Proteasome Inhibitor Treatment in Relapsed/Refractory ... · *Orlowski RZ, et al. J Clin Oncol 2002;20:4420-7; 1. US Department of Health and Human Services. Letter, NDA 21-602. Rockville,

$Page 1: Proteasome Inhibitor Treatment in Relapsed/Refractory ... · *Orlowski RZ, et al. J Clin Oncol 2002;20:4420-7; 1. US Department of Health and Human Services. Letter, NDA 21-602. Rockville,$
Proteasome Inhibitor Treatmentin Relapsed/Refractory Multiple

Myeloma: Real World vs Clinical Trial Data

Evangelos Terpos

This meeting is organized by Takeda Pharmaceuticals International AG.Takeda medicines will be discussed during this meeting.Full Prescribing Information is available at this meeting.EM/IXZ/0519/0017 June 2019.

Evangelos Terpos, MD, PhD

Department of Clinical Therapeutics,

National and Kapodistrian University of Athens,

School of Medicine, Athens, Greece

Evangelos TerposName of company Research support Advisory board Honoraria

Amgen X X X

Janssen X X X

Celgene X X X

Novartis X

Takeda X X

BMS X X

BM, bone marrow; E, euchromatin; G, golgi complex; H, heterochromatin; M, mitochondria; MM, multiple myeloma; Nu, nucleus; RER, rough endoplasmic reticulum

1. http://missinglink.ucsf.edu/lm/IDS_101_histo_resource/images/cell_structure_lab_micrograph_B.jpg. Last accessed 21 February 2017.

2. Kurtoglu M, et al. Cancer Chemother Pharmacol 2010;66:129-40.3. Obeng EA, et al. Blood 2006;107:4907-16.

4. Vincenz L, et al. Mol Cancer Ther 2013;12:831-43.

Plasma cell from BM1

• MM cells rapidly synthesize and secrete large

amounts of immunoglobulin from the endoplasmic

reticulum2,3

• Active proteasomes are needed for quality control

to degrade misfolded immunoglobulins3

• Proteasome inhibition overwhelms the capacity

of the cell to manage the large protein volume

and leads to apoptosis of MM cells4

*Orlowski RZ, et al. J Clin Oncol 2002;20:4420-7; 1. US Department of Health and Human Services. Letter, NDA 21-602. Rockville, MD: US Dept of Health and Human Services; May 13, 2003; 2. Richardson PG, et al. N Engl J Med 2003;348:2609-17; 3. Richardson PG. et al. N Engl J Med 2005;352:2487-98; 4. San Miguel JF, et al. N Engl J Med 2008;359:906-17; 5. Moreau P, et al. Lancet Oncol 2011;12:431-40; 6. Siegel DS, et al. Blood 2012;120:2817-25; 7. Stewart AK, et al. N Engl J Med 2015;372:142-52; 8. Dimopoulos MA, et al. Lancet Oncol 2016;17:27-38; 9. Moreau P, et al. N Engl J Med 2016;374:1621-34.

2002 2016TOURMALINE-MM1

NEJM published9

Ixazomib approved

in RRMM

2015ENDEAVOR

Lancet Oncol

published8

2014ASPIRE NEJM published7

2012- Bortezomib SC administration approved5

- Single agent carfilzomib

approved in RRMM6

2008VISTA NEJM published—

bortezomib approved in

frontline4

2005APEX study published3

2003- Bortezomib approved1

- SUMMIT study

published2

*



NEJM published9

Ixazomib approved

in RRMM

2015ENDEAVOR

Lancet Oncol

published8




approved in RRMM6



frontline4



- SUMMIT study

published2

*



NEJM published9

Ixazomib approved

in RRMM

2015ENDEAVOR

Lancet Oncol

published8




approved in RRMM6



frontline4



- SUMMIT study

published2

*



NEJM published9

Ixazomib approved

in RRMM

2015ENDEAVOR

Lancet Oncol

published8




approved in RRMM6



frontline4



- SUMMIT study

published2

*



NEJM published9

Ixazomib approved

in RRMM

2015ENDEAVOR

Lancet Oncol

published8




approved in RRMM6



frontline4



- SUMMIT study

published2

*



NEJM published9

Ixazomib approved

in RRMM

2015ENDEAVOR

Lancet Oncol

published8




approved in RRMM6



frontline4



- SUMMIT study

published2

*



NEJM published9

Ixazomib approved

in RRMM

2015ENDEAVOR

Lancet Oncol

published8




approved in RRMM6



frontline4



- SUMMIT study

published2

*



NEJM published9

Ixazomib approved

in RRMM

2015ENDEAVOR

Lancet Oncol

published8




approved in RRMM6



frontline4



- SUMMIT study

published2

*



NEJM published9

Ixazomib approved

in RRMM

2015ENDEAVOR

Lancet Oncol

published8




approved in RRMM6



frontline4



- SUMMIT study

published2

*

1st relapse (if ASCT is not an option)

Lenalidomide-based regimens

Induction Bortezomib-based combination

ASCT (melphalan 200)

