Treatment for advanced multiple myeloma (MM) in...

Treatment for advanced multiple myeloma (MM) in Korea

Chang-Ki Min, MDSeoul St. Mary’s Hospital,

The Catholic University of Korea

MM is characterized by a pattern of remission and relapse

Outcomes in relapse and refractory MM

Treatment lines

Leukemia 2018; 32: 252–262

Evidence-based algorithm for treatment of patients with relapsed and/or refractory myeloma using our currently approved novel agents.

Robert Z. Orlowski, and Sagar Lonial Clin Cancer Res 2016;22:5443-5452

Now in RRMM

• A backbone of therapy of IMiDs+dex or PIs+dex remains in most of MM patients.

• Refractory to one or both of 2 classes• To switch the class of agent from the

previous lines or • To switch to another treatment option

within the same class of agent

Lenalidomide-refractory MM

Pom+dex: MM-003

• Pomalidomide improved outcomes compared with high-dose dexamethasone regardless of lenalidomide-refractory status.

• Median PFS was significantly longer with pomalidomide in patients who were refractory to lenalidomide (3.9 months vs. 1.9 months; P < 0.0001).

Jesus San Migual et al. Lancet Oncol 2013;14:1055-1066

Pom+dex: STRATUS

Meletios A. Dimopoulos et al. Blood 2016;128:497-503

→ Similar results were obtained in patients refractory to lenalidomide, patients refractory to bortezomib, and patients refractory to both lenalidomide and bortezomib.

Phase 1/2 study of lenalidomide combined withlow-dose CY and Pred (REP)

Inger S. Nijhof et al. Blood 2016;128:2297-2306

PFS in Len-refractory at the Last Prior Line of TherapyIn CASTOR

Asher A. Chanan-Khan et al. Blood 2016;128:3313

Daratumumab plus BD versus BD in RRMM: updated analysis of CASTOR

Haematologica. 2018 Sep 20. pii: haematol.2018.194118, E-Pub

https://www.ncbi.nlm.nih.gov/pubmed/30237264

Kyp+dex vs. Bort+dex: Endeavor study

Meletios A. Dimopoulos et al. Lancet Oncol 2016;17:27-36

P. Moreau et al. Leukemia 2017;35:115-122

received prior lenalidomide

no prior lenalidomide

Bortezomib-refractory MM

Median PFS 8.3 months and median DOR 9.9 months

Bort+dex+Pan vs. Bort+dex: Panorama- adding a novel class of agent

Jesús F. San-Miguel et al. Blood 2015;126:3026

In patients with bortezomib-refractory patients with RRMM: the ORR was 34.5% and the median duration of response was 6.0 months

Len+dex±Dara: Pollux trial• 28% of patients receiving

Dara and 27% of those receiving Len+dex alone were refractory to the last line of previous therapy

• 20% of patients receiving Dara and 16% of those in the control group were PI refractory

• Treatment with Dara resulted in a HR of 0.37 for the total population and 0.50 for those refractory to a PI for PFS

Philippe Moreau et al. Blood 2016;128:489

Among patients who were refractory to bortezomib, PFS was significantly longer with Dara than in the control group(NR vs. 10.3 months; HR, 0.46; P = 0.0117)

PFS in Bortezomib-refractory Patients who Received 1 to 3 Prior Lines of Therapy

Updated analysis of POLLUX

(A) PFS in the ITT population and (B) a forest plot summary of PFS HRs in subgroups (B) by prior lines, prior therapies, treatment-free intervals.

Meletios A. Dimopoulos et al. Haematologica 2018;103:2088-2096

Double-refractory MM

Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter International Myeloma Working Group study

Leukemia 2012; 26(1): 149-157

Xavier Leleu et al. Blood 2013;121:1968-1975

overall survival: 14.9 months

Pom+ dex is active and well tolerated in double (bortezomiband lenalidomide)–refractory multiple myeloma: IFM 2009-02

Treatment scheme.

