class: center, middle, inverse, title-slide # Cost Effective Analysis of Second Line Therapies in Relapsed Refractory Multiple Myeloma in Indian Scenario ## @ Indian Myeloma Congress, 2018 ###
Suman Kumar
, Army Hospital (Research & Referral), New Delhi ### 10 Feb 2017 --- class: center, middle, inverse # Introduction --- # Background - Incurable malignancy of plasma cells - Most patients diagnosed above 55 years - **Chronic disease** with **multiple remissions and relapses** - **Negative impact** on patient's overall **health related QoL** --- # Relapsed Refractory Multiple Myeloma - Improved survival in past 20 years (5 years survival 29.2% in 1992 to 50.2% in 2012)<sup>1</sup> - It remains incurable with multiple relapses with multiple lines of treatment - **Very poor prognosis** with median OS of 9 months<sup>2</sup> - Recently **Novel Agents** approved for RRMM - Pomalidomide (IMId) - Daratumumab (anti CD 38 antibody) - Carfilzomib (Proteosome Inhibitor) - Panobinostat (HDAc inhibitor) - Major economic burden on individuals and society .footnote[ 1. [CA Cancer J Clin 2016;7–30](10.3322/caac.21332) 2. [S K Kumar, Leukemia, 2012](10.1038/leu.2011.196)] ??? ## References 1. CAAC:CAAC21332 1. After previous reference --- class: center, middle, inverse # Parent Study ### Christopher G. Pelligra, Kejal Parikh, Shien Guo et al. ### Cost-effectiveness of Pomalidomide, Carfilzomib, and Daratumumab for the Treatment of Patients with Heavily Pretreated Relapsed–refractory Multiple Myeloma in the United States _Clinical Therapeutics, Volume 39, Issue 10, 2017_ <http://www.sciencedirect.com/science/article/pii/S0149291817308998> --- # Conduct of study - Compared three protocols - Pomalidomide-dexamethasone (POMd): [MM-002 trial](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962162/) - Single agent Daratumumab (DARA): [SIRIUS trial](http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01120-4/fulltext) - Single agent Carfilzomib (CARF): [PX-171-003-A1 trial](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123387/) - **Multiple relapsed or refractory** patients (Median previous therapies: 5) - Absence of head to head comparison trial - **Matching adjusted indirect comparison** done to get **unbiased estimate of relative efficacy** - **Parametric fits** were made for **POMd** arm of MM-002 data and **HR were derived** for DARA and CARF from their respective trials --- # State diagram for outcomes <img src="figs/state_diag.jpg" width="90%" style="display: block; margin: auto;" /> .center[**28 days cycles**] --- # Distribution of second line therapies (in %) Initial Line | POM-d | DARA | CAR | LEN-d | BORT | THAL-d | PanVD ---------------|:--------:|:-------:|:-----:|:---------:|:---------:|:-----------:|:--------: POM-d | 0 | 7.5 | 38.4 | 22.2 | 17.8 | 6.6 | 7.5 DARA | 40.2 | 0 | 24.8 | 14.4 | 11.5 | 4.3 | 4.8 CARF | 50.2 | 6.0 | 0 | 18.0 | 14.4 | 5.4 | 6.0 --- # Definitions of outcome measures ### Progression free survival Time from randomisation to disease progression (IMWG criteria) or death -- ### Post progression survival Time from disease progression till death -- ### Fatal progression probability Per cycle probability that a patient in PF state would die --- # Definitions of outcome measures ### Premature treatment discontinuation Time from randomisation till discontinuation of treatment prior to disease progression due to unacceptable toxicity, patient's preference or other reasons -- ### Adverse Events 4 adverse events included (Grade 3/4, occuring in > 5% of patients on treatment) - Anemia - Fatigue - Neutropenia - Thrombocytopenia Percentages converted to monthly incidence rates --- # Utilities ### Weights assigned to each state for calculating QALM lived - **PF state:** 0.7 to 0.76 - **PP state decrement:** -0.084 to -0.025 - **AE decrement:** -0.049 to -0.009 --- class: center, middle, inverse # Present Study --- class: center, middle, inverse ## Definitions and Assumptions --- # Outcome parameters - All outcome parameters taken from the Parent trial - Adverse event parameters were derived from the percentages given in the original trials and converted into **per cycle incidence rates** - Fatigue was not considered as AE --- # Economic parameters - All costings were done with Jan 2018, which was taken as **base time** - All costings were converted to **per cycle unit costs** - **Annual inflation rate** of 3.5% to 6% was assumed - **Annual discount rate** of 3% was used --- # Subclassification of costs - **Regimen associated costs** (= Regimen cost + Cost of adjuncts) - **Cost of prophylaxis** (VTE/Herpes) (= Cost of adjunct) - **Cost of AEs** (= PRBC txn + Plt txn + GCSF administration + 7 days of 3rd generation cephalosporin [10% of neutropenia]) - **Health care resource cost stratified according to health state** (= Clinical Visits + CBC + Biochemistry + SPEP/SFLC/SIFE) --- # Regimen related costs (per cycle) Regimens | Variable Cost (INR), (unit) | Fixed Cost (INR) ------------|:-------------------------------------:|:------------: POM-d | - | 20080.00 DARA (cycles 1-2) | 2400.00, (per kg) | 4200.00 DARA (cycles 3-6) | 1200.00, (per kg) | 2100.00 DARA (cycles > 6) | 600.00, (per kg) | 1050.00 CARF (cycle 1) | 24675.30, (per sq m) | - CARF (cycles 2-12) | 26973.00, (per sq m) | - CARF (cycles > 12) | 17982.00 (per sq m) | - LEN-d | - | 15788.00 BORT | - | 45200.00 THAL-d | - | 7568.00 PAN-V-d (cycles 1-8) | - | 110280.00 PAN-V-d (cycles > 8) | - | 87640.00 --- # Regimen related costs (per cycle) ### Cost of Prophylaxis - **VTE:** (90% on Aspirin and rest on Enoxaparin) INR 1459.20 - **Antiviral:** INR 360.00 --- # Cost of AEs (per episode) ### Anemia - 2 units of PRBC transfusion - **INR 2100.00** ### Neutropenia - 5 days of GCSF transfusion and 7 days of 3rd generation cephalosporin (10% of neutropenia) - **INR 5000.00** ### Thrombocytopenia - 1 unit of SDP/6 units of PRP - **INR 1800.00** --- # Health care resource utilisation cost (per cycle) Headings | Unit Cost (INR) | PFS (T+) | PFS (T-) | PPS ----------------|:-----------------------------:|-------------------:---------------------:-------- Hematologist clinical visit | 1000.00 | 2000.00 | 1000.00 | 3000.00 Full Blood Count | 350.00 | 700.00 | 350.00 | 1050.00 Biochemistry (RFT/LFT) | 1400.00 | 2800.00 | 1400.00 | 4200.00 SPEP | 700.00 | 233.33 | 116.67 | 233.33 SIFE | 5000.00 | 1666.67 | 833.33 | 1666.67 SFLC | 6500.00 | 2166.67 | 1083.33 | 2166.67 **Total** | - | **9566.67** | **4783.33** | **12316.67** --- class: center, middle, inverse ## Conduct of Study _(Computer simulation study)_ --- # Sample Size - **Horizon of 3 years** was chosen for the simulation (stable economic condition). Patients were censored after 36 months. - **100 patients** for each of the 3 arms - Total of 500 simulations were done <img src="figs/conduct.svg" width="90%" style="display: block; margin: auto;" /> --- # Few examples (POM-d arm) <img src="figs/anim_time_line.gif" width="70%" style="display: block; margin: auto;" /> --- class: center, middle, inverse ## Results --- class: center, middle, inverse ### Clinical Outcomes --- # Median Overall Survival (months) <img src="presentation_actual_files/figure-html/med_os_plot-1.png" width="45%" style="display: block; margin: auto;" /> <table> <thead> <tr> <th style="text-align:left;"> init_reg </th> <th style="text-align:right;"> mean_median_surv </th> <th style="text-align:right;"> 95LCL </th> <th style="text-align:right;"> 95UCL </th> <th style="text-align:right;"> 25centile </th> <th style="text-align:right;"> 75centile </th> </tr> </thead> <tbody> <tr> <td style="text-align:left;"> pomd </td> <td style="text-align:right;"> 17.1570 </td> <td style="text-align:right;"> 13.3333 </td> <td style="text-align:right;"> 21.3575 </td> <td style="text-align:right;"> 15.8512 </td> <td style="text-align:right;"> 18.4071 </td> </tr> <tr> <td style="text-align:left;"> dara </td> <td style="text-align:right;"> 17.0114 </td> <td style="text-align:right;"> 13.5000 </td> <td style="text-align:right;"> 21.0000 </td> <td style="text-align:right;"> 15.6667 </td> <td style="text-align:right;"> 18.3333 </td> </tr> <tr> <td style="text-align:left;"> carf </td> <td style="text-align:right;"> 16.7497 </td> <td style="text-align:right;"> 13.5000 </td> <td style="text-align:right;"> 20.6667 </td> <td style="text-align:right;"> 15.5000 </td> <td style="text-align:right;"> 18.0000 </td> </tr> </tbody> </table> --- ## Overall Survival at 3, 6, 12, 18, 24, 36 months <img src="presentation_actual_files/figure-html/os_plot-1.png" width="70%" style="display: block; margin: auto;" /> --- # Median Progression Free Survival (months) <img src="presentation_actual_files/figure-html/med_pfs_plot-1.png" width="45%" style="display: block; margin: auto;" /> <table> <thead> <tr> <th style="text-align:left;"> init_reg </th> <th style="text-align:right;"> mean_median_pfs </th> <th style="text-align:right;"> 95LCL </th> <th style="text-align:right;"> 95UCL </th> <th style="text-align:right;"> 25centile </th> <th style="text-align:right;"> 75centile </th> </tr> </thead> <tbody> <tr> <td style="text-align:left;"> pomd </td> <td style="text-align:right;"> 17.1425 </td> <td style="text-align:right;"> 13.3333 </td> <td style="text-align:right;"> 21.3575 </td> <td style="text-align:right;"> 15.8000 </td> <td style="text-align:right;"> 18.4000 </td> </tr> <tr> <td style="text-align:left;"> dara </td> <td style="text-align:right;"> 17.0007 </td> <td style="text-align:right;"> 13.5000 </td> <td style="text-align:right;"> 20.8812 </td> <td style="text-align:right;"> 15.6667 </td> <td style="text-align:right;"> 18.2708 </td> </tr> <tr> <td style="text-align:left;"> carf </td> <td style="text-align:right;"> 16.7488 </td> <td style="text-align:right;"> 13.5000 </td> <td style="text-align:right;"> 20.6667 </td> <td style="text-align:right;"> 15.5000 </td> <td style="text-align:right;"> 18.0000 </td> </tr> </tbody> </table> --- ## PFS at 3, 6, 12, 18, 24, 36months <img src="presentation_actual_files/figure-html/pfs_plot-1.png" width="70%" style="display: block; margin: auto;" /> --- # Progression Free Life Months (PFLM) <img src="presentation_actual_files/figure-html/pflm_plot-1.png" width="45%" style="display: block; margin: auto;" /> <table> <thead> <tr> <th style="text-align:left;"> init_reg </th> <th style="text-align:right;"> med_pfm </th> <th style="text-align:right;"> 95LCL </th> <th style="text-align:right;"> 95UCL </th> <th style="text-align:right;"> 25tile </th> <th style="text-align:right;"> 75tile </th> </tr> </thead> <tbody> <tr> <td style="text-align:left;"> carf </td> <td style="text-align:right;"> 4 </td> <td style="text-align:right;"> 3 </td> <td style="text-align:right;"> 4 </td> <td style="text-align:right;"> 3 </td> <td style="text-align:right;"> 4.0 </td> </tr> <tr> <td style="text-align:left;"> dara </td> <td style="text-align:right;"> 4 </td> <td style="text-align:right;"> 3 </td> <td style="text-align:right;"> 5 </td> <td style="text-align:right;"> 4 </td> <td style="text-align:right;"> 4.0 </td> </tr> <tr> <td style="text-align:left;"> pomd </td> <td style="text-align:right;"> 4 </td> <td style="text-align:right;"> 3 </td> <td style="text-align:right;"> 5 </td> <td style="text-align:right;"> 4 </td> <td style="text-align:right;"> 4.5 </td> </tr> </tbody> </table> --- # Quality Adjusted Life Months (QALM) <img src="presentation_actual_files/figure-html/qalm_plot-1.png" width="45%" style="display: block; margin: auto;" /> <table> <thead> <tr> <th style="text-align:left;"> init_reg </th> <th style="text-align:right;"> med_qalm </th> <th style="text-align:right;"> 95LCL </th> <th style="text-align:right;"> 95UCL </th> <th style="text-align:right;"> 25tile </th> <th style="text-align:right;"> 75tile </th> </tr> </thead> <tbody> <tr> <td style="text-align:left;"> carf </td> <td style="text-align:right;"> 11.0293 </td> <td style="text-align:right;"> 8.8127 </td> <td style="text-align:right;"> 13.7548 </td> <td style="text-align:right;"> 10.2393 </td> <td style="text-align:right;"> 11.9131 </td> </tr> <tr> <td style="text-align:left;"> dara </td> <td style="text-align:right;"> 11.2297 </td> <td style="text-align:right;"> 9.0112 </td> <td style="text-align:right;"> 13.7750 </td> <td style="text-align:right;"> 10.3453 </td> <td style="text-align:right;"> 12.1640 </td> </tr> <tr> <td style="text-align:left;"> pomd </td> <td style="text-align:right;"> 11.3767 </td> <td style="text-align:right;"> 8.9134 </td> <td style="text-align:right;"> 14.0928 </td> <td style="text-align:right;"> 10.5132 </td> <td style="text-align:right;"> 12.2253 </td> </tr> </tbody> </table> --- class: center, middle ## No difference in clinical efficacy between all three arms --- class: center, middle, inverse ### Economic Outcomes --- # Regimen associated Discounted Cost <img src="presentation_actual_files/figure-html/reg_cost_plot-1.png" width="45%" style="display: block; margin: auto;" /> <table> <thead> <tr> <th style="text-align:left;"> init_reg </th> <th style="text-align:right;"> med_cost_month </th> <th style="text-align:right;"> 95LCL </th> <th style="text-align:right;"> 95UCL </th> <th style="text-align:right;"> 25tile </th> <th style="text-align:right;"> 75tile </th> </tr> </thead> <tbody> <tr> <td style="text-align:left;"> dara </td> <td style="text-align:right;"> 55143.72 </td> <td style="text-align:right;"> 48638.94 </td> <td style="text-align:right;"> 63355.32 </td> <td style="text-align:right;"> 52726.57 </td> <td style="text-align:right;"> 57723.10 </td> </tr> <tr> <td style="text-align:left;"> pomd </td> <td style="text-align:right;"> 32370.84 </td> <td style="text-align:right;"> 21656.73 </td> <td style="text-align:right;"> 37982.45 </td> <td style="text-align:right;"> 29379.04 </td> <td style="text-align:right;"> 34890.15 </td> </tr> <tr> <td style="text-align:left;"> carf </td> <td style="text-align:right;"> 25769.79 </td> <td style="text-align:right;"> 23650.16 </td> <td style="text-align:right;"> 29015.03 </td> <td style="text-align:right;"> 24905.19 </td> <td style="text-align:right;"> 26911.36 </td> </tr> </tbody> </table> --- # Cost per QALM <img src="presentation_actual_files/figure-html/cost_qalm_plot-1.png" width="45%" style="display: block; margin: auto;" /> <table> <thead> <tr> <th style="text-align:left;"> init_reg </th> <th style="text-align:right;"> med_cost_qalm </th> <th style="text-align:right;"> 95LCL </th> <th style="text-align:right;"> 95UCL </th> <th style="text-align:right;"> 25tile </th> <th style="text-align:right;"> 75tile </th> </tr> </thead> <tbody> <tr> <td style="text-align:left;"> dara </td> <td style="text-align:right;"> 86609.35 </td> <td style="text-align:right;"> 76026.52 </td> <td style="text-align:right;"> 99518.78 </td> <td style="text-align:right;"> 82721.20 </td> <td style="text-align:right;"> 90635.68 </td> </tr> <tr> <td style="text-align:left;"> pomd </td> <td style="text-align:right;"> 55897.85 </td> <td style="text-align:right;"> 44735.16 </td> <td style="text-align:right;"> 61518.81 </td> <td style="text-align:right;"> 51986.42 </td> <td style="text-align:right;"> 58222.93 </td> </tr> <tr> <td style="text-align:left;"> carf </td> <td style="text-align:right;"> 41495.18 </td> <td style="text-align:right;"> 37974.16 </td> <td style="text-align:right;"> 47988.91 </td> <td style="text-align:right;"> 40129.71 </td> <td style="text-align:right;"> 43575.42 </td> </tr> </tbody> </table> --- # Conclusions - All the three treatment arms are equally effective clinically - **Daratumumab** has the highest median cost per QALM lived of **INR 86609.00 (95% CI: 76027.00 - 99519.00)**. Incremental cost per QALM lived is **INR 30711.00 than POM-d** - **Carfilzomib** has the lowest median cost per QALM lived of **INR 41495.00 (95% CI: 37974.00 - 47989.00)**. Incremental cost per QALM lived is **INR (- 14403.00) than POM-d** - **Pomalidomide dexamethasone** has the median cost per QALM lived of **INR 55897.85 (95% CI: 44735.16 - 61518.81)** --- class: center, middle, inverse # Thank You