at the start of treatment. This approachhas been validated and accepted by health economics experts during advisoryboards for previous economic models assessing the cost-effectiveness ofdaratumumab in MM. Additionally, this approach has also been used in theseprevious economic models of daratumumab in MM.

107

AE cost per patient per treatment was calculated using the following formula:
𝐴𝐴𝐴𝐴 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝑃𝑃𝑃𝑃𝑃𝑃 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 = �(𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝑜𝑜𝑜𝑜 𝐴𝐴𝐴𝐴 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑖𝑖 ∗ 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑜𝑜𝑜𝑜 𝐴𝐴𝐴𝐴 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑖𝑖𝑖𝑖 )Where: i = each AE event presented in 4.2.1.2 and j = treatment
AE costs applied in the model are presented in Table 4-12.
•

Table 4-12 Adverse Event Cost Per Patient Used in Base-Case Analysis
Treatment

AE Cost per Patient

DRd (SC)Rd
DVd (SC)
Vd

4.2.3.6 Medical Resource Utilization (Cost Utility Analysis)
Medical resource utilization (MRU) costs were evaluated for each health state
separately in the RRMM models and were derived from the Japanese MDV
database (May 2021 data cut). In addition, a one-time end of life cost wasestimated and applied to patients who died in the model. The methodology for
estimating these MRU costs is presented on Table H1 (Appendix H). Compared tothe micro-costing approach, which relies on the frequency of resource usereported by a panel of experts, the Japanese HTA guideline prefers the use ofreal-world claims database as it reflects the actual clinical practice in Japan at a
population level [42]. Annualized MRU costs were converted to weekly cost in themodel analysis and presented on Table 4-13.
•

Table 0-13. Medical Resource Utilization Costs in RRMM
Category

Annual Costs

Weekly Costs

One-Time Cost

PFS cost
PPS cost
End of life cost108

5. Analytical Results
5.1 Results of the Analysis
Analysis performed
Main analysis: Dara SC vs. Dara IV in Multiple Myeloma patients■Cost Minimization Analysis (Compare costs as equivalent effects)□Cost-effectiveness analysis (calculate incremental cost-effectiveness ratio)
5.1.1 Incremental cost, effect, and ratio of cost-effectiveness in the baseanalysis
The results of the cost minimization analysis of Dara SC versus Dara IV are shown
below in Table 5-1. In all three combination regimens, Dara SC results in lower
total cost compared with Dara IV. The cost saving ranged from ¥443,078 to¥721,951. Compared with Dara IV, Dara SC reduced total costs by ¥546,091(weighted average) in the base case.
•

Table 5-1 Results of Cost Comparison [base case]
RegimenTotal Cost

(population)
DVMP(TIE NDMM
and RRMM)
DRd(TIE
NDMM)*DRd(RRMM)*

Dara SC
Dara IV

Cost

% of

difference

Regi(SC-IV)men

Total costdifference

9,682,869
JPY-718,434

10,401,303

JPY（Comparator） JPY
Dara SC
Dara IV

14,340,450
JPY-443,228

14,783,678

JPY（Comparator） JPY
Dara SC
Dara IV-546,091
JPY

14,340,600
JPY-443,078

14,783,678

JPY（Comparator） JPY
DVd(RRMM)

Dara SC
Dara IV

10,909,818
JPY-721,951
JPY

109

Regimen

Total Cost

(population)（Comparator）

Cost

% of

difference

Regi(SC-IV)men

Total costdifference

11,631,769
JPY*The dosing schedule is slightly different between TIE NDMM and RRMM in DRd regimen, thecost was calculated separately.

5.1.2 Sensitivity analyses
Sensitivity analysis 1 was performed with the duration of 52 weeks. Sensitivity
analysis 2 was performed assuming% of patients receiving Dara SC regimen(due to the improved administration and safety) will not require hospitalization
for regimen initiation.
The results of the sensitivity analysis are shown below. The cost savings of DaraSC versus Dara IV were observed in both sensitivity analysis.
•Table 5-2 Results of Cost Comparison [Sensitivity Analysis 1]
RegimenTotal Cost

(population)
DVMP(TIE NDMM
and RRMM)
DRd(TIE
NDMM)*DRd(RRMM)*

Dara SC
Dara IV

Cost

% of

difference

Regi(SC-IV)men

Total costdifference

14,497,436
JPY-723,888

15,221,324

JPY（Comparator） JPY
Dara SC
Dara IV

20,766,657
JPY-447,093

21,213,750

JPY（Comparator） JPY
Dara SC
Dara IV-550,036
JPY

20,766,807
JPY-446,943

21,213,750

JPY（Comparator） JPY
DVd(RRMM)

Dara SC
Dara IV

13,081,863
JPY-725,816
JPY

110

Regimen

Total Cost

(population)（Comparator）

Cost

% of

difference

Regi(SC-IV)men

Total costdifference

13,807,679
JPY*The dosing schedule is slightly different between TIE NDMM and RRMM in DRd regimen, thecost was calculated separately.

•

Table 5-3 Results of Cost Comparison [Sensitivity Analysis 2]
RegimenTotal Cost

(population)
DVMP(TIE NDMM
and RRMM)
DRd(TIE
NDMM)*DRd(RRMM)*

Dara SC
Dara IV

Cost

% of

difference

Regi(SC-IV)men

Total costdifference

9,759,092
JPY-642,211

10,401,303

JPY（Comparator） JPY
Dara SC
Dara IV

14,397,567
JPY-386,111

14,783,678

JPY（Comparator） JPY
Dara SC
Dara IV-481,985
JPY

14,397,687
JPY-385,991

14,783,678

JPY（Comparator） JPY
DVd(RRMM)

Dara SC
Dara IV

10,985,848
JPY-645,921

11,631,769

JPY（Comparator） JPY*The dosing schedule is slightly different between TIE NDMM and RRMM in DRd regimen, thecost was calculated separately.

5.1.3 Assessing the validity of the analysis•

MM is a plasmacytic malignant tumor which is a type of white cell, and it isessential to be treated by the multidisciplinary treatment at the department of111

hematology as centered in close collaboration with other department for its
treatment. From this reason, in the setting of the coefficient for DPC code, it isconsidered as that MM patients was visiting a special function hospital where
facilities and systems are established that can provide advanced medical care,
especially in the initial stage of treatment with a new drug. This is the rationaleof setting the functional assessment factor I and it is considered as appropriate.
For the setting of the basic coefficient and the functional assessment factor II,
the conservative approach as taking mean value was applied.
•In the setting of the hospitalization rate at the initiation of the treatment, for the
management of infusion reaction which was identified as one of the important
identified factors for both Dara IV and Dara SC was took into the consideration.
In the appropriate use guide, it is recommended as "Patients should be closely
monitored for symptoms of infusion reactions during and after treatment withthis drug.". In the real world clinical practice, from MDV database analysis, allpatients treated with Dara IV were hospitalized at the start of treatment, and themean length of hospitalization wasdays (mean asdays and median asdays). For Dara SC, setting of the hospitalization rate at the initiation of thetreatment, the data from MDV database was used. In the case of Dara SC,
considering the MMY3012 study results for the time of onset of initial infusion
reactions after administration (median as 1,440 mins), it was considered as
appropriate to assume that patients were hospitalized for

day to monitor

infusion reactions even after the first dose of this drug. As a sensitivity analysis,
it was assumed that% of Dara SC patients were not hospitalized at theinitiation of the treatment due to convenient administration.
•

The treatment duration was set from the mean duration of treatment with Dara
IV based on the MDV database analysis. Also in an epidemiological data in Japan[43], the median time to next treatment (TTNT) in MM patients aged 80 years orolder was 7.8 months, and the median TTNT was 3.8 months for the period 2016
to 2020 years as the treatment started. This setting was considered as
appropriate which took into account that the target population for this analysis
includes populations in relatively younger age groups. Since the actual durationof treatment with Dara SC is not yet available, the duration of treatment with
Dara SC and Dara IV is assumed to be the same based on the non-inferiority
result in ORR and PFS from the clinical trial. In the Australian PBAC evaluation
the cost-minimisation analysis comparing the annual cost of Dara SC and Dara112

IV was performed and was considered appropriate. Therefore, as a sensitivity
analysis, an analysis with a treatment duration of 1 year was also performed.
5.1.4 Interpretation of Analysis Results
Population
Comparative
Control
ICER reference
rangesMultiple Myeloma
Dara IV□ Usual products ■ Products requiring consideration■ Cost reduction or dominantInterval□considered to□ > 5 million yen (> 7.5 million yen) and ≤ 7.5 million yen

have the highest
probability of(≤ 11.25 million yen)
□ > 7.5 million yen (> 11.25 million yen) and ≤ 10 million

belonging to theICER

5 million yen or less (7.5 million yen or less)yen (≤ 15 million yen)
□ > 10 million yen (> 15 million yen)
□ Equivalent (or inferior) efficacy and high cost

Reason for such
judgment

It was shown to be cost saving in total costs in the basecase as well as the 2 sensitivity analysis that were
performed.