Jatin J. Shah et al. Blood 2015;126:2284-2290

Carfilzomib, pomalidomide, and dexamethasone for RRMM- Phase 1 study

The MTD of the regimen was dose level 1 (carfilzomib20/27 mg/m2, pomalidomide4 mg, dexamethasone 40 mg).

Survival in the overall study population

Jatin J. Shah et al. Blood 2015;126:2284-2290

Survival by response

an ORR of 50% and median OS of 20.6 months

Mechanisms of action of monoclonal antibodies targeting surface antigens on MM cells

Niels W. C. J. van de Donk et al. Blood 2016;127:681-695

ORR in patient subgroups in the combined daratumumab 16 mg/kg group.

Saad Z. Usmani et al. Blood 2016;128:37-44

Efficacy of retreatment with IMiDs and PIs following daratumumab monotherapy in relapsed and refractory multiple myeloma patients.

Efficacy of PI treatment after daratumumab in PI-refractory patients.

Efficacy of IMiD treatment after daratumumab in IMiD refractory patients.

Br J Haematol 2018, 183, 60–67

Korean data

• Pom(C)D versus K2D

• Dara monotherapy (EAP data)

• PomCD for elderly patients as third line or more (PORYOU study)

Real world experience of carfilzomib, and dexamethasone versus

pomalidomide-based combination chemotherapy after a 2nd-Line

therapy in RRMM - KMM-1903 study -

Oral presentation: OP08-03

Kd vs Pom-based therapy• Patient data from 16 hospitals were retrospectively

analyzed by review of medical records. • Patients who relapsed or were refractory to 2 or more

lines of chemotherapy regimens and who had been treated with Kd, pomalidomide-based chemotherapy (Pomdex or PomCydex) were included.

EAP for Daratumumab monotherapy

• Jan 2017 – Oct 2018, 3 university hospitals• Total N=65• Excluded N=2 (f/u loss before 3 months)

Baseline Characteristics: Prior Lines of Therapy

Kd Pd PCd

Total number of patients 44 108 73

Median number of prior regimens (range)

3 (2-7) 4 (2-14) 3 (2-7)

Number of prior regimens ≥4, n (%)

10 (22.7) 75 (69.4) 28 (38.4)

Diagnosis to treatment (median months, range)

37.37 (6.57-207.47)

59.07 (9.60-193.43)

46.2 (9.60-109.07)

Prior therapies, n (%)

Bortezomib 44 (100) 108 (100) 72 (98.6)Thalidomide 22 (50) 62 (57.4) 32 (43.8)Lenalidomide 42 (95.5) 105 (97.2) 73 (100)Autologous transplant 21 (47.7) 54 (50)) 36 (49.3)

Response to prior therapiesPrimary refractory to bortezomib 13 (29.5) 25 (23.1) 11 (15.3)Primary refractory to Lenalidomide 12 (28.6) 30 (28.6) 23 (31.5)

Kd or Pom-based Tx

Demographics and Baseline Disease Characteristics: Prior

Lines of Therapy Variables No.No. of patients 65Age of patients, years, median (range) 67 (40-88)≥ 65 years 35 (52.2%)

GenderMale 35 (52.2%)

ECOG performance states0 6 (9.0%)

1 35 (52.2%)

2 18 (26.9%)

3 7 (10.4%)

Unknown 1 (1.5%)

Extramedullary plasmacytomaPresent 17 (23.8%)

Time to treatment of daratumumab from diagnosis,months, median (range) 68.0 (9.5-183.9)

Absolute neutrophil counts, x109/L, median (range) 2.18 (0.16-10.5)

Absolute neutrophil counts < 1.0 x109/L 8 (11.9%)

Unknown 1 (13.3%)

Absolute lymphocyte counts, x109/L, median (range) 1.1 (0.56-30.6)

Platelet, x109/L, median (range) 75 (14-224)

Platelet counts < 75 x109/L 33 (49.3%)Renal function (creatinine clearance) at baseline, mL/min, median (range) 57.5 (6.8-202.8)

> 60 19 (28.4%)≥ 20 to < 60 14 (20.9%)< 20 7 (10.4%)Unknown (to be update ) 27 (40.3%)

ISS stage at diagnosisI 10 (14.9%)II 28 (41.8%)III 22 (32.8%)Unknown 7 (10.4%)

Cytogenetic profilet(4;14) (unknown, n=36) 8 (25.8%)del17p (unknown, n=35) 8 (25.0%)

t(14;16) (unknown, n=62) 0 (0.0%)

Prior treatmentNumber of prior lines of therapy, median (range) 4 (2-9)

≥ 3 prior lines of therapy 66 (98.5%)Prior autologous stem cell transplantation 46 (60.5%)Prior proteasome inhibitor (PI)

Bortezomib 67 (100.0%)Carfilzomib 27 (40.3%)Ixazomib 1 (6.3%)

Prior immunomodulatory drugs (IMiDs)Lenalidomide 66 (98.5%)Pomalidomide 59 (88.1%)Thalidomide 42 (62.7%)

Refractory toDrugs, median, n 5 (0-10)Last line of therapy 59 (88.1%)Bortezomib 36 (53.7%)Carfilzomib 18 (28.4%)

Lenalidomide 52 (77.6%)Pomalidomide 51 (76.1%)Thalidomide 20 (29.9%)Alkylating agent 51 (761.%)

Daratumumab Tx

Kd Pd PCd P value

Total number of patients 44 108 73

Cycles chemotherapy, median (range)

3 (1-11)

3 (1-37)

4 (1-22)

Treatment durations Median (range)

2.75 (0.27-11.43)

3.12 (0.17-36.83)

3.57 (0.40-28.40)

Response evaluable patients, n 40 97 63

sCR 0 0 0

CR 2 (4.5) 2 (1.9) 1 (1.4)

VGPR 4 (9.1) 11 (10.2) 11 (15.1)

PR 11 (25.0) 25 (23.1) 20 (27.4)

MR 4 (9.1) 8 (7.4) 8 (11.0)

SD 6 (13.6) 26 (24.1) 7 (9.6)

PD 13 (29.5) 25 (23.1) 16 (21.9)

ORR (%) 17 (38.6) 38 (35.2) 32 (43.8) 0.582

Median days to the best response (range)

1.88 (0.43-9.33)

1.93 (0.27-15.53)

2.43 (0.33-23.43)

Efficacy of Kd vs. Pd vs. PCd

Overall best response No. (N=65)

Overall response 27 (41.5%)

Complete response 9 (13.8%)

Very good partial response 6 (9.2%)

Partial response 10 (15.4%)

Minimal response 3 (4.6%)

Stable disease 19 (29.2%)

Refractory 16 (24.6%)

Efficacy of Daratumumab monotherapy

• Kd vs. Pd vs. PCd:5.27 mo (95% CI, 2.41-8.13) vs. 4.97 mo (95% CI, 4.28-5.66) vs. 9.33 mo (95% CI, 5.71-12.96)(P=0.032)

PFS of Kd vs. Pd vs. PCd- KMM 1903 study

OS of Kd vs. Pd vs. PCd- KMM 1903 study


• Median follow-up duration: 6.23 months (range, 0.30-47.03)

PFS of Kd vs. Pd vs. PCd- In prior lenalidomide non-responders


Lenalidomide refractory vs. others4.8 mo (n=50) vs. 7.4 mo (n=15)

Prob

abili

ty o

f pro

gres

sion-

fee

surv

ival

Months from treatment of daratumumab

P=0.531

Dara

PFS of Kd vs. Pd vs. PCd- In prior bortezomib non-responders


Bortezomib refractory vs. others5.9 mo (n=36) vs. 5.4 mo (n=29)

Prob

abili

ty o

f pro

gres

sion-

fee

surv

ival


P=0.791

Dara

PFS of Kd vs. Pd vs. PCd- In double refractory patients


Double refractory vs. others4.8 mo (n=29) vs. 5.4 mo (n=36)

Prob

abili

ty o

f pro

gres

sion-

fee

surv

ival


P=0.603

Dara

OS of Kd vs. Pd vs. PCd- In double refractory patients (n=219)


Double refractory vs. others13 mo (n=29) vs. N.E (n=36)

Prob

abili

ty o

f pro

gres

sion-

fee

surv

ival


P=0.494

Dara

Univariate and multivariate analysis affecting PFS of of Kd vs. Pd vs. PCd

- KMM 1903 study

Total (n=219) Univariate analysis Multivariate analysis

HR P value HR P value

Age < 65 years vs ≥ 65 years

0.725 (95%CI, 0.501-1.050)

P=0.0880.865 (95%CI, 0.462-1.619)

P=0.650

ISSI and II vs. III

1.456 (95%CI, 0.967-2.193) P=0.072

1.076 (95%CI, 0.472-2.455) P=0.861

R-ISSI and II vs. III

1.663 (95%CI, 0.923-2.996)

P=0.0901.590(95%CI, 0.554-4.561)

P=0.388

Cytogenetic risk groupStandard vs High

1.889 (95%CI, 1.109-3.218) P=0.019 1.240 (95%CI,

0.582-2.640) P=0.577

Prior lenalidomide responseResponders vs. Non-responders

1.624 (95%CI, 1.095-2.408) P=0.016 2.466 (95%CI,

1..188-5.118) P=0.015

Drugs used in advanceKd and Pd vs. PCd

0.568 (95%CI, 0.325-0.992) P=0.047 0.345 (95%CI,

0.152-0.783) P=0.011

The safety and efficacy of POmalidomide in combination with cyclophosphamide and dexamethasone (PCD) in the transplant-ineligible patients with Relapsed and/or

refractorY multiple myeloma (MM) who had lenalidomide+dexamethasone (LD) following frontline bortezomib combined chemotherapy,

Open-labeled, mUlticentre Phase II study ; PORYOU study

- KMM-164 study -

Study designThe efficacy and safety of the completely oral regimen, PCD combinationfor patients who failed both bortezomib and lenalidomide treatment

Patient characteristicsCharacteristics (N=55) N (%) or

median (range) Characteristics (N=55) N (%) or median (range)

Age, years (median [range]) 73.3 [64.4-85.6]. ISS (%) I 18 (32.7)

Gender (%) Male 33 (60.0) II 21 (38.2)Female 22 (40.0) III 14 (25.5)

ECOG PS (%) 0-1 47 (85.5) NA 2 (3.6)≥2 7 (12.7) R-ISS (%) I 13 (23.6)NA 1 (1.8) II 30 (54.5)

Subtype (%) IgG, κ or λ 22 (40.0) III 8 (14.5)IgA, κ or λ 10 (18.2) NA 4 (7.3)Light chaindisease 7 (12.7) Time from diagnosis to

Pomalidomide, years (median [range]) 2.66 [0.92-7.14]

Others 3 (5.5) Previous no. of therapy (median [range]) 2 [2-6]

NA 13 (23.6) >2 previous treatments n (%) 18 [32.7]

β2MG, mg/L (median [range]) 3.6 [1.7-17.6]Type of previous therapy, n (%)

Prior lenalidomideand bortezomib

55 (100.0)

LDH (%) Normal 29 (55.8)Prior lenalidomide, bortezomib andthalidomide

8 (14.5)

Abnormal 19 (36.5)

NA 4 (7.7)

Cytogenetic risk (%) Standard 31 (56.4)

High 11 (20.0)

NA 2 (3.6)

Response of PCd

ALL ≤2 prior treatment >2 prior treatment

8% 9% 6%

23% 23%22%

30% 29% 33%

15% 11%

22%

17%17%

17%8% 11%

CR VGPR PR MR SD PD

58.2% 60.0%

All patients (n=53) PCD line = 2 (n=35) PCD line > 2 (n=18)

61.1%

PFS, median

Events Censored Median PFS (95% CI)

42 (76.4) 13(23.6) 7.332 (4.91, 9.75)

number at risk

55 34 20 18 15 15 14 13

Median f/u duration : 11.51 [0.72–37.55]

OS, median

Events Censored Median OS (95% CI)

22 (40.0) 33 (60.0) 21.34 (14.95, 27.72)

number at risk

55 48 43 38 36 34 34 33

Median f/u duration : 11.51 [0.72–37.55]

Response of PCd- previous response to lenalidomide

CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response.

All patients Refractory Responder

N=55 N=14 N=41

Parameter N (%) or median [range] N (%) or median [range]N (%) or median

[range]ORR (at least PR) 32 (58.2) 7 (50.0) 25 (61.0)

CBR (at least MR) 40 (72.7) 9 (64.3) 31 (75.6)

Best response to Pomalidomide

CR 4 (7.3) 2 (14.3) 2 (4.9)

VGPR 12 (21.8) 2 (14.3) 10 (24.4)

PR 16 (29.1) 3 (21.4) 13 (31.7)

MR 8 (14.5) 2 (14.3) 6 (14.6)

SD 9 (16.4) 3 (21.4) 6 (14.6)

PD 4 (7.3) 2 (14.3) 2 (4.9)

NA 2 (3.6) (0.0) 2 (4.9)

Time to best response (months) 1.73 [0.89, 12.53] 1.33 [0.89, 12.53] 1.61 [0.89, 9.21]

Discontinued before first response evaluation : 3 patients died from SAE and unknown cause, one progression during first cycles and one stopped due to pancytopenia.

Response of PCd- previous response to bortezomib

CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response.

All patients Refractory Responder

N=55 N=3 N=52

Parameter N (%) or median [range] N (%) or median [range]N (%) or median

[range]ORR (at least PR) 32 (58.2) 1 (33.3) 31 (59.6)

CBR (at least MR) 40 (72.7) 2 (66.7) 38 (73.1)

Best response to Pomalidomide

CR 4 (7.3) 0 (0.0) 4 (7.7)

VGPR 12 (21.8) 0 (0.0) 12 (23.1)

PR 16 (29.1) 1 (33.3) 15 (28.8)

MR 8 (14.5) 1 (33.3) 7 (13.5)

SD 9 (16.4) 1 (33.3) 8 (15.4)

PD 4 (7.3) 0 (0.0) 4 (7.7)

NA 2 (3.6) (0.0) 2 (3.8)

Time to best response (months) 1.73 [0.89, 12.53] 0.92 [0.92, 1.48] 1.73 [0.89, 12.53]

Discontinued before first response evaluation : 3 patients died from SAE and unknown cause, one progression during first cycles and one stopped due to pancytopenia.

Comparison survival according to response to lenalidomide

p=0.418

Refractory

Median PFS Responder : 7.332 (4.91, 9.75)Refractory : 3.847 (2.78, 4.91)

Responder

p=0.676

Median OS Responder : 22.981 (14.36, 31.61)

Refractory : 21.337 (0.00, 49.31)

Responder

Refractory

PFS OS

Comparison survival according to response to bortezomib

p=0.420

Median PFS Responder : 7.332 (5.00, 9.66)

Refractory : 3.222 (2.01, 4.43)

Refractory

Responder

Median OS Responder : 21.337 (14.88, 27.80)

Refractory : NA

p=0.724

PFS OS

Refractory

Responder

Factors to be weighed in deciding on therapy for“advanced MM”

Clin Cancer Res 2016;22:5443-5452

To choose another treatment option within the same class of agent orTo switch the class of agent from the previous lines

Conclusions

• Class switch is not the only thing• Fit patients should be treated with triplet-

regimens if possible.• More effective combination regimens

should be developed to overcome drug resistance

• Biomarkers are needed to choose the appropriate class of agents

Acknowledgements• Ji Hyun Lee, M.D.

- Dong-A University, College of Medicine

• Sung-Soo Park, M.D.- Seoul St. Mary’s Hospital, The Catholic University of Korea

• Ho Sup Lee, M.D.- Kosin University College of Medicine

Treatment for advanced multiple myeloma (MM) in...

Documents

Transcript of Treatment for advanced multiple myeloma (MM) in...