No more therapy/Consolidation/Maintenance

Elotuzumab plus RdPFS: 19.4m, HR: 0.73

Carfilzomib plus RdPFS: 26.3m, HR: 0.69

Daratumumab plus RdPFS: NR, HR: 0.37

Ixazomib plus RdPFS: 20.6m, HR: 0.74

KdHR:0.53 PFS: 18.7 months

DaraVD HR:0.33 PFS: NR

IMiDs based combinations PIs based combinations

Rd or Td ±chemo (cyclo)

Thalidomide-based regimens (MPT, CTD)

Vd, VCD, VMP, VTD

Kd, HR:0.53 PFS: 18.7m

OR

*IV bortezomib. HR, hazard ratio; IMiD, immunomodulatory drug; NDMM, newly diagnosed multiple myeloma; NR, not reached; OS, overall survival; PFS, progression-free survival; PI, proteasome inhibitor; RRMM, relapsed/refractory MM

1. Stewart AK, et al. N Engl J Med 2015;372:142–52. 2. Moreau P, et al. N Engl J Med 2016;374(17):1621–34.

4842363024181260

1.0

0.8

0.6

0.4

0.2

0.0

Pro

port

ion s

urv

ivin

g w

ithout

pro

gre

ssio

n

Months since randomization

Median PFS 26.3 vs 17.6 months

HR=0.69 [0.57–0.83]

p=0.0001

KRd vs Rd in RRMM1

Time from randomization (months)

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Pro

babili

ty o

f P

FS

0.8

0.6

0.4

0.2

0.0

Log-rank test p=0.01

HR (95% CI): 0.74 (0.59, 0.94)

Number of events: IRd 129; placebo-Rd 157

Median PFS:

IRd: 20.6 months

Placebo-Rd: 14.7 months

IRd vs Rd in RRMM2

KRd

Rd

Mateos M, et al. Blood 2016;128:1150.Matos MV, et al. Presented at ASH 2018 (Abstract 3270), poster presentation.

DVdn=243

Vdn=237Grade 3/4 AE (%)

Hematologic

Thrombocytopenia 45 33

Anemia 15 16

Neutropenia 13 5

Lymphopenia 10 3

Non-hematologic

Pneumonia 9 10

Hypertension 7 1

PSN 5 7

Fatigue 5 3

Diarrhea 4 1

URTI 3 <1

DVd vs Vd in RRMM

Route of administration Dosing schedule

Bortezomib1 IV/SCDays 1, 4, 8, 11, 22, 25, 29, 32 of 6-week cycle (cycles 1–4)

Days 1, 8, 22, 29 of 6-week cycle (cycles 5–9)

Carfilzomib2 IV Days 1, 2, 8, 9, 15, 16 of 28-day cycle (cycles 1–12)

Ixazomib3 Oral Days 1, 8, 15 of 28-day cycle

Oprozomib4 OralNCT01416428 (Ph 1/2)

Days 1, 2, 8, and 9 of a 14-day cycle (2/7 schedule) Days 1–5 of a 14-day cycle (5/14 schedule)

IV, intravenous; PI, proteasome inhibitor; SC subcutaneous

1. Velcade SmPC (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000539/WC500048471.pdf).

2. Kyprolis® Prescribing Information. Amgen Inc.,11/2016.3. Ninlaro® Prescribing Information. Millennium Pharmaceuticals Inc., 11/2016.

4. Ghobrial IM, et al. Blood 2016;128:2110.

Real-world evidence vs clinical trials

Reflects the heterogeneity of all pts treated in clinical practice incl. pts with:

Comorbidities, advanced age etc.

Can serve as a validation of clinical evidence in clinical practice

Provides evidence on actual treatment patterns incl. dosing, duration, resource use etc.

Does not constitute a scientific platform assessing efficacy under controlled settings

Not necessarily balanced patient arms (cf. RCTs), or blinded/randomised

Data sets may lack formal end-points e.g. PFS instead using TTNT as proxy

Limited to data available – susceptible to selection bias

Sometimes small or immature data sets

Strengths Weaknesses

A number of MM patient populations are typically under-represented in clinical trials

1. Shah JJ, et al. Clin Lymphoma Myeloma Leuk 2017;17:575–83.2. Costa L, et al. Leuk Lymphoma 2016;57:2827–32.3. Fiala MA, et al. Leuk Lymphoma 2015;56:2643–9.4. Pulte E, et al. Blood Advances 2018;2:116–9.

*Where unavailable, time to next treatment was used as proxy for PFS in RWE

Patients with comorbidities1 or

advanced disease1,2

Elderly, frail patients1,2

Patients from lower socio-economic backgrounds3

Ethnic or racial minorities1,2,4

These characteristics are linked to worse outcomes to treatment1–4

A substantial proportion of real-world patients are not eligible for clinical trials, driving differences in outcomes

*Common RCT exclusion criteria included: M-protein ≤1.0 g/dL, creatinine >2.5 mg/dL (13.9%), ow absolute neutrophil count (≤1.5 x 109/L), and low haemoglobin (≤8 g/dL). CI, confidence interval; HR, hazard ratio; NDMM, newly diagnosed multiple myeloma;MM, multiple myeloma; OS, overall survival; RCT, randomised controlled trial.

1. Shah JJ, et al. Clin Lymphoma Myeloma Leuk 2017;17:575–83.

• Clinical trial eligibility criteria may exclude many patients from trial participation1

• 40% of NDMM patients from the Connect MM registry are ineligible for enrollment in RCTs, based on common RCT exclusion criteria from published studies*,1

• 3-year OS rate significantly lower in RCT-ineligible vs RCT-eligible patients (63% vs 70%; p<0.05)1

• Thus, clinical trial findings may not reflect the overall MM population1

Surv

ival

pro

bab

ility

1

0.2

0.4

0.6

0.8

1.0

Duration (months)No. at riskRCT-eligible 820 758 699 636 479 291RCT-ineligible 548 491 431 391 280 165

HR: 0.8195% CI: 0.67‒0.99p=0.0392

00 12 36 7224 66605448426 18 30

RCT-eligibleRCT-ineligible


Real-world duration of therapy: limited feasibility of continuous treatment

DoT, duration of therapy; IMiD, immunomodulatory drug; MM, multiple myeloma;PI, proteasome inhibitor.1. Jagannath S et al. Expert Rev Hematol 2016;9:707–717;2. Tatarczuch M et al. EHA 2017 abstract #E1457.

Aggregate treatment regimen, monthsFirst line,median

Second line,median

Third line, median

Overall 4.1 4.2 3.1

Bortezomib alone or + non-IMiD 3.9 3.8 3.7

Lenalidomide alone or + non-PI 3.8 5.6 3.1

Bortezomib + IMiD (thalidomide or lenalidomide)

4.1 3.6 3.4

Thalidomide alone or + non-PI 3.3 5.1 2.7

Melphalan alone or + non-IMiD, non-PI 6.5 3.4 2.9

Melphalan + thalidomide 8.3 7.8 5.2

Carfilzomib alone or + IMiD - 2.7 2.4

Pomalidomide - 3.8 1.4

Other 0.5 2.1 2.0

Patient burden associated with office visits2

DoT estimates were significantly lower than those reported in

clinical trials1

MM patients who received ≥3 lines of therapy during 2007–2014 within a real-world US-based community oncology practice setting1


Poorer long-term clinical outcomes have been reported in real-world analyses vs clinical trials

Ixazomib, in combination with lenalidomide and dexamethasone, is approved for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.*Data shown are ranges of median PFS/TTNT (months) reported from multiple studies/analyses.†Data from two phase II studies of VCd. K, carfilzomib; NA, not applicable; PI, proteasome inhibitor; PFS, progression-free survival; RRMM, relapsed/refractory multiple myeloma; TTNT, time to next therapy; V, bortezomib; VCd, bortezomib, cyclophosphamide, dexamethasone.

1. Richardson PG, et al. Blood 2017;130(Suppl):3149.2. Rifkin R, et al. Blood 2017;130(Suppl):3434.3. Terpos E, et al. Blood 2017;130(Suppl):3087.

• Literature review of real-world PFS/TTNT datawith PI-based regimens in RRMM and comparison of real-world effectiveness vs clinical trials efficacy1

• Shorter ranges of median PFS/TTNT values in real-world reports vs phase III clinical studies

Median PFS/TTNT* data from phase III clinical trials and real-world reports in RRMM patients with 1–3 prior therapies1

Regimens Phase III clinical

studies

Real-world

reports

All regimens combined NA 6–15.1

PI doublet/PI-based V: 6.2–9.4

K: 14.9–22.2

V: 5.7–11.9

K: 3.2–9.4

PI-alkylator triplet 12–18.4† 6.5–16.21,2

Injectable PI-immunomodulatory drug

triplet

18.3–29.6 9.4–12.7

Oral PI-immunomodulatory drug triplet 17.5–20.6 19.2–27.61,3


DOT and TTNT of VRd, KRd, or IRd in patients with RRMM: Clinical practice in the US vs clinical trial experience

DOT, duration of treatment; EMR, electronic medical record; IRd, ixazomib, lenalidomide, dexamethasone;IV, intravenous; KRd, carfilzomib, lenalidomide, dexamethasone; NR, not reported; PI, proteasome inhibitor; Pts, patients; Rd, lenalidomide, dexamethasone; RRMM, relapsed/refractory multiple myeloma; TTNT, time-to-next-therapy; VRd, bortezomib plus Rd.

1. Chari P, et al. Blood 2017;132(suppl):1818.

Retrospective cohort study design: Pts who initiated KRd, VRd, or IRd (index regimen) as treatment line 2, 3, or 4 between Jan 2008 and

Dec 2016 in Humedica, a large US-based EMR database, were identified

Endpoints: DOT, TTNT, discontinuation rates

VRd KRd IRd

n 343 139 49

Median age (years) 69 65 73

Median follow-up (months) 17.3 8.3 5.2

Median DOT (months)

PI component alone 5.4 6.1 NR

Entire regimen 8.7 6.3 NR

Median TTNT (months) 12.9 8.7 NR

Discontinuation rates for PI component (%)

9 months 63 71 40

12 months 72 76 NR

18 months 83 89 NR

DOT (PI component)

Month from start of regimen

100

80

60

40

20

0

0 6 12 21 24

Tre

atm

en

t co

ntin

ua

tio

n

pro

ba

bility (

%)

3 9 15 18

IRdKRdVRd

TTNT

Month from start of regimen

100

80

60

40

20

0

0 6 12 21 24

Eve

nt-

fre

e p

rob

ab

ility (

%)

3 9 15 18

IRdKRdVRd

• A US-based EMR analysis of 531 pts treated with VRd, KRd, or IRd indicated that pts were able to stay on the PI component of an oral PI-Rd triplet for longer than

pts receiving IV PI-Rd triplets; this may translate into improved TTNT

Retrospective analysis of patients from Greece, UK, and Czech Republic participating in a Named-Patient Program of compassionate-use of IRd

AEs, adverse events; ASCT, autologous stem cell transplant; CI, confidence interval; IRd, ixazomib, lenalidomide, dexamethasone; OR, odds ratio; ORR, overall response rate; PFS, progression-free survival; PI, proteasome inhibitor; PN, peripheral neuropathy; PR, partial response; pts, patients;RRMM, relapsed/refractory multiple myeloma; TTP, time-to-progression.

1. Terpos E, et al. Br J Haematol submitted

• Pts who received prior ASCT

were 3.48 times more likely to

achieve ≥PR (OR 3.48; 95%

CI,

1.24–9.80; p=0.018)

• 8.7% of pts experienced

treatment interruptions, mostly

due to AEs (75%)

• 13.7% discontinued IRd,

mainly due to AEs (53%) and

second ASCT (26%)

• 28.3% pts experienced PN;

this was resolved in 38.5% of

cases or graded as 1/2

• ORR and median PFS closely resemble outcomes seen in the phase 3 TOURMALINE-MM1 study

(ORR: 78%, median PFS: 20.6 months), supporting IRd as an effective oral therapeutic option for RRMM

Results

n 155

Median age, years (range) 68.1 (40–85)

Median no. prior therapies, n (range) 1 (1–7)

Median follow up, mo (range) 15.9 (0.6-37.8)

Prior therapies, %

PI / bortezomib 97 / 91

Immunomodulatory drug / lenalidomide 56 / 17

ASCT 52

Median treatment duration, months (range) 9.6 (0.6–29.8)

Median PFS, months (95% CI) 27.6 (11.3–27.6)

Estimated median TTP, months(95% CI)

27.6 (15.2–27.6)

Response rate, %*

ORR (≥PR),(95% CI)

73.8 (60.5–76.4)

sCR/CR 15.6

VGPR 19.1

ORR (≥PR), by no. of prior therapies

1 / ≥2 76.5 / 71.2

ORR (≥PR), by duration of IRd therapy

≥6 months 84.4

≥7 months 87.0

≥8 months 94.2

*Among 91% (141/155) of

response-evaluable

patients

Takeda Pharmaceuticals International AGTerpos E, et al. manuscript submitted

PFS distributions with 95% CI in (A) the overall NPP

population (with the PFS curve for IRd from TOURMALINE-MM1 overlaid for comparison

(B) (B) NPP patients receiving IRd as second-line therapy (median PFS 27.6 months) or as third-line therapy and beyond (median PFD 19.9 months),

(C) (C) NPP patients according to prior ASCT,

(D) (D) NPP second-line patients according to prior ASCT

Takeda Pharmaceuticals International AGTerpos E, et al. manuscript submitted

Takeda Pharmaceuticals International AG

Terpos E, et al. manuscript submitted

28

Characteristic All patients (N=127)

Median age (range), years 66 (41–84)

Bortezomib-refractory, % 18.9

Lenalidomide-refractory, % 7.9

*Risk status undeterminable in 34 patients. †By individual drugs.IRd, ixazomib, lenalidomide, dexamethasone; MR, minimal response; RMG, registry of monoclonal gammopathies; RRMM, relapsed/refractory multiple myeloma.

1. Minarik et al, Blood 2018;132(suppl):1959.

1st line treatment† Patients, %

Bortezomib 94.5

Thalidomide 40.9

Lenalidomide 18.9

Carfilzomib 5.5

IRd use per line of treatment Patients, %

Second 58.5

Third 23.7

Fourth 7.6

Fifth and beyond 10.1

Efficacy outcomes

ORR (≥PR), % 67.1

CR 11.4

VGPR 16.5

PR 39.2

MR 10.1

≤SD 22.8

PFS after 1 line, months Not reached

After 2 lines 23.1

After 3 lines 8.7

After ≥4 lines 4.6

Grade ≥3 toxicities Patients, %

Neutropenia 35.1

Thrombocytopenia 22.8

Anaemia 12.3

Infection 19.3

INSIGHT MM

• RRMM patients with 1–3 prior therapies who had been treated with IRd

• 50 eligible patients identified for pooled analysis

Czech RMG

• RRMM patients with ≥1 prior therapies who had been treated with IRd

• 113 eligible patients* identified for pooled analysis

*The majority of RMG patients were from the Czech Named Patient Program. From 183 patients with IRd induction therapy in the RMG, 113 (61.7%) patients were included in the analysis. Data from Slovak centers(57 patients), incomplete data/switch (11 patients) and missing data in primary endpoints (4 patients) were considered as reasons for exclusion from analysis (one patient could have more than one reason for exclusion)."DOT, duration of treatment; IMWG, International Myeloma Working Group; OS, overall survival; TTNT, time to next therapy

SPSS software: IBM Corp. Released 2017. IBM SPSS Statisticsfor Windows, version 25.0. Armonk, NY: IBM Corp.R version 3.3.0: www.r-projec.orgSAS version 9.4: https://www.sas.com/en_gb/software/sas9.html

1. Cook, G et al. BSH 2019, abstract #508.

All included patients had prospectively collected data on IRd therapy

•Patients who received another regimen or additional treatment within the same line of therapy as IRd were excluded

Individual patient-level data on demographics, disease characteristics, treatment history, effectiveness, and safety were integrated and analysed

•Analyses performed in SPSS software, software R version 3.3.0, and software SAS version 9.4

•PFS, TTNT, DOT, and OS estimated using Kaplan-Meier methodology

Descriptive analyses performed on integrated data and on data from INSIGHT MM and the Czech RMG individually

http://www.r-projec.org/

https://www.sas.com/en_gb/software/sas9.html

All (N=163) RMG (N=113) INSIGHT MM (N=50)

Line of therapy at which IRd was received, n (%)

2nd line 82 (50) 59 (52) 23 (46)

3rd line 49 (30) 32 (28) 17 (34)

4th line 14 (9) 7 (6) 7 (14)

>4th line 18 (11) 15 (13) 3 (6)

Median lines of prior therapy, n (range) 1 (1–9) 1 (1–9) 2 (1–4)

1. Moreau P, et al. N Engl J Med 2016;374:1621–34.

• Patients had received a median of 1 prior line (range, 1–9); approximately 80% received IRd in either the 2nd (50%) or 3rd (30%) line

In TOURMALINE-MM1, IRd patients received a median of 1 prior line (range, 1–3)1

62%, 27%, and 11% received IRd in the 2nd, 3rd, and 4th line, respectively

*n=150/73/47/111/39 1. Moreau P, et al. N Engl J Med 2016;374:1621–34.

Characteristic All (N=163)

Median f/u

2nd line (n=82)

3rd line (n=49)

RMG (N=113)

INSIGHT MM (N=50)

Male/female, % 53/47 50/50 57/43 55/45 48/52

Median follow-up 9.3 months - - 9.0 months 10.5 months

Median age at start of IRd, years (range)

67 (39–84) 68 (41–84) 67 (42–84) 67 (41–84) 66 (39–84)

Median time from initial diagnosis, months (range)*

42.6(1.8–234.3)

29.0(1.8–196.2)

58.1(5.2–234.3)

38.4(3.0–234.3)

49.8(1.8–162.6)

IRd treatment facility, %

Academic/university 95 96 98 100 84

Community hospital/clinic 5 4 2 0 16

Patients receiving IRd on a clinical trial, %

2 1 4 2 2

Median age in this analysis comparable to that in IRd arm (N=360) of TOURMALINE-MM1 (66 years; range, 38–91)1


89

61

42

2111

3 20

20

40

60

80

100

All (N=163)

% o

f p

atients

Bortezomib Transplantation Thalidomide Lenalidomide

Prior therapies in IRd arm of TOURMALINE-MM1 (N=360) included: bortezomib (69%), transplantation (59%), thalidomide (44%), lenalidomide (12%), and carfilzomib (<1%)1

• Overall, median DOT was 14.0 months (95% CI, 11.2–23.0)

• Median duration of follow-up: 9.3 months (64 patients on study at 12 months)

• At data cut off*, – 62 (38%) patients

had discontinued– 101 (62%) patients

remained on IRd

*Data cutoffs: RMG: June 20, 2018;INSIGHT MM: June 4, 2018

CI, confidence interval; NR, not reached

1.00

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6 12 18 24 30 36

0.75

0.50

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2nd line (n=82)Median DOT: 20.2 months (95% CI,12.4–NR)12-month rate: 64.6% (95% CI, 51.0–75.3)Events: 28 (34%)

3rd line (n=49)

Median DOT: 14.0 months (95% CI, 9.6–NR)12-month rate: 62.6% (95% CI, 44.2–76.4)Events: 17 (35%)

No. of patients at risk:2nd line 82 53 31 13 2 03rd line 49 29 11 3 1 0

Results should be interpreted with caution due to the short follow up and low number of patients who remain at risk

CR, complete response; MR, minimal response; PD, progressive disease; PR, partial response;SD stable disease


Response, %All*

(N=105)2nd line(n=58)

3rd line(n=28)

RMG*(N=73†)

INSIGHT MM*(N=32†)

ORR

(95% CI)

74

(65–82)

91

(81–97)

57

(37–76)

71

(59–81)

81

(64–93)

≥VGPR 31 41 25 32 31

CR 10 16 7 12 6

VGPR 21 26 18 19 25

PR 43 50 32 40 50

MR 8 3 14 8 6

SD 12 3 25 12 13

PD 6 2 4 8 0

*Data for 2nd to >4th line†73 out of 113 patients in RMG had a first response recorded. 32 out of 50 patients in INSIGHT had a best response recorded

• Median time to first response of ≥PR was 1.1 months (range, 0.5–16.8) among Czech RMG patients

• Median time to best response was 3.7 months (range, 0.9–15.0) among INSIGHT MM patients

ORR was comparable to that reported in the TOURMALINE-MM1 study (78%)1

• Overall, median PFS was 20.9 months (95% CI: 13.0–28.7)

• At data cut-off, 53 (33%) patients had progressed

• 12-month PFS rate was 64.9% (95% CI, 55.3–72.9)

1.00

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0

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6 12 18 24 30 36

0.75

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0.25

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3rd line (n=49)

Median PFS: 23.2 months (95% CI, 12.8–33.6)12-month rate: 70.9% (95% CI, 52.4–83.3)Events: 15 (31%)

2nd line (n=82)Median PFS: NR 12-month rate: 70.2% (95% CI, 56.4–80.3)Events: 23 (28%)


Median PFS was comparable to that reported in the TOURMALINE-MM1 study (20.6 months)1

1. Moreau P, et al. N Engl J Med 2016;374:1621–34.Results should be interpreted with caution due to the short follow up and low number of patients who remain at risk

• At data cut-off, 29 (18%) patients had died

• Median OS was not reached

• 80.8% (95% CI, 72.5–86.8) of patients were alive at 12 months

1.00

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OS

0

Time (months)

6 12 18 24 30 36

0.75

0.50

0.25

0

3rd line (n=49)

Median OS: 23.0 months (–)12-month rate: 85.0 (95% CI, 69.3–93.0)Events: 9 (18%)

2nd line (n=82)

Median OS: NR12-month rate: 88.8% (95% CI, 77.7–94.6)Events: 8 (10%)


Results should be interpreted with caution due to the short follow up and low number of patients who remain at risk

AE, adverse event; PN, peripheral neuropathy*Number of patients. †Number of events associated with respective actions (more than one event could be recorded for each action). ‡Unknown whether the interruption was permanent or temporary.

Action on drug, n (%)*

All (N=163)

Ixazomib Lenalidomide

Dose delays, n (%)* 86 (53) 85 (52)

Number of individual AEs recorded associated with dose delays, n† 77 75

Dose increase, n (%)* 0 (0) 2 (1)

Dose reduction, n (%)* 29 (18) 61 (37)

Number of individual AEs recorded associated with dose reduction, n† 29 73

Permanent/temporary discontinuation, n (%)* 95 (58) 97 (60)

Permanent discontinuation, n (%)* 7 (4) 8 (5)

Number of individual AEs recorded associated with permanent discontinuations, n† 6 3

Interruption status unknown, n (%)*‡ 2 (1) 4 (2)

• The reasons for permanent discontinuation of ixazomib were (number of events): rash / skin toxicity (2), diarrhoea (1), nausea / vomiting (1), PN (1), relapse – biochemical progression (1), thrombocytopenia (1), and other reasons (1)

• The reasons for permanent discontinuation of lenalidomide were (number of events): total cumulative dose of lenalidomide reached (3), rash (1), relapse –biochemical progression (1), renal insufficiency (1), thrombocytopenia (1), and not specified (1)

• This pooled analysis of the Czech RMG and INSIGHT MM registries shows that the effectiveness of IRd in routine clinical practice, including an ORR of 74% and a median PFS of 20.9 months, is comparable to the efficacy of IRd reported in the TOURMALINE-MM1 trial (ORR 78%, median PFS 20.6 months)1

– In line with previous real-world data reports, patients treated with IRd in earlier lines of relapse appear to have improved outcomes over patients in later lines2–5

– Outcomes should be interpreted with caution due to limited maturity of data

• Discrepancies seen between data from the two registries may be associated with differences in patient and treatment characteristics, including time from initial diagnosis and treatments received prior to IRd

• IRd is well tolerated in RRMM patients treated in routine clinical practice, with low rates of permanent discontinuations for ixazomib (4%) and lenalidomide (5%)

• The INSIGHT MM study is ongoing and is continuing to accrue patients– Additional interim data summaries and formal interim analyses are planned to confirm these results

Many of the patients included in this analysis were treated at academic centres, therefore, these results may not be representative of the community practice setting

1. Moreau P, et al. N Engl J Med 2016;374:1621–34.2. Minarik J, et al. Blood 2018;132(suppl):1959.3. Terpos E, et al. Blood 2017;130(suppl):3087.4. Varga G, et al. Blood 2017;130(suppl):1865.5. Ziff M, et al. Haematologica 2017;102(s2):786–7.