5.1.5 Price Adjustment Rate Weight
本剤の追加効能である全身性 AL アミロイドーシスについて、費用対効果評価の対象として指定され現在企業分析を実施中である。本剤の各効能の患者数と患者割合を以下に示す。

本剤の対象集団MM
未治療の全身性 AL ア

患者数（人）

患者割合

6,900
[44]

ミロイドーシス**
Total*悪性腫瘍; **指定難病
5.1.6 Price increases
Not applicable1135.2 Analysis Including Public Nursing Care Expenses and Productivity
loss [only if applicable]
Not applicable
5.3 Other Analyses
5.3.1 Other analysis: cost difference from HCP time perspective.
One of the important benefits of Dara SC is to reduce the infusion burden of Dara
IV. A Time and Motion study was conducted to quantify this benefit.
5.3.1.1 Result
From the Time and Motion study [5], the breakdown of the time required fromdifferent types of HCPs in the first and a subsequent drug administration visit forDara SC and Dara IV were acquired as following.
•

Table 5-4 HCP time per administration visit
HCP Time perintervention

administration
(min)

First
infusion/injection
Subsequentadministration

Dara SC
Dara IV(Comparator)
Dara SC
Dara IV(Comparator)

Time

differenceperadministration (SC-IV)

96.3
265.9

-169.6 min (-2.8 hours)

90.4
179.2

-88.8 min (-1.5 hours)

To convert the HCP time into monetary term, the average hourly wage for thecorresponding type of Japan HCP were applied. The detail of the analysis wasprovided in Appendix K.
•

Table 5-5 Cost per administration by converting the time to monetary terminterventionFirst
infusion/injection

Dara SC
Dara IV(Comparator)

Cost per the

Cost difference

administration(SC-IV)7,928 JPY
21,139 JPY-13,211 JPY

114

Dara SC

Subsequent

7,450 JPY

Dara IVadministration(Comparator)-6,466 JPY

13,916 JPY

5.3.1.2 Interpretation of Analysis Results
The analysis results provided an additional evaluation on HCP time/cost savingthat contribute to overall health care system efficiency.
5.3.2 Other analysis: CUA (Scenario analysis)
5.3.2.1 Incremental cost, effect, and ratio of cost-effectivenessThe results of the analysis are summarized and described in detail in the tablebelow for each analysis population.
1) Daratumumab in Combination with Bortezomib and Dexamethasone
Subcutaneous Injection (DVd SC) vs Bortezomib and Dexamethasone(Vd) in Patients with RRMM
Total discounted QALYs gained are 3.99 years for DVd (SC) and 2.69 years for
Vd. The incremental QALYs gained is 1.30 years, which indicates that DVd (SC)is a more effective treatment than Vd. Total discounted costs areyen

for DVd (SC) andyen.

yen for Vd. The incremental cost is

The ICER of DVd (SC) versus Vd is calculated to be

yen/QALY (Table

5-6). Details of cost breakdown is presented in Table 5-7.
•

Table 5-6 Summary of Analytical Results (RRMM DVd model)
Total

Incrementa

Total

Incremental

ICER

QALYs

l QALYs

Costs (yen)Costs (yen)(yen/QALY)

DVd

3.99

1.30

Vd

2.69

Regimen•Table 5-7 Details of Cost Breakdown (RRMM DVd model)

115Comparative
Technology

Control

Evaluated (yen)Technology(yen)Progression-Free
Drug costs
Administration costs
Medical resource use costs
Adverse event costs
Post-Progression
Subsequent treatment drug
costs
Subsequent treatment
administration costs
Medical resource use costs
End of life costs
Total Costs

2) DaratumumabinCombination

with

Lenalidomide

andDexamethasone Subcutaneous Injection (DRd SC) vs Lenalidomide
and Dexamethasone (Rd) in Patients with RRMM
Total discounted QALYs gained are 5.54 years for DRd (SC) and 4.33 years for
Rd. The incremental QALYs gained is 1.20 years, which indicates that DRd (SC)is a more effective treatment than Rd. Total discounted costs arefor DRd (SC) andfor Rd. The incremental cost is

The ICER of DRd (SC) versus Rd is calculated to be.
/QALY (Table

5-8). Details of cost breakdown are presented in Table 5-9.
•

Table 5-8 Summary of Analytical Results (RRMM DRd model)

116

TotalQALYsTechnology
Evaluated

5.54

Increment
al QALYs

Total

Increment

ICER

Costs

al Costs(yen/QALY

(yen)

(yen)

)

1.20

Comparativ
e Control

4.33

Technology•

Table 5-9 Details of Cost Breakdown (RRMM DRd model)
Technology
Evaluated (yen)Comparative
ControlTechnology (yen)Progression-Free
Drug Costs
Administration Costs
Medical Resource Use Costs
Adverse Event Costs
Post-Progression
Subsequent Treatment Drug
Costs
Subsequent

Treatment

Administration Costs
Medical Resource Use Costs
End Of Life Costs
Total Costs

5.3.2.2 One-Way Sensitivity Analysis
One-way sensitivity analysis (OWSA) was conducted for key model parameters.
In the absence of the 95% confidence intervals, an standard error (SE) of 10%117

of the base-case estimate was assumed for each parameter, except for discountrates for health and costs which were varied from 0% to 4% per the Japan HTA
guidelines.
1) Daratumumab in Combination with Bortezomib and Dexamethasone
Subcutaneous Injection (DVd SC) vs Bortezomib and Dexamethasone(Vd) in Patients with RRMM
Table O1 (Appendix O) presents a list of parameters included in the OWSA, theirranges, and the impact on the ICER. Figure 5-1 presents the 10 most influential
parameters as a tornado diagram.
•

Figure 5-1 Tornado Diagram of 10 Most Influential Parameters on the ICER of
DVd (SC) vs. Vd2) DaratumumabinCombination

with

Lenalidomide

andDexamethasone Subcutaneous Injection (DRd SC) vs Lenalidomide
and Dexamethasone (Rd) in Patients with RRMM
Table O2 (Appendix O) presents a list of parameters included in the OWSA, theirranges, and the impact on the ICER. Figure 5-2 presents the 10 most influential
parameters as a tornado diagram.
•

Figure 5-2 Tornado Diagram of 10 Most Influential Parameters on the ICER of
DRd (SC) vs. Rd

118

5.3.2.3 Internal validity
The model was assessed by an external peer reviewer not involved with theoriginal programming. Throughout the validation process a comprehensive andrigorous quality check was fulfilled, including validating the logical structure of
the model, mathematical formulas, sequences of calculations, and the values ofnumbers supplied as model inputs. Unexpected model behavior, implementationand typing errors were all identified by this review. The appropriateness of
distributions used in the probabilistic analysis of the model was also checked.
Following the validation, correction of identified errors or bugs was incorporated
in the revised model.
5.3.2.4 External validity
As external validation, the model’s survival predictions were also checked against
data observed in the clinical trials used as data sources. The estimation yieldedfrom the model is appropriate in comparison to existing other clinical data.
5.3.2.5 Interpretation of Analysis Results
This analysis only focused on a subset of Multiple Myeloma patients, RRMM, whencomparing to Vd and Rd. As it is agreed that the main evaluation focuses on adifferent population and comparator, this analysis was served as supplementary
analysis.

