treatment for advanced multiple myeloma (mm) in...
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Treatment for advanced multiple myeloma (MM) in Korea
Chang-Ki Min, MDSeoul St. Mary’s Hospital,
The Catholic University of Korea
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MM is characterized by a pattern of remission and relapse
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Outcomes in relapse and refractory MM
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Treatment lines
Leukemia 2018; 32: 252–262
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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
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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
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Lenalidomide-refractory MM
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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
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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.
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Phase 1/2 study of lenalidomide combined withlow-dose CY and Pred (REP)
Inger S. Nijhof et al. Blood 2016;128:2297-2306
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PFS in Len-refractory at the Last Prior Line of TherapyIn CASTOR
Asher A. Chanan-Khan et al. Blood 2016;128:3313
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Daratumumab plus BD versus BD in RRMM: updated analysis of CASTOR
Haematologica. 2018 Sep 20. pii: haematol.2018.194118, E-Pub
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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
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Bortezomib-refractory MM
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Median PFS 8.3 months and median DOR 9.9 months
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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
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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
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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
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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
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Double-refractory MM
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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
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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
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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).
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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
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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
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ORR in patient subgroups in the combined daratumumab 16 mg/kg group.
Saad Z. Usmani et al. Blood 2016;128:37-44
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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
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Korean data
• Pom(C)D versus K2D
• Dara monotherapy (EAP data)
• PomCD for elderly patients as third line or more (PORYOU study)
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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
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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)
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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
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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
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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
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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
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• 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
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OS of Kd vs. Pd vs. PCd- KMM 1903 study
• Kd vs. Pd vs. PCd:11.50 mo (95% CI, 4.18-18.82) vs. 10.20 mo (95% CI, 5.89-14.51) vs. 24.67 mo (95% CI, 12.47-36.86)(P=0.294)
• Median follow-up duration: 6.23 months (range, 0.30-47.03)
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PFS of Kd vs. Pd vs. PCd- In prior lenalidomide non-responders
• Kd vs. Pd vs. PCd:4.16 mo (95% CI, 1.54-6.80) vs. 5.10 mo (95% CI, 1.03-9.18) vs. 5.37 mo (95% CI, 0.00-20.06)(P=0.234)
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
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PFS of Kd vs. Pd vs. PCd- In prior bortezomib non-responders
• Kd vs. Pd vs. PCd:8.97 mo (95% CI, 2.51-8.03) vs. 5.10 mo (95% CI, 3.85-6.35) vs. 6.30 mo (95% CI, 4.79-7.81)(P=0.835)
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
Months from treatment of daratumumab
P=0.791
Dara
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PFS of Kd vs. Pd vs. PCd- In double refractory patients
• Kd vs. Pd vs. PCd:5.28 mo (95% CI, 2.43-8.10) vs. 4.97 mo (95% CI, 4.35-5.59) vs. 9.33 mo (95% CI, 5.96-12.71)(P=0.047)
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
Months from treatment of daratumumab
P=0.603
Dara
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OS of Kd vs. Pd vs. PCd- In double refractory patients (n=219)
• Kd vs. Pd vs. PCd:11.50 mo (95% CI, 4.15-18.85) vs. 10.20 mo (95% CI, 5.67-14.73) vs. 24.67 mo (95% CI, 12.45-36.88)(P=0.394)
Double refractory vs. others13 mo (n=29) vs. N.E (n=36)
Prob
abili
ty o
f pro
gres
sion-
fee
surv
ival
Months from treatment of daratumumab
P=0.494
Dara
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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
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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 -
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Study designThe efficacy and safety of the completely oral regimen, PCD combinationfor patients who failed both bortezomib and lenalidomide treatment
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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)
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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%
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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]
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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]
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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.
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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.
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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
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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
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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
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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
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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