General scheme of treatment in symptomatic myeloma requiring therapy.

Mehta J et al. How I treat Myeloma Blood 2010;116:2215-2223

Thalidomide maintenance after ASCT and conventional therapyStudy group Median age, y

(no. of patients)

Induction

therapy

Maintenance Improvement in

quality of

response

EFS or PFS*

OS*

Survival after

relapse

Thalidomide

tolerance

IFM 99-02: Attal

et al (2006)

Mean 59 ± 8 (N

= 597)

VAD: 3 or 4

cycles, Single

ASCT

Thal400 mg/d

until PD vs

Pamidron

VGPR: (A) 67% 3-y EFS: (A)

52%

4-y OS: (A) 87% 1-y OS: (A) 75% 39% stopped

PNP, all 68%,

III/IV7%

ALLG MM6:

Spencer et

al(2009)

≤ 70 (N = 243) Mostly VAD

Single ASCT

Thal100-200

mg/d, for 12 m

+pred vs pred

VGPR: (A) 65% 3-y PFS

estimate: (A)

42%

3-y OS estimate:

(A) 86%

1-y OS estimate:

(A) 79%

30% stopped

PNP:10%

MRC Myeloma

IX: Morgan et al

(2012)

Intensive, 59 (N

= 493)

CVAD vs CTD,

single ASCT

Thal50-100

mg/day, until

PD†

None

Thalidomide, 50-

100 mg/day,

until PD†

None

No difference in

the percentage

of patients that

upgraded

response

status P = .19

PFS: 30 mo

27 mo P = .003

PFS 11 mo

9 mo P = .014

3-year OS: 75%

80%P = .26

38 mo

39 mo P = .995

20 mo

36 mo P = .003

21 mo

26 mo P = .25

52.2%

discontinued

Nonintensive, 73

(N = 327)

CTD attenuated

vs MP

TT2: Barlogie et

al (2008)

Median follow-

up: 70 mo

Thal 100 mg-.50

mg

Vs none

CR: 64%†

43%P = .001

EFS median: 6.0

y

4.1y P = .001

8-y OS estimate:

57%

44%P = .09

5-y OS estimate:

27%

23%P = .11

∼ 80% stopped

<2yr

HOVON 50:

Lokhorst et al

(2008)

56 (N = 556) VAD vs TAD

Single or double

ASCT

Thal50 mg/d,

until PD

IFN 3MU 3wkly

VGPR:

66%

54%

0.005

EFS:

34M

22M

P<0.001

Median:

73m

60 m

0.77

Median OS: 20

m

31m

0.009

PNP grades 2-4:

∼ 50%

Bortezomib MaintenanceStudy group Median age,

N

Induction

therapy

Maintenance quality of

response

EFS or PFS*

OS*

Tolerance

PETHEMA:

Mateos et al

(2011)

73 (N = 260) VMP vs

VTP

bortezomib 1.3 mg/m2,

days 1, 4, 8, and 11

every 12 wks for 3 y;

thal50 mg/d for 3 y

CR IF 24%-

46%

PFS 39 mo not reached G3 and G4

PNP 9% vs 3%

bortezomib 1.3 mg/m2,

days 1, 4, 8, and 11

every 12 wks for 3 y;

pred 50 mg every 2 d

for 3 y

24%-39% 32 mo P= .1 60 mo P = .1 Discontinuation

13% vs 9%

GIMEMA:

Palumbo et al

(2010)

71 (N = 511) VMPT-VT

VMP

Bortezomib 1.3 mg/m2,

days 1 and 15, every 4

wks; thalidomide 50

mg/d until PD or

intolerance

CR 38%

24%

P = .0008

3-y PFS 60%

42%

P < .07

3-y OS 88.8%

89.2%

P = .9

G3 and G4

Neutropenia

38%vs 28.1%

HOVON/GMM

G: Sonneveld

et al (2010)