119

6. 再分析用のデータ使用したソフトウェア

Microsoft®
Excel® forMicrosoft 365
MSO
Microsoft®
Excel® forMicrosoft 365
MSO
Microsoft®
Excel® forMicrosoft 365
MSO
Microsoft®
Excel® forMicrosoft 365
MSO

バージョン

Version 2108
(Build14326.20600)

ファイル名

Daratumumab_CMA_JP_
MM_v1.0

Version 2108

Daratumumab_Cost(Builddifference from HCP

14326.20600)

time_v1.0

Version 2108
(Build14326.20600)
Version 2108
(Build14326.20600)

Daratumumab_PSM_JP_
RRMM_DVd_v5.0

Daratumumab_PSM_JP_
RRMM_DRd_v5.0

提出メディア

Email

Email

Email

Email

120

7. 実施体制
該当せず

121

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Weisel K, Spencer A, Lentzsch S, Avet-Loiseau A, Mark TM, Spicka I, et.
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Kaufman JL, Dimopoulos MA, White D, Benboubker L, Cook G, Leiba M,
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Bahlis N, Dimopoulos MA, White DJ, Benboubker L, Cook G, Leiba M, etal. Three-Year Follow up of the Phase 3 POLLUX Study of Daratumumab
Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide andDexamethasone (Rd) Alone in Relapsed or Refractory Multiple Myeloma(RRMM). Proceedings of the 61st ASH Annual Meeting; Dec 7-10;
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Dimopoulos MA, San-Miguel J, White D, Benboubker L, Cook G, Leiba M,
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Appendix A: Parameters Used in the Analysis (DVd [SC] vs Vd, Cost Utility Analysis)•Table A1 RRMM DVd (SC) vs Vd Base-Case Analysis Parameters
Variable Name

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Rationale

Settings
Based on ISPOR ModelingGood Practices toModel Cycle Length

1 week----accurately represent thefrequency of clinicalevents while reducing
errorTime Horizon (Years)

30

--

--

Discount Rate

2.0%

--

--

Age (Years)

NormalAssumed to be a lifetime

In alignment withJapanese HTA Guidelines
Based on MMY3004 trial[8]

Variable Name

Value

Patient Body Weight (kg)– mean (SD)Patient Height (m) –mean (SD)

95% CI*

Distribution(If Applicable)(If Applicable)

Rationale

NormalPMS [4]

NormalPMS [4]
Calculated based on bodyPatient Body Surface

--

Area

--

weight and height using
the DuBois & DuBois
algorithm [45]Intervention

DVd (SC)

--

--

--

Comparators

Vd

--

--

--

Clinical Inputs

Overall Survival:
DVd (SC)

Based on lowest AIC/BIC
Fitted curve--

Exponential

goodness-of-fit values
and clinical plausibility of130

Variable Name

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Rationale
long-term extrapolation

Based on lowest AIC/BIC
Overall Survival: Vd

Fitted curve--

Exponential

goodness-of-fit values
and clinical plausibility oflong-term extrapolation
Based on lowest AIC/BIC

Progression-Free
Survival: DVd (SC)

Fitted curve--

Generalized Gamma

goodness-of-fit values
and clinical plausibility oflong-term extrapolation

Progression-Free
Survival: Vd

KM estimator----

Fitted curve--

Gompertz

DVd (SC)
Time-To-TreatmentDiscontinuation: Vd

in the MMY3004 trial
Based on lowest AIC/BIC

Time-To-Treatment
Discontinuation:

Full KM data is available

goodness-of-fit values
and clinical plausibility oflong-term extrapolation
Based on lowest AIC/BIC

Fitted curve--

Lognormal

goodness-of-fit values
and clinical plausibility of131

Variable Name

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Rationale
long-term extrapolation

Subsequent Treatment Specific Probabilities
Based on MMY 3004 trial
DVd (SC)

Normal– IA3 data cut; Assumed
same as DVd (IV) [40]Vd

NormalBased on MMY 3004 trial– IA3 data cut [40]Incidence of AEs Over Time

Incidence of Anemia:
DVd (SC)

Incidence of Anemia: Vd

Based on MMY3004 trial;----

Assumed same as DVd(IV) [8]----Based on MMY3004 trial

132

Variable Name

Incidence of Diarrhea:
DVd (SC)
Incidence of Diarrhea:
Vd
Incidence of Fatigue:
DVd (SC)

Incidence of Fatigue: Vd

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Based on MMY3004 trial;
--

--

--

--

Neutropenia: Vd----

DVd (SC)[8]

Assumed same as DVd(IV) [8]----Based on MMY3004 trial[8]
Based on MMY3004 trial;----

Assumed same as DVd(IV) [8]----Incidence ofHypertension:

Based on MMY3004 trial

Based on MMY3004 trial;

DVd (SC)
Incidence of Febrile

Assumed same as DVd(IV) [8]Incidence of Febrile
Neutropenia:

Rationale

Based on MMY3004 trial[8]
Based on MMY3004 trial;----

Assumed same as DVd(IV) [8]133Variable Name
Incidence ofHypertension: Vd

Value

95% CI*

Distribution(If Applicable)(If Applicable)

--

--

--

--

--

--

Incidence of Infusion
Related Reaction:
DVd (SC)
Incidence of Infusion
Related Reaction: Vd
Incidence of
Lymphopenia:

Lymphopenia: Vd

--

--

--

--

Neutropenia: Vd

Based on MMY3012 trial[7]

Assumed same as DVd

Based on MMY3004 trial[8]
Based on MMY3004 trial;----

DVd (SC)
Incidence of[8](IV) [8]Incidence of
Neutropenia:

Based on MMY3004 trial

Based on MMY3004 trial;

DVd (SC)
Incidence ofRationale

Assumed same as DVd(IV) [8]----Based on MMY3004 trial
[8]

134

Variable Name

Incidence of Peripheral
Neuropathy: DVd (SC)
Incidence of Peripheral
Neuropathy: Vd
Incidence ofPneumonia: DVd (SC)
Incidence ofPneumonia: Vd

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Based on MMY3004 trial;
--

--

--

--

Thrombocytopenia: Vd

Based on MMY3004 trial[8]
Based on MMY3004 trial;----

Assumed same as DVd(IV) [8]----Based on MMY3004 trial[8]
Based on MMY3004 trial;----

DVd (SC)
Incidence ofAssumed same as DVd(IV) [8]Incidence ofThrombocytopenia:

Rationale

Assumed same as DVd(IV) [8]----Based on MMY3004 trial[8]

Drug Costs

135

Variable Name

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Daratumumab (SC)434,209.00 yen

353,289.77-523,347.54

Gamma

Dexamethasone

29.90 yen24.33-36.04

Gamma

Bortezomib

134923.00 yen

109,778.74-162,621.27

Gamma

Rationale

MHLW list in November
2021 [32][33]

Drug Administration Costs

IV Administration % for
Bortezomib

NormalProportion of Patients
Initiating DARA (SC) in

NormalHospital
Duration of Hospital Stay
(Days) DARA (SC)NormalBased on Japan Market
Intelligence
MDV database analysis in
Appendix L
MDV database analysis in
Appendix L

136

Variable Name

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Hospitalization Fee

Gamma(Day 1 - Day 4)

Hospitalization Fee

Gamma(Day 5 - Day 14)

Hospitalization Fee

Gamma(Day 15 - Day 21)

DARA (SC)
Administration(Outpatient)

Rationale

Ministry of Health Labour
200.00 yen

162.73-241.06

Gamma

and Welfare. Revision of
Medical Fee for FY 2020

137

Variable Name

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Non-DARA IV
Administration

Rationale(Reiwa 2) [in Japanese]

490.00 yen

398.68-590.59

Gamma

200.00 yen

162.73-241.06

Gamma

680.00 yen

553.28-819.60

Gamma

[34]

(Outpatient)
Non-DARA SC
Administration(Outpatient)
Oral Drug Initiation

Annual Subsequent
Treatment Drug Costs

Gamma
MDV database analysis in

Annual Subsequent
Treatment Administration

Appendix L
Gamma

Costs
MRU Costs

End of Life(One Time Cost)

Gamma

MDV database analysis in
Appendix L

138

Variable Name

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Weekly MRU Cost: PFS

Gamma

Weekly MRU Cost: PPS

Gamma

Rationale

Adverse Event Management Costs

AnemiaGamma

Diarrhea

Gamma
MDV database analysis in
Appendix L

Fatigue

Gamma

Febrile Neutropenia

Gamma

139

Variable Name

Hypertension

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Rationale

Gamma
Microcosting approachfrom the literture 'How to

Infusion Related Reaction

Gamma

use and concept of new
drugs for multiple
myeloma'(2017)[InJapanese] [41]Lymphopenia

Gamma

Neutropenia

Gamma
MDV database analysis in
Appendix L

Peripheral Neuropathy

Gamma

Pneumonia

Gamma

140

Variable Name

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Thrombocytopenia

Rationale

Gamma

Utility Inputs

Pre-Progression (PFS)

0.81

0.69-0.95

Lognormal

van Agthoven, 2004 [38]Post-Progression (PPS)

0.64

0.56-0.73

Lognormal

van Agthoven, 2004 [38]Lognormal

See Appendix F for details

Lognormal

See Appendix F for details

Utility Decrement
Due to AE: DVd (SC)Utility Decrement
Due to AE: Vd

Abbreviations: AIC = Akaike Information Criterion; BIC = Bayesian Information Criterion; CI = Confidence Interval; DRd =daratumumabin combination with lenalidomide and dexamethasone; IV = Intravenous; Kg = Kilograms; M = meters; RRMM = relapsed/refractory
multiple myeloma; SC = Subcutaneous; SD = Standard Deviation

141

Variable Name

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Rationale*For some parameters uncertainty information was not available therefore, 95% confidence intervals (CI) were derived based on theunderlying distribution of the parameter and the assumption that the standard error was 10% of the base case value. The lower and upperbound values of the 95% CI were used in one-way sensitivity analysis (OWSA).

142

Appendix B: Parameters Used in the Analysis (DRd [SC] vs Rd, Cost Utility Analysis)•Table B1 RRMM DRd (SC) vs Rd Base-Case Analysis Parameters
Variable Name

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Rationale

Settings
Based on ISPOR ModelingGood Practices toModel Cycle Length

1 week----accurately represent thefrequency of clinicalevents while reducing
errorTime Horizon (Years)

30

--

--

Discount Rate

2.0%

--

--

Age (Years)

NormalAssumed to be a lifetime

In alignment withJapanese HTA Guidelines
Based on MMY3003 trial
[10]

143

Variable Name

Value

Patient Body Weight (kg)– mean (SD)Patient Height (m) –mean (SD)

95% CI*

Distribution(If Applicable)(If Applicable)

Rationale

NormalPMS [4]

NormalPMS [4]
Calculated based on bodyPatient Body--

Surface Area--

weight and height using
the DuBois & DuBois
algorithm [45]Intervention

DRd (SC)

--

--

--

Comparator

Rd

--

--

--

Clinical Inputs

Overall Survival: DRd(SC)

Based on lowest AIC/BIC
Fitted curve

Exponential

goodness-of-fit values
and clinical plausibility of144

Variable Name

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Rationale
long-term extrapolation;
Assumed same as DRd(IV) in MMY 3003 trial
Based on lowest AIC/BIC

Overall Survival: Rd

Fitted curve

Exponential

goodness-of-fit values
and clinical plausibility oflong-term extrapolation
Based on lowest AIC/BIC
goodness-of-fit values

Progression-Free
Survival: DRd (SC)

Fitted curve

Lognormal

and clinical plausibility oflong-term extrapolation;
Assumed same as DRd(IV) in MMY 3003 trial
Based on lowest AIC/BIC

Progression-Free
Survival: Rd

Fitted curve

Lognormal

goodness-of-fit values
and clinical plausibility oflong-term extrapolation

Time-To-Treatment
Discontinuation:
DRd (SC)

Based on lowest AIC/BIC
Fitted curve

Exponential

goodness-of-fit values
and clinical plausibility of145

Variable Name

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Rationale
long-term extrapolation

Based on lowest AIC/BIC
Time-To-TreatmentDiscontinuation: Rd

Fitted curve

Exponential

goodness-of-fit values
and clinical plausibility oflong-term extrapolation

Subsequent Treatment Specific Probabilities
Based on MMY 3003 trial
DRd (SC)

Normal– IA3 data cut; Assumed
same as DRd (IV) [39]Rd

NormalBased on MMY 3003 trial– IA3 data cut [39]Incidence of AEs Over Time

Incidence of Anemia:
DRd (SC)----

Based on MMY3003 trial;
Assumed same as DRd146

Variable Name

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Rationale(IV) [10]Incidence of Anemia: Rd

Incidence of Diarrhea:
DRd (SC)
Incidence of Diarrhea:
Rd
Incidence of Fatigue:
DRd (SC)

Incidence of Fatigue: Rd----

DRd (SC)[10]
Based on MMY3003 trial----[10]; Assumed same as
DRd (IV)----

Based on MMY3003 trial[10]
Based on MMY3003 trial----[10]; Assumed same as
DRd (IV)----

Incidence of Febrile
Neutropenia:

Based on MMY3003 trial

Based on MMY3003 trial[10]
Based on MMY3003 trial----[10]; Assumed same as
DRd (IV)

147

Variable Name
Incidence of Febrile
Neutropenia: Rd

Value

--

95% CI*

Distribution(If Applicable)(If Applicable)--

Incidence ofHypertension:

Hypertension: Rd

--

--

--

--

--

--

--

--

(SC)
Incidence of Infusion
Related Reaction: Rd
Incidence of
Lymphopenia: DRd

Lymphopenia: Rd[10]; Assumed same as

Based on MMY3003 trial[10]
Based on MMY3012 trial[7]
Based on MMY3003 trial[10]
Based on MMY3003 trial

--

--

(SC)
Incidence of[10]

DRd (IV)

Incidence of Infusion
Related Reaction: DRd

Based on MMY3003 trial

Based on MMY3003 trial

DRd (SC)
Incidence ofRationale[10]; Assumed same as
DRd (IV)----

Based on MMY3003 trial
[10]

148

Variable Name

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Incidence of
Neutropenia:

Based on MMY3003 trial----

DRd (SC)
Incidence of
Neutropenia: Rd

--

--

--

--

--

--

Neuropathy: Rd

Pneumonia: DRd (SC)
Incidence ofPneumonia: Rd

DRd (SC)[10]; Assumed same as

Based on MMY3003 trial[10]
Based on MMY3003 trial----[10]; Assumed same as
DRd (IV)----

Incidence ofThrombocytopenia:[10]

DRd (IV)

Incidence ofIncidence ofBased on MMY3003 trial

Based on MMY3003 trial

Neuropathy: DRd (SC)Peripheral[10]; Assumed same as
DRd (IV)

Incidence of
Peripheral

Rationale

Based on MMY3003 trial[10]
Based on MMY3003 trial----[10]; Assumed same as
DRd (IV)

149

Variable Name

Value

Incidence ofThrombocytopenia: Rd

95% CI*

Distribution(If Applicable)(If Applicable)----

Rationale
Based on MMY3003 trial[10]

Drug Costs

Daratumumab (SC)434,209.00 yen

353,289.77-523,347.54

Gamma

Dexamethasone

29.90 yen24.33-36.04

Gamma

Lenalidomide

8,085.30 yen

6,578.52-9,745.13

Gamma

MHLW list in November
2021 [32][33]

Drug Administration Costs
Proportion of Patients
Initiating DARA (SC) in
Hospital

Normal

MDV database analysis in
Appendix L

150

Variable Name

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Duration of Hospital Stay

Normal(Days) DARA (SC)

Hospitalization Fee

Hospitalization Fee

Gamma(Day 5 - Day 14)

Hospitalization Fee

Gamma(Day 15 - Day 21)

Administration

Assumption

Gamma(Day 1 - Day 4)

DARA (SC)

Rationale

200.00 yen

162.73-241.06

Gamma

Ministry of Health Labourand Welfare. Revision of151

Variable Name

Value

95% CI*

Distribution(If Applicable)(If Applicable)(Outpatient)

Rationale
Medical Fee for FY 2020
(Reiwa 2) [in Japanese][34]

Non-DARA IV
Administration

490.00 yen

398.68-590.59

Gamma

200.00 yen

162.73-241.06

Gamma

680.00 yen

553.28 - 819.60

Gamma(Outpatient)
Non-DARA SC
Administration(Outpatient)
Oral Drug Initiation

Weekly Subsequent
Treatment Drug Costs

Gamma

Appendix L

Weekly Subsequent
Treatment Administration

MDV database analysis in

Gamma

Costs
MRU Costs

152

Variable Name

Value

End of Life (One Time
Cost)

95% CI*

Distribution(If Applicable)(If Applicable)

Rationale

Gamma
MDV database analysis in

Weekly MRU Cost: PFS

Gamma

Weekly MRU Cost: PPS

Gamma

Appendix L

Adverse Event Management Costs

AnemiaGamma
MDV database analysis in

Diarrhea

Gamma

Fatigue

Gamma

Appendix L

153

Variable Name

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Febrile Neutropenia

Gamma

Hypertension

Gamma

Rationale

Micro costing approachfrom the literature 'How
Infusion Related ReactionGamma

to use and concept of new
drugs for multiple
myeloma'(2017) [InJapanese] [41]Lymphopenia

Gamma

Neutropenia

Gamma

Peripheral Neuropathy

Gamma

MDV database analysis in
Appendix L

154

Variable Name

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Pneumonia

Gamma

Thrombocytopenia

Gamma

Rationale

Utility Inputs

Pre-Progression (PFS)

0.81

0.69-0.95

Lognormal

van Agthoven, 2004 [38]Post-Progression (PPS)

0.64

0.56-0.73

Lognormal

van Agthoven, 2004 [38]Lognormal

See Appendix F for details

Lognormal

See Appendix F for details

Utility Decrement
Due to AE: DRd (SC)Utility Decrement
Due to AE: Rd

155

Variable Name

Value

95% CI*

Distribution(If Applicable)(If Applicable)

Rationale

Abbreviations: AIC = Akaike Information Criterion; BIC = Bayesian Information Criterion; CI = Confidence Interval; DRd =daratumumabin combination with lenalidomide and dexamethasone; IV = Intravenous; Kg = Kilograms; M = meters; RRMM = relapsed/refractory
multiple myeloma; SC = Subcutaneous; SD = Standard Deviation*For some parameters uncertainty information was not available therefore, 95% confidence intervals (CI) were derived based on theunderlying distribution of the parameter and the assumption that the standard error was 10% of the base case value. The lower and upperbound values of the 95% CI were used in one-way sensitivity analysis (OWSA).

156

Appendix C: Time-to-Event Analysis for Progression-Free Survival (PFS)The recommended distribution to model PFS for each pair of possible comparators is shown in Table C1. All relevant datafrom the fitting exercises, including parameters of the distributions and goodness-of-fit statistics (AIC/BIC) can be found in0.
•

Table C1 Recommended Parametric Distributions for Long-Term Estimation of Progression-Free Survival in the RRMM Models
Recommended
Distribution for PFS

Source/Rationale
MMY3004 263 OS events data cut (median follow-up

DVd (SC)

Generalized Gamma

months); Assumed

the same as DVd IV; Based on lowest AIC/BIC goodness-of-fit values andclinical plausibility of long-term extrapolation

Vd

KM estimator

MMY3004 263 OS events data cut (median follow-up

months); KM

estimator used because full follow-up data was available
MMY3003 IA3 (median follow-up 32.9 months); Assumed the same as DRd IV;

DRd (SC)

Log-normal

Based on lowest AIC/BIC goodness-of-fit values and clinical plausibility of longterm extrapolation

Rd

Log-normal

MMY3003 IA3 (median follow-up 32.9 months); Based on lowest AIC/BIC
goodness-of-fit values and clinical plausibility of long-term extrapolation

157

Recommended
Distribution for PFS

Source/Rationale

Abbreviations: DRd =daratumumab in combination with lenalidomide and dexamethasone; DVd = daratumumab in combination withbortezomib and dexamethasone; IV = intravenous; RRMM = relapsed/refractory multiple myeloma; SC = subcutaneous;158

Appendix D: Time-to-Event Analysis for Overall Survival (OS)The recommended distribution to model OS for each pair of possible comparators is shown in Table D1. All relevant data fromthe fitting exercises, including parameters of the distributions and goodness-of-fit statistics (AIC/BIC) can be found in 0.
•

Table D1 Recommended Parametric Distributions for Long-Term Estimation of Overall Survival in the RRMM Models
Recommended
Distribution for OS

Source/Rationale
MMY3004 263 OS events data cut (median follow-up

DVd (SC)

Exponential

months); Assumed

the same as DVd IV; Based on lowest AIC/BIC goodness-of-fit values andclinical plausibility of long-term extrapolation
MMY3004 263 OS events data cut (median follow-up

Vd

Exponential

months); Based on

lowest AIC/BIC goodness-of-fit values and clinical plausibility of long-term
extrapolation
MMY3003 IA3 (median follow-up 32.9 months); Assumed the same as DRd IV;

DRd (SC)

Exponential

Based on lowest AIC/BIC goodness-of-fit values and clinical plausibility of longterm extrapolation

Rd

Exponential

MMY3003 IA3 (median follow-up 32.9 months); Based on lowest AIC/BIC
goodness-of-fit values and clinical plausibility of long-term extrapolation

Abbreviations: DRd =daratumumab in combination with lenalidomide and dexamethasone; DVd = daratumumab in combination withbortezomib and dexamethasone; IV = intravenous; RRMM = relapsed/refractory multiple myeloma; SC = subcutaneous

159

160

Appendix E: Time-to-Event Analysis for Time-To-Treatment Discontinuation (TTD)
The recommended distribution to model TTD for each pair of possible comparators is shown in Table E1. All relevant datafrom the fitting exercises, including parameters of the distributions and goodness-of-fit statistics (AIC/BIC) can be found in
Appendix K.
•

Table E1. Recommended Parametric Distributions for Long-Term Estimation of Time-to-Treatment Discontinuation in the RRMM
ModelsRecommended
Distribution for TTD

Source/Rationale
MMY3004 263 OS events data cut (median follow-up

DVd (SC)

Gompertz

months); Assumed

the same as DVd IV; Based on lowest AIC/BIC goodness-of-fit values andclinical plausibility of long-term extrapolation
MMY3004 263 OS events data cut (median follow-up

Vd

Lognormal

months); Based on

lowest AIC/BIC goodness-of-fit values and clinical plausibility of long-term
extrapolation
MMY3003 IA3 (median follow-up 32.9 months); Assumed the same as DRd IV;

DRd (SC)

Exponential

Based on lowest AIC/BIC goodness-of-fit values and clinical plausibility oflong-term extrapolation

Rd

Exponential

MMY3003 IA3 (median follow-up 32.9 months); Based on lowest AIC/BIC
goodness-of-fit values and clinical plausibility of long-term extrapolation

161

Recommended
Distribution for TTD

Source/Rationale

Abbreviations: DRd =daratumumab in combination with lenalidomide and dexamethasone; DVd = daratumumab in combination withbortezomib and dexamethasone; IV = intravenous; RRMM = relapsed/refractory multiple myeloma; SC = subcutaneous162

Appendix F: Details of QOL Values (Disutility Inputs)•

Table F1. Disutility Inputs for RRMM DRd and DVd Models
Adverse Event

FebrileNeutropenia

Duration of AE(Days)

Disutility

Adjusted
Disutility

Source[46]

Neutropenia[47]

Anemia[47]

Thrombocytopenia[47]

Lymphopenia

[47]

163

Adverse Event

Duration of AE(Days)

Disutility

Adjusted
Disutility

SourcePneumonia[47]

Diarrhoea[48]

Fatigue[48]

Peripheral
Neuropathy

Hypertension[47]

Assume no QoL impact, controlled by
medication

164

Appendix G: Subsequent Treatment Costs in RRMM Models•

Table G1 Protocol for Estimating Subsequent Treatment Costs in RRMM Models
Steps

Description

Step 1

Identify the 3rd MM regimen and its first administration date (D1)

Step 2

Identity the end of timeframe – either the end of follow up or death (D2)

Step 3Calculate the MM-related drug and administration costs between D1 and D2

Step 4

Annualize the MM-related drug and administrations costs by dividing the cost by patient-year

165

•

Table G2 Subsequent Treatment Drug and Administration Costs in RRMM
Category

Annual Costs

Weekly Costs

Drug cost
Admin cost

166

Appendix H: Medical Resource Utilization•

Table H1 Protocol for Estimating Medical Resource Utilization Costs in the RRMM Models
Steps

Description

PFS
Step 1

Identify the first diagnosis of MM in the database, then identify the 1st MM regimen following
the diagnosis

Step 2

Identify the 2nd MM regimen and its first administration date (D1)

Step 3

Identify the 3rd MM regimen and its first administration date (D2)

Step 4
Step 5
Step 6

Exclude patients who had autologous stem cell transplantation within 12 weeks prior to D1 andpatients who had allogeneic stem cell transplantation at any time prior to D1
Calculate the non-drug costs between D1 and D2, and exclude the following: drug
administration cost, and cost associated with managing AEs
Annualize the costs by dividing the cost by patient-year

PPS
Step 1

Identify the end of timeframe – either the end of follow up or death (D3)
Calculate the non-drug costs between D2 and D3, and exclude the following: drug

Step 2administration cost, cost associated with managing AEs, transplant cost, and end of life cost
(MRU costs between 30 days from death and death)167

StepsDescription

Step 3

Annualize the costs by dividing the cost by patient-year

End of Life
Step 1

MRU costs between 30 days from death and death, and exclude the following: drug
administration cost, cost associated with managing AEs, and transplant cost168

Appendix I: Progression-Free Survival Distribution Parameters (Cost Utility Analysis)•Table I1 PFS Distribution Parameters (RRMM) – DRd (SC) and DVd (SC)Distribution

RRMM (DVd SC)
Intercept

Scale1Shape

RRMM (DRd SC)
AIC

BIC

Intercept

Scale1

Shape

AIC

BIC

Weibull
Log-normal
Log-logistic
Exponential
Generalised
Gamma
Gompertz[1] Gamma value for Gompertz Distribution

169

•

Table I2 PFS Distribution Parameters (Cost-Utility | RRMM) – Rd and Vd
Distribution

RRMM (Vd)2

RRMM (Rd)Intercept

Scale1

Shape

AIC

BIC

Weibull

--

--

--

--

--

Log-normal

--

--

--

--

--

Log-logistic

--

--

--

--

--

Exponential

--

--

--

--

--

--

--

--

--

--

--

--

--

--

--

Generalised
Gamma
Gompertz

Intercept

Scale1

Shape

AIC

BIC

[1] Gamma value for Gompertz Distribution[2] Kaplan-Meier Estimator used because full follow-up time was available

170Appendix J: Overall Survival Distribution Parameters (Cost Utility Analysis)•Table J1 OS Distribution Parameters (RRMM) – DRd (SC) and DVd (SC)Distribution

RRMM (DVd SC)
Intercept

Scale1Shape

RRMM (DRd SC)
AIC

BIC

Intercept

Scale1

Shape

AIC

BIC

Weibull
Log-normal
Log-logistic
Exponential
Generalised
Gamma
Gompertz[1] Gamma value for Gompertz Distribution

171

•

Table J2 OS Distribution Parameters (Cost-Utility | RRMM) – Rd and Vd
Distribution

RRMM (Vd)Intercept

Scale1Shape

RRMM (Rd)
AIC

BIC

Intercept

Scale1

Shape

AIC

BIC

Weibull
Log-normal
Log-logistic
Exponential
Generalised
Gamma
Gompertz[1] Gamma value for Gompertz Distribution

172

Appendix K: Time-to-Treatment Discontinuation Distribution Parameters (Cost Utility Analysis)•Table K1 TTD Distribution Parameters (RRMM) – DRd (SC) and DVd (SC)Distribution

RRMM (DVd SC)
Intercept

Scale1Shape

RRMM (DRd SC)
AIC

BIC

Intercept

Scale1

Shape

AIC

BIC

Weibull
Log-normal
Log-logistic
Exponential
Generalised
Gamma
Gompertz[1] Gamma value for Gompertz Distribution

173

•

Table K2 TTD Distribution Parameters (Cost-Utility | RRMM) – Rd and Vd
Distribution

RRMM (Vd)Intercept

Scale1Shape

RRMM (Rd)
AIC

BIC

Intercept

Scale1

Shape

AIC

BIC

Weibull
Log-normal
Log-logistic
Exponential
Generalised
Gamma
Gompertz[1] Gamma value for Gompertz Distribution

174Appendix L: MDV database analysis•

Table L1 The methodology for MDV database analysis
Item

Description

Data source

Retrospective claims data obtained from the Medical Data Vision (MDV) database were analyzed
from 01 January 2003 to 31 May 2021. The MDV database comprises standardized health-careinsurance claims data provided by hospitals in Japan, which is using the Japanese Diagnosis andProcedure Combination (DPC) fixed-payment reimbursement system for over 36 million individuals
since the year 2003 and contains about 30 thousand patients with MM.

Study

DesignandPatient Population• Adult patients with a diagnosis of MM were considered for this analysis. MM diagnosis was
defined as the presence of at least one record with a confirmed MM diagnosis code.
• Index diagnosis date was defined as the date on which the patient had first record of confirmed
MM diagnosis. The baseline period was the 12-month period before the index diagnosis date
and the follow-up period consisted of ≥60 days from the index diagnosis date; however, patients
who died within this 60-day period were followed for <60 days.

Outcomes evaluated• Proportion of the treatment regimens for each line and the duration of therapy.
• The rate of hospitalization and the duration of the hospitalization in the treatment.
• Subsequent treatment drug cost and subsequent treatment administration cost
• Annual MRU cost in PFS/PPS• MRU cost in End of life (EOL)• Adverse event cost
175

Publication

A part of the results was published at the 46th Annual meeting of the Japanese Society of Myeloma
[6].

176

Appendix M: Cost per the administration from the perspectiveof HCP workload
From the Time and Motion study [5], the breakdown of the first and thesubsequent administration time for each HCP was acquired as following.
By multiplying the wage per time for the corresponding Japan HCP role, the cost
per the administration from the perspective of HCP workload was calculated asfollowing.
•

Table M1 Time required by each HCP role for the administration
HCP roleAll
Pharmacist

Subsequent administration

90.4

179.2

First infusion/injection
Subsequent administration
Subsequent administration

Transport

First infusion/injection

assistant

Subsequent administration
First infusion/injection
Subsequent administration
First infusion/injection
Subsequent administration

Licensed practicalFirst infusion/injection

nurse

Subsequent administration

Healthcare

First infusion/injection

Support worker

Subsequent administration

Haematologist
Phlebotomist(minutes)
265.9

technician

Registered nurse(minutes)
96.3

First infusion/injection

Auxiliary nurse

Dara IVFirst infusion/injection

Pharmacy

Receptionist

Dara SCFirst infusion/injection
Subsequent administration
First infusion/injection
Subsequent administration
First infusion/injection
Subsequent administration

•

Table M2 Wage per time for each HCP role in JapanHCP role

HourlyWage perwage

minute

(JPY)

(JPY)

SourcePharmacist

Pharmacist [49]Pharmacy technician

Pharmacist [49]Transport assistantGeneral hourly wage [50]

Receptionist

General hourly wage [50]Auxiliary nurse

Registered nurse [50]

Licensed practical nurse

Registered nurse [50]Healthcare Support
worker

General hourly wage [50]Registered nurse

Registered nurse [49]

Haematologist

Physician [49]Phlebotomist

Physician [49]178Appendix N: Literature of Asian and Japanese-only population•

Table N1 List of literature of Asian and Japanese-only population for COLUMBA
study
Study name

COLUMBA study

Bibliographic

Iida S, Ishikawa T, Min CK, Kim K, Yeh SP, Usmani

information

SZ, Mateos MV, Nahi H, Heuck C, Qin X,
Parasrampuria DA. Subcutaneous daratumumab in
Asian patients with heavily pretreated multiple
myeloma: subgroup analyses of the noninferiority,
phase 3 COLUMBA study. Annals of hematology.
2021 Apr;100(4):1065-77.[12]Clinicaltrials.gov

NCT03277105

registry information
Study sites

Multicenter (147 sites in 18 countries)

Study enrollment

Oct 31, 2017 to Dec 27, 2018

periodTarget population

Recruited patients with RRMM who had received atleast three previous lines of therapy and had
evidence of response to at least one previous
treatment regimen.

Eligibility criteria•

Eligible patients were aged ≥18 years.

•

Patients had a documented diagnosis ofmultiple myeloma according to the International
Myeloma Working Group (IMWG) diagnostic
criteria.

•

Patients with relapsed or refractory multiple
myeloma had received at least three previouslines of therapy, including a proteasome
inhibitor and an immunomodulatory drug, orwere double refractory to both a proteasome
inhibitor and an immunomodulatory drug.

•

Patients had evidence of response to at least
one previous treatment regimen.

179

•

Pretreatment clinical laboratory values during
the screening phase were required to showadequate bone marrow, liver, and kidney
function.

•

Women of childbearing potential had to agree
to use two methods of birth control at least 4
weeks before first treatment dose and had tohave a negative pregnancy test 2 weeks before
randomization.

Key exclusion•

criteria

Previous treatment with daratumumab or otheranti-CD38 therapies.

•

Anti-myeloma treatment within 2 weeks or fivepharmacokinetic half-lives before
randomization.

•

Receipt of an autologous stem cell transplantwithin 12 weeks before randomization.

•

Malignancies other than multiple myeloma,
unless all treatment of that malignancy had
been completed at least 2 years before consent
and the patient had no evidence of the disease.

•

Meningeal involvement of the myeloma.

•

Chronic obstructive pulmonary disease with aforced expiratory volume in 1 s of less than
50% of the predicted normal.

•

Moderate or severe persistent asthma or ahistory of asthma within the last 2 years.

•

Clinically significant cardiac disease.

•

Seropositivity for HIV, hepatitis B, or hepatitis
C.

•

Known allergies to study-relevant compounds
and any other conditions that might interferewith the study protocol.

Details of•Dara SC group: n=263

interventional•

Asian patients: n=30

180method

Dosing: 1800 mg of daratumumab co-formulatedwith rHuPH20 2000 U/mL.
Patients received daratumumab once weekly (cycles
1 and 2), every 2 weeks (cycles 3–6), and thenevery 4 weeks (28-day cycles).

Details of•Dara IV group: n=259

comparators•

Asian patients: n=37

Dosing: 16 mg/kg of daratumumab
Patients received daratumumab once weekly (cycles
1 and 2), every 2 weeks (cycles 3–6), and thenevery 4 weeks (28-day cycles).
Study design•

Randomized, phase 3 trial•

Randomization was stratified based on baseline
bodyweight, previous therapy lines, andmyeloma type (IgG vs non-IgG).

Blinding method

Open labelPrimary endpoint

Overall response (partial response or better)

Key secondary•

endpoints

Proportion of patients with very good partial
response or better and complete response or
betterStatistical methods•

Time to response•

Duration of response•

Progression-free survival•

Overall survival•

Time to next therapy•

Patient reported treatment satisfaction•

Incidence of infusion-related reactions•

The Kaplan-Meier method was used to estimate
time-to-event distributions.

•Hazard ratios and 95% CIs were estimatedusing a stratified Cox proportional hazards
regression model.

•

The infusion-related reaction rate and rates ofvery good partial response or better were181

compared between groups using a stratified
Cochran-Mantel-Hansel test.
Sample size

Dara SC Asian patients (n=30):•

Korean n=4•

Taiwanese n=8•

Japanese n=18

Dara IV Asian patients (n=37):•

Korean n=7•

Taiwanese n=6•

Japanese n=24

Follow-up period

Median, 7.5 months (IQR 6.5–9.3)

Main background

Dara SC group vs IV groupfactors of subjects•

Male, n (%):20 (54.1) vs 15 (50.0)•

Median age (range), years: 70.0 (33–83) vs70.5 (48–84)•

Median weight, kg: 56.7 (32.8–93.0) vs 60.1
(40.5–83.2)•

Cytogenetic risk, n (%)•

Standard risk: 29 (78.4) vs 18 (69.2)•

High risk: 8 (21.6) vs 8 (30.8)

Efficacy in Asian

ORR

population

An overall response was observed in 66.7%(n=20/30) patients in the SC group (median NR,
95% CI 7.39-NE) and 43.2% (n=16/37) in the IV
group (median 10.41, 95% CI 8.31-NE)
PFS•

Median PFS was 11.1 vs 6.6 months for SC
group vs IV group, respectively (HR 0.62,
95% CI 0.32–1.22, p=0.16).

•

6-month and 12-month PFS rates were
72.4% versus 50.3% and 46.6% versus
28.3%, respectively.

Safety in Asian
population

IRR•

Dara SC group: 10%, n=3/30

182

•

Dara IV group: 18.9%, n=7/37•

OR, 0.48; 95% CI, 0.11–2.03; p=0.3120

Grade 3/4 TEAEs•

Dara SC group: 53.3% (n=16)•

Dara IV group: 56.8% (n=21)

SAEs•

Dara SC group: 13.3% (n=4)•

Dara IV group: 40.5% (n=15)

PRO in AsianPatients in the SC group responded more positively

population

to individual components of following parameters vsIV group:•

Satisfied with form of cancer therapy•

Taking cancer therapy as difficult as expected

Efficacy in Japanese

ORR

population

An overall response was observed in 61.1%(n=11/18) patients in the SC group (Median- NR,
95% CI 4.53-NE) and 54.2% (n=13/24) in the IV
group (median 10.41, 95% CI 8.31-10.41)
PFS•Median PFS was 8.3 months with DARA SC
versus 9.3 months with DARA IV (HR, 0.89;
95% CI, 0.36–2.16; p= 0.7870)•

6-month and 12-month PFS rates were
70.6% versus 54.2% and 34.3% versus 0%,
respectively.

Safety in JapaneseIRR

population

The IRR rate was the same for patients receiving
DARA SC and DARA IV in Japanese cohort.
•

Dara SC group: 16.7%, n=3/18•

Dara IV group: 16.7%, n=4/24

Grade 3/4 TEAEs•

Dara SC group: n=10 (55.6%)•

Dara IV group: n=10 (41.7%)

The rates of grade 3/4 neutropenia (27.8% for183

DARA SC and 0% for DARA IV, respectively),
lymphopenia (16.7% and 8.3%) and leukopenia(11.1% and 4.2%) were higher in the Japaneseonly cohort as compared to Asian cohort.
Grade 3/4 anemia was reported at a higher ratewith DARA SC (22.2%) compared to the global
COLUMBA safety population and occurred in nopatients receiving DARA IV.
SAEs•

Dara SC group: n=2 (11.1%)•

Dara IV group: n=7 (29.2%)

PRO in Japanese

Mean scores of CTSQ assessment were similar

population

between the DARA SC and DARA IV groups.

Conclusion

Efficacy and safety of DARA SC in Asian patientsand Japanese sub-analysis were generally
consistent with those of the global COLUMBA
population.

•

Figure N1 Progression free survival for (A) Asian and (B) Japanese-only
population

184

Dara: daratumumab; IV: intravenous; PFS: progression-free survival; SC:
daratumumab subcutaneous
Source: Iida et al. 2021[12]•Table N2 List of literature of East Asian (Japanese, Korean, and Taiwanese)
population for POLLUX study

185

Study name

POLLUX study

Bibliographic

Suzuki K, Dimopoulos MA, Takezako N, Okamoto S,

information

Shinagawa A, Matsumoto M, Kosugi H, Yoon SS,
Huang SY, Qin X, Qi M. Daratumumab,
lenalidomide, and dexamethasone in East Asianpatients with relapsed or refractory multiple
myeloma: subgroup analyses of the phase 3
POLLUX study. Blood cancer journal. 2018 May
1;8(4):1-9.[27]Clinicaltrials.gov

NCT02076009

registry information
Study sites

Multicenter

Study enrollment

Randomized between June 2014 and July 2015, andperiodthe clinical cutoff date for this analysis was 7 March
2017.

Target population

Patients had documented multiple myeloma andmeasurable disease at screening according to serumor urinary M-protein levels and they had received
and had a response to one or more lines of previous
therapy.

Eligibility criteria

Eligible patients had progressive disease according
to International Myeloma Working Group (IMWG)
criteria during or after their last regimen and hadreceived and responded to ≥1 line of prior therapy

Key exclusion•

criteria

Key exclusion criteria were lenalidomiderefractory disease.

•

The discontinuation of previous lenalidomide
treatment owing to adverse events.

•

A neutrophil count of 1.0×109 or less per liter.

•

A hemoglobin level of 7.5 g or less per
deciliter.

•

A platelet count of less than 75×109 per liter.

•

An alanine aminotransferase or aspartate
aminotransferase level of 2.5 or more times

186the upper limit of the normal range.
•

An alkaline phosphatase level of 2.5 or moretimes the upper limit of the normal range.

•

A bilirubin level of 1.5 or more times theupper limit of the normal range, and acreatinine clearance of less than 30 ml per
minute.

Details of•interventional
methodDaratumumab plus lenalidomide anddexamethasone (DRd): n=286•

East Asian patients: n=52•

Dosing: Lenalidomide: 25 mg orally on Days
1-21 of each 28-day cycle; dexamethasone:
40 mg orally weekly) with daratumumab (16mg/kg intravenously weekly for 8 weeks,
every 2 weeks for 16 weeks, and then every 4
weeks.

Details of•comparators

Lenalidomide and dexamethasone (Rd):
n=283

•

East Asian patients: n=44•

Japanese patients: n=15

Dosing: lenalidomide: 25 mg orally on Days 1-21 ofeach 28-day cycle; dexamethasone: 40 mg orally
weekly) without daratumumab (16 mg/kg
intravenously weekly for 8 weeks, every 2 weeks for
16 weeks, and then every 4 weeks.
Study design

Randomized, phase 3 trial

Blinding method

Open labelPrimary endpoint

Progression-free survival

Key secondary•

Overall response (partial response or better)endpoints•

Proportion of patients with very good partial
response or better.

•

Proportion of patients with complete responseor better•

Median duration of response

187

Statistical methods•

Time to response•

Overall survival•

Health-related Quality of Life•

Progression-free survival was compared
between treatment groups based on a
stratified log-rank test.
Hazard ratios and 95% confidence intervals•

were estimated using a Cox regression modelwith treatment as the sole explanatory
variable.
The Kaplan-Meier method was used to•estimate the distributions.
Stratified Cochran-Mantel-Haenszel tests were•used to test treatment differences in overall
response rate and rates of very good partial
response or better and complete response or
better.
Sample size

DRd group East-Asian patients: n=52
Japanese patients: n=21•

Rd group East-Asian patients: n=44
Japanese patients: n=15•
Follow-up period

Main backgroundfactors of subjects

Median (range)•

East Asian patients: 24.7 (0.7–30.5) months•

Japanese patients: 21.4 (4.4–24.1) months

East Asian patients (DRd vs Rd group):•

Male, %: 50 vs 61.4•

Median age (range), years: 64 (34–80) vs 65(44–85)•

Cytogenetic risk, n (%)•

Standard risk: 46 (92.0) vs 35 (83.3)•

High risk: 4 (8.0) vs 7 (16.7)

Japanese patients (DRd vs Rd group):•

Male, %: 52.4 vs 60•

Median age (range), years: 68 (45–80) vs 67

188

(50–81)•

Efficacy in East
Asian population

Cytogenetic risk, n (%)•

Standard risk: 17 (85.0) vs 10 (66.7)•

High risk: 3 (15.0) vs 5 (33.3)

PFS•Median PFS was NR vs. 13.8 months for DRd
vs Rd, respectively (HR, 0.42; 95% CI, 0.23–0.76).

•The 24-month PFS rate for DRd vs. Rd was
65.6% (95% CI, 50.5–77.0) vs. 32.2% (95%CI, 18.3–46.9).

ORR•

Overall response rate was 90.2% (n=46/51)
patients in the DRd and 72.1% (n=31/43) in
Rd.

•

Stringent complete responses (sCRs): 17(33.3%) and 5 (11.6%) of patients receiving
DRd and Rd, respectively.

•

CRs: 10 (19.6%) and 4 (9.3%) of patients
receiving DRd and Rd.

•

Very good partial responses (VGPRs): 11(21.6%) and 8 (18.6%) of patients receiving
DRd and Rd.

•

Partial responses (PRs): 8 (15.7%) vs. 14(32.6%) of patients receiving DRd and Rd.

Safety in East Asian•

population

Higher rates of neutropenia, diarrhea,
nasopharyngitis, and pyrexia were observedin the DRd group compared with those in theRd group, consistent with the overall
population.

•

Serious TEAEs were observed in 26 (51.0%)
patients in the DRd group vs. 19 (43.2%)
patients in the Rd group, most common
being pneumonia.

189

IRRs
•

In daratumumab treated patients, IRR
occurred in 25 (49.0%) patients.

•

Grade 3 IRRs occurred in 6 (11.8%) patients.

•

Most common IRR was dyspnea, which
occurred in 5 (9.8%) patients.

Efficacy inJapanese-only

PFS•

population

Median PFS was NR vs. 17.6months for DRd
vs Rd, respectively (HR, 0.32; 95% CI, 0.11–0.96).

ORR•

Overall response rate was 90% (n=18/20)
patients in the DRd and 60% (n=9/15) in Rd.

•

Stringent complete responses (sCRs): 9(45.0%) and 1 (6.7%) of patients receiving
DRd and Rd, respectively.

•

CRs: 1 (5.0%) and 0 (0.0%) of patients
receiving DRd and Rd.

•

Very good partial responses (VGPRs): 5(25.0%) and 4 (26.7%) of patients receiving
DRd and Rd.

•

Partial responses (PRs): 3 (15.0%) and 4(26.7%) of patients receiving DRd and Rd.

Safety in Japanese-•

only population

Higher rates of neutropenia, diarrhea,
nasopharyngitis, and pyrexia were observedin the DRd group compared to Rd group.

•

Serious TEAEs were observed in 10 (50.0%)
patients in the DRd group vs. 4 (26.7%)
patients in the Rd group, most common
being pneumonia.

IRRs•

In daratumumab treated patients, IRR
occurred in 7 (35.0%) patients.

•

Grade 3 IRRs occurred in 1 (5.0%) patient.

190

•

Most common IRR was dyspnea, which
occurred in 2 (10.0%) patients.

Conclusion

The addition of daratumumab to Rd led to better
PFS as compared with Rd alone in both East Asianpatients and Japanese patients from POLLUX,
consistent with findings in the global POLLUX
population.

191

Appendix O: One-Way Sensitivity Analysis•

Table O1 Parameter Ranges and Analytical Results (RRMM DVd Model)
Parameter Ranges
Parameter

Lower

Upper

Limit

Limit

normal distribution
Assuming 10% SE andWeightnormal distribution
Assuming 10% SE andHeight(Costs)Discount Rate
(Health)normal distribution
0%

4%

Per HTA guideline

0%4%

Per HTA guideline

Proportion
receiving

Assuming 10% SE andsubsequent

normal distribution

treatment after

Scope of ICER
Lower Limit

Assuming 10% SE andAge

Discount Rate

Rationale

Upper LimitParameter Ranges
Parameter

Lower

Upper

Limit

Limit

Rationale

Scope of ICER
Lower Limit

Upper Limit

DVd (SC)

Proportion
receiving
subsequent
treatment after

Assuming 10% SE andnormal distribution

Vd
Proportion
Hospitalized
Dara (SC)

Assuming 10% SE andnormal distribution

Length of Stay

Assuming 10% SE andDara (SC)normal distribution

Hospital Fee

Assuming 10% SE and(Days 1-4)

Gamma distribution

Hospital Fee

Assuming 10% SE and(Days 5-14)

Gamma distribution

Hospital Fee

Assuming 10% SE and(Days 15-21)

Gamma distribution
193

Parameter Ranges
Parameter

Lower

Upper

Limit

Limit

Rationale

Lower Limit

Admin Cost:

Assuming 10% SE andDara (SC)Gamma distribution

Admin Cost:

Assuming 10% SE andOther IV

Gamma distribution

Admin Cost:

Assuming 10% SE and

Oral

Gamma distribution% IV for

Assuming 10% SE andbortezomib

normal distribution

Subsequent
Tx: Weekly
Drug Cost

Scope of ICER
Upper Limit

Assuming 10% SE andGamma distribution

Subsequent
Tx: Weekly

Assuming 10% SE andAdministration

Gamma distribution

Cost
Weekly MRU

Assuming 10% SE andCost: PFS

Gamma distribution

Weekly MRU

Assuming 10% SE andCost: PPS

Gamma distribution
194

Parameter Ranges
Parameter

Lower

Upper

Limit

Limit

End of Life

Scope of ICER
Lower Limit

Upper Limit

Assuming 10% SE andCost (One-Gamma distribution

Time)

Assuming 10% SE andUtility: PFS

lognormal distribution
Assuming 10% SE andUtility: PPS

lognormal distribution

Utility

Assuming 10% SE and

Decrement:

lognormal distribution

DVd (SC)•

Rationale

Utility

Assuming 10% SE and

Decrement: Vd

lognormal distribution

Table O2. Parameter Ranges and Analytical Results (RRMM DRd Model)
Parameter Ranges
Parameter

Age

Rationale

Scope of ICER

Lower

Upper

Lower

Limit

Limit

Limit

Upper Limit

Assuming 10% SE andnormal distribution
195Parameter Ranges
Parameter

Upper

Lower

Limit

Limit

Limit

Discount Rate
(Health)Upper Limit

Assuming 10% SE andnormal distribution
Assuming 10% SE andHeight(Costs)Scope of ICER

Lower

WeightDiscount Rate

Rationale

normal distribution

0%

4%

Per HTA guideline

0%4%

Per HTA guideline

Proportion
receiving
subsequent
treatment after

Assuming 10% SE andnormal distribution

DRd (SC)
Proportion
receiving
subsequent

Assuming 10% SE andnormal distribution
196

Parameter Ranges
Parameter

Rationale

Scope of ICER

Lower

Upper

Lower

Limit

Limit

Limit

Upper Limit

treatment after
Rd
Proportion
Hospitalized
Dara (SC)

Assuming 10% SE andnormal distribution

Length of Stay

Assuming 10% SE andDara (SC)normal distribution

Hospital Fee

Assuming 10% SE and(Days 1-4)

Gamma distribution

Hospital Fee

Assuming 10% SE and(Days 5-14)

Gamma distribution

Hospital Fee

Assuming 10% SE and(Days 15-21)

Gamma distribution

Admin Cost:

Assuming 10% SE andDara (SC)Gamma distribution

Admin Cost:

Assuming 10% SE and

Oral

Gamma distribution

Subsequent

Assuming 10% SE andTx: Weekly

Gamma distribution
197

Parameter Ranges
Parameter

Rationale

Scope of ICER

Lower

Upper

Lower

Limit

Limit

Limit

Upper Limit

Drug Cost
Subsequent
Tx: Weekly

Assuming 10% SE andAdministration

Gamma distribution

Cost
Weekly MRU

Assuming 10% SE andCost: PFS

Gamma distribution

Weekly MRU

Assuming 10% SE andCost: PPS

Gamma distribution

End of Life
Cost (OneTime)
Utility: PFS
Utility: PPS
Utility
Decrement:
DRd (SC)

Assuming 10% SE andGamma distribution
Assuming 10% SE andlognormal distribution
Assuming 10% SE andlognormal distribution
Assuming 10% SE andlognormal distribution
198

Parameter Ranges
Parameter

Rationale

Scope of ICER

Lower

Upper

Lower

Limit

Limit

Limit

Utility

Assuming 10% SE and

Decrement: Rdlognormal distribution

Upper Limit

199