Case 1

• A 74-year-old woman diagnosed with MM in 2016, treated with VMP – best response nCR

• Relapsed in 2017, 8 months after ending treatment, presenting with ISS-II and Del(17p)

• Has known history of diabetes and chronic renal insufficiency

CR – complete response; Del – deletion; ISS – international staging system;MM – Multiple Myeloma; VMP – Bortezomib, Melphalan and prednisone

van Beurden-Tan CHY, et al. J Clin Oncol 2017;35:1312-9.

Treatment outcomes in R/R MMNetwork meta-analysis results

Favorsexperimental

Favorsdexamethasone

Duplets

Triplets

Bor, bortezomib; Car, carfilzomib; CrI, credible interval; Dara, daratumumab; Dex, dexamethasone; Elo, elotumumab; HR, hazard ratio; Ixa, ixazomib; Len, lenalidomide; Obl, oblimersen;Pano, panobinostat; PegDox, pegylated doxorubicin; Pom, pomalidomide; Rd, lenalidomide, dexamethasone; Thal, thalidomide; Vd, bortezomib, dexamethasone; Vorino, vorinostat

*p<0.05 for comparison between regimens. Data not included on patients with t(14:16) alone due to small numbers (n=7).ITT, intent-to-treat; PR, partial response

High Risk Cytogenetics in the RR MM: TOURMALINE-MM1

30 33 34 39

36 32 33 19

12 712

2

0

20

40

60

80

100

IRd Placebo-Rd IRd Placebo-Rd

PR VGPR CR

Response rates

ITT population(N=722)

High-risk cytogenetic population (N=137)

1. Moreau P, et al. N Engl J Med 2016;374:1621–342. Avet-Loiseau H, et al. Haematologica. 2016;101(suppl 1):80 (abstract P269)

This graph is provided for ease of viewing information from multiple trials. Direct comparison between trials is not intended and should not be inferred.

1. Avet-Loiseau H, et al. Presented at: American Society of Hematology Annual Meeting. December 5-8, 2015. Orlando, FL. Abstract 731;2. San Miguel J, et al. Presented at: 22nd Congress of European Hematology Association. June 22-25, 2017. Madrid, Spain. Abstract S101.

23.1

13.9

29.6

19.5

0

10

20

30

40

KRd(n = 48)

Rd(n = 52)

KRd(n = 147)

Rd(n=170)

High Risk Standard Risk

PFS

(m

on

ths)

HR = 0.70

HR = 0.66

KRd vs Rd (ASPIRE)1

10.2

NR 18.5

0

10

20

30

40

DRd(n = 28)

Rd(n = 37)

DRd(n = 133)

Rd(n = 113)


DRd vs Rd (POLLUX)2

PFS

(m

on

ths)

22.6

HR = 0.30

HR = 0.53

New Agents for RRMM: PFS by Cytogenetic Risk

This graph is provided for ease of viewing information from multiple trials. Direct comparison between trials is not intended and should not be inferred.

1. Richardson PG, et al. Presented at: American Society of Clinical Oncology Annual Meeting. June 3-7, 2016. Chicago, Illinois. Abstract 8018;2. Lonial S, et al. Presented at: American Society of Clinical Oncology Annual Meeting. June 3-7, 2016. Chicago, Illinois. Abstract 8037.

21.2

14.918.5

14.8

0

10

20

30

40

ERd(n = 102)

Rd(n = 104)

ERd(n = 213)

Rd(n = 218)

HR = 0.70 HR = 0.73

Del(17p) No Del(17p)

21.4

9.7

20.6

15.6

0

10

20

30

40

IRd(n = 75)

Rd(n = 62)

IRd(n = 199)

Rd(n = 216)


HR = 0.54HR = 0.64

IRd vs Rd (TOURMALINE-MM1)1 ERd vs Rd (ELOQUENT-2)2

PFS

(m

on

ths)

PFS

(m

on

ths)

Kaplan-Meier estimates of PFS according to presence of individual cytogenetic abnormalities. PFS in patients with (A) del(17p), alone or in combination with t(4;14)

and/or t(14;16); (B) t(4;14) alone; and (C) amp 1q21 alone.

0

Comorbidities are common in patients with multiple myeloma

KPS, Karnofsky performance status.Engelhardt M, et al. Haematologica 2017;102:910–21.

20

40

60

80

100

Pa

tie

nts

(%

)

KPS Renal Frailty Cardiac Disability Lung Infection GI

disease

ThrombosisLiver

Mild–severe impairment

Moderate–severe impairment

Comorbidities may impact treatment decisions

Key comorbidities that may affect treatment choice in MM:• Cardiovascular/cardiopulmonary disease1–3

• Renal insufficiency1,3

• Peripheral vascular disease3

• Pre-existing peripheral neuropathy2,3

• Pre-existing infection/poor immune response2

• Reduced glucose metabolism/diabetes2

• Bone marrow insufficiency2

• Hepatic dysfunction3

• GI disease3

• Malignancy31. Hari P, et al. J Geriatr Oncol 2018;9:138–44;2. Ludwig et al. Oncologist 2014;19:829–44; 3. Engelhardt M, et al. Haematologica 2016;101:1110–9.

Consider number, severity, controlled/uncontrolled

Defining Frailty

– Fitness is dynamic and should be assessed throughout

– MM frailty score

• Combines age, functional status, and comorbidities1

• Predicts survival and toxicity incidence1

• Calculator available at http://www.myelomafrailtyscorecalculator.net2

1. Palumbo A, et al. Blood. 2015;125:2068-2074.

2. Larocca A, et al. Blood. 2015;126:2179-2185.

IMWG frailty scoreRisk factor Definition Score

Age ≤75 years 0

76–80 years 1

>80 years 2

ADL >4 0

≤4 1

IADL >5 0

≤5 1

CCI ≤1 0

≥2 1

ADL, Katz Activity of Daily Living; AE, adverse event; CCI, Charlson Comorbidity Index; IADL, Lawton Instrumental Activity of Daily Living; IMWG, International Myeloma Working Group. Palumbo A, et al. Blood 2015;125:2068–74.

Score 0: FitScore 1: Intermediate

Score ≥2: Frail

• 3-year OS was 84% in fit, 76% in intermediate-fit and 57% in frail patients

• Cumulative incidence of grade ≥3 non-haematological AEs at 12 months was 22.2% in fit, 26.4% in intermediate-fitness, and 34.0% in frail (HR 1.74; P<0.001) patients

Comorbidities: Revised Myeloma Comorbidity Index

*The Fried definition for frailty was used, which takes into account the added presence of weakness, poor endurance, low physical

activity, slow gait speed and shrinking, with ≤2 factors defining frailty as moderate and with ≥3

factors determining frailty as severe.eGFR, estimated glomerular filtration rate.

Engelhardt M, et al. Haematologica 2017;102:91021.

Risk category Definition Score

Renal eGFR ≥90 0

eGFR 60–89 0

eGFR <60 1

Lung No/mild disease 0

Moderate/severe disease 1

Karnofsky performance status

100% 0

80–90% 2

≤70% 3

Age <60 years 0

60–69 years 1

≥70 years 2

Frailty* No/mild 0

Moderate 1

Severe 1

± cytogenetics Favourable 0

Unfavourable 1

Unavailable 0

Score ≤3: FitScore 4–6: Intermediate

Score >6: Frail

Case Presentation: Treatment

Patient Received IRd in the NPP

Achieved a VGPR after 3 cycles of therapy

Next relapse after 23 months of IRd

Case 2

• A 54-year-old woman diagnosed with IgGkappa-MM in September 2010. Standard risk cytogenetics. Has a history of hypertension

• She was treated with PAD in first line followed by ASCT with no maintenance. Progressed after 7.5 years with anemia. No high-risk cytogenetics again.

• Refused to receive a ASCT

Bort – Bortezomib; Dex - dexamethasone ; CR – complete response; MM – multiple myeloma; MPT – Melphalan, prednisone and thalidomide

Safety reported in ph3 trials

Delforge et al Blood 2017D: daratumumab; d: dexamethasone; E: elotuzumab; K: carfilzomib; I: ixazomib; R: lenalidomide; V: bortezomib; AE: adverse event; N/A: not available

Carfilzomib: Cardiovascular toxicity reported in ph3 trials

D: daratumumab; d: dexamethasone; E: elotuzumab; K: carfilzomib; I: ixazomib; R: lenalidomide; V: bortezomib;AE: adverse event; N/A: not available Adapted from Salvini M, et al. Expert Rev Anticancer Ther 2017;17(1):75-87.

Case Presentation: Treatment

Patient Received IRd in the NPP

Achieved a VGPR after 2 cycles of therapy, sCR after 4 cycles and MRD negativity at the same time

Continues on sCR for 20 months

NINLARO+Rd Real-world evidenceSummary

1. Richardson P, et al. Blood Cancer J. 2018 Nov 9;8(11):109. + supplementary appendix.

2. Moreau P, et al. N Engl J Med. 2016 Apr 28;374(17):1621-34.

3. Terpos E, et al. Blood 2017 130:3087 (ASH 2017 abstract)

NINLARO real-world evidence:

Demonstrates real-world PFS* in the range 19.2 to 27.6 months1

Confirms the median PFS of 20.6 months observed in Tourmaline-MM2

Shows an increased benefit when used after just 1 prior line of treatment3

Validates continued improvement of response rates beyond 6-7 cycles3


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Proteasome Inhibitor Treatment in Relapsed/Refractory ... · *Orlowski RZ, et al. J Clin Oncol 2002;20:4420-7; 1. US Department of Health and Human Services. Letter, NDA 21-602. Rockville,