57 (N = 613) PAD

VAD

Bortezomib 1.3 mg/m2,

biweekly, for 2 y; vs

thalidomide 50 mg/d for

2 y

(CR/nCR

50%

≥ VGPR 65%

CR/nCR 38%

≥ VGPR 61%

3-y PFS

48%

42%

P = .047

3-y OS

78%

71%

P = .048

G3 and G4

PNP

16%

7%

Lenalidomide Maintenance

EFS

OS

Bo Yang,Lenalidomide Treatment for Multiple Myeloma: Systematic Review and Meta-Analysis of Randomized Controlled Trials.PLoS One. 2013; 8(5): e64354

IMWG consensus on maintenance therapy in MMDrug Dose/regi

men

Duration of

therapy

Impact on Risk groups Tolerance Comments

PFS OS

Thal 50-100

mg/d

Up to 1 y,no

correlation

between duration

and outcome

Yes Yes, No benefit In

FISH defined

high-risk

patients

PNP,

fatigue

Poor tolerance

Len 5-15 mg/d

continuousl

y or days 1-

21, q28d

Until PD or

intolerance

Yes Presently

shown in

one-third

of studies

Does not

overcome

negative impact

of FISH-defined

unfavorable

cytogenetics

Few

discontinu

ations

because

of AEs

Increase in

PFS, increase

in OS in 1 of 3

studies;

increased 2nd

primary

malignancies

Bortez

omib

1.3 mg

biweekly

2 y or until PD or

intolerance

Yes Yes Active in

patients with

renal failure and

cytogenetic risk

groups

PNP

grades 3

or 4: 16%

Only

comparison

between PAD-

ASCT

Ludwig H,IMWG consensus on maintenance therapy in multiple myeloma,Blood. 2012 Mar 29;119(13):3003-15. Epub 2012 Jan 23..

RATIONALE OF THE STUDY:HYPOTHESIS.

• Improvements in OS/PFS with novel therapies have raised questions about the role of transplantation in

comparison with conventional chemotherapy and about the timing of transplantation, since the survival benefit

has not been clearly established.

• Though 3 large randomized studies, continuous therapy with lenalidomide, as compared with placebo,

significantly reduced the risk of disease progression, but the survival advantage was inconsistent

• Is currently not clear whether maintenance therapy after combination therapy will have the same effect that it

does after transplantation

• Hypothesis: HD Mel based consolidation improves OS/PFS as compare to Chemotherapy and Lenalidomide

therapy post transplant has OS/PFS advantage.

MATERIALS AND METHODS

STUDY POPULATION

• Randomized, open-label trial with a 2-by-2 factorial design

• Approved by The Institutional Review Board, University of Turin, Italy.

• November 2007 through July 2009 at 62 centers in Italy and Israel.

• A simple randomization sequence, stratified according to International Staging System disease stage (stage I or II vs. stage III, with higher stages indicating more severe disease) and age (≤60 years vs. 61to 65 years), was generated by a computer program

• results of the random assignment wereconcealed until patients reached the end of the induction period

Inclusion criteria• Patients with symptomatic, measurable, newly diagnosed multiple myeloma who were 65 years

of age or younger were eligible

• Karnofsky performance-status score of at least 60%

• Life expectancy longer than 6 months

• An absolute neutrophil count greater than 1500 per cubic millimeter and a platelet count greater than 75,000 per cubic millimeter

• Normal cardiac and pulmonary function findings creatinine clearance ≥30 ml per minute

Exclusion criteria• Previous treatment with anti-myeloma therapy (does not include radiotherapy, bisphosphonates,

or a single short course of steroid; < to the equivalent of dexamethasone 40 mg/day for 4 days).

• Prior history of malignancies, other than multiple myeloma, unless the subject has been free of the disease for >3 years.

• Neuropathy of > grade 2 severity.

• Patients previously diagnosed as bearing deep venous thrombosis or arterial thromboembolic event within the latest 6 months

DATA COLLECTION…

• The primary study end point was progression-free survival. Progression-free survival was calculated until the date of disease progression, death from any cause during treatment, or data censoring at the last date on which the patient was known to be free of disease progression

• Secondary end points included overall survival, the overall response rate, the time to a response, and safety.

• Time-to-event end points were estimated from the time of enrollment and from the time when the random assignment was disclosed (for the patients who underwent randomization).

• Overall survival was calculated until the date of either death from any cause or data censoring at the last date on which the patient was known to be alive.

• Response was assessed with the use of the International Uniform Response Criteria for Multiple Myeloma.

• Bone marrow samples were collected at enrollment and analyzed by FISH for chromosome deletions 13 and 17 and for the t(4:14) and t(14:16). No prospective decisions regarding therapy were based on the results.

• Adverse events were graded according to the NCI-CTC AE v 3.0

STATISTICAL ANALYSIS• Response and safety data were compared among the treatment groups by chi-square test or

Fisher’s exact test

• Time-to-event data were analyzed with the use of the Kaplan–Meier method, and the groups were compared with the use of the log-rank test.

• Cox proportional-hazards models were used to estimate hazard ratios and 95% confidence intervals for the main comparisons., with the use of interaction terms.

• Between-group differences in patient characteristics were evaluated with the use of the Mann–Whitney U test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables

• Statistical analyses were performed with the use of SAS software, v 8.2 (SAS Institute), and STATA v11.0 (StataCorp)

• Two interim analyses, according to the O’Brien–Fleming design, were 65 progression events (40% of the expected number) and 97 events (60% of the expected number) had occurred

• the study was completed as originally planned

RESULTS

Characteristic Enrolled population (N = 402

MEL200x2 (N = 141)

MPR (N = 132)

Maintenance (N = 126)

No maintenance (N = 125)

Median age, years (IQR) 58 (52–62 58 (52–62) 57 (50–61)) 57 (50–61 57 (50–61)

Male, n (%) 219 (54.5) 81 (57.4) 80 (60.6) 69 (54.8) 68 (54.4)

ISS I 192 (47.8) 75 (53.2) 66 (50.0) 69 (54.8) 64 (51.2)

ISS II 115 (28.6) 43 (30.5) 37 (28.0) 36 (28.6) 37 (29.6)

ISS III 95 (23.6) 23 (16.3) 29 (22.0) 21 (16.7) 24 (19.2)

Median creatinine, mg/dl (IQR) 0.9 (0.8–1.1) 0.9 (0.7–1)* 0.9 (0.8–1.1) 0.9 (0.7–1) 0.9 (0.7–1.1)

Median LDH, U per liter (IQR)

278 (197–350) 261 (195–327) 282 (214–357) 275 (195–338) 271 (210–320)

Median hemoglobin, g per liter (%) 11.2 (9.7–12.6) 11.7 (10.3–13.1) 11.5 (9.8–12.7) 11.7 (10–13) 11.5 (10.1–12.7)

Median platelet count ×103/L(IQR) 238 (188–287) 240 (193–287) 242 (195–283) 237 (196–296) 247 (194–285)

Deletion 17p, n (%) 42 (14.4) 11 (11.1) 13 (13.0) 9 (9.6) 11 (12.2)

Median time of follow-up from consolidation, months

44.0 43.3 44.5 -- --

Median time of follow-up from maintenance, months

38.8 -- --- 38.9 38.6

Median duration of consolidation, months

5.9 4.9 5.9 -- --

Demographic and Baseline Characteristics of the Enrolled Population

Randomization, Treatment, and Follow-up of the Enrolled Patients.

CATAGORY EFS 5YR OS

HDMEL+LEN 54.7m 78.4%

HDMEL-LEN 37.4m 66.6%

MPR+LEN 34.2 70.2%

MPR-LEN 21.8m 58.7%

Results:-total enrolled population :402 patients

Results: Consolidation HD Mel vs MPR

PFS hazard ratio for progression or death, 0.44; 95% CI 0.32 to 0.61; P<0.001)

4 YR OS hazard ratio for death, 0.55; 95% CI, 0.32 to 0.93; P = 0.02HD-MEL 43 m 81.6%

MPR 22.4 m 65.3%;

Results: Len maintenance therapy

PFS hazard ratio for progression or death, 0.47; 95% CI, 0.33 to 0.65; P<0.001

3 YR OS hazard ratio for death, 0.64; 95% CI, 0.36 to 1.15; P=0.14Len 41.9 months 88%

No Len 21.6 months 79.2%;

Subgroup Analysis: OS

Patient Responses during the Different Treatment Phases

Salvage Treatment at Relapse

Among patients with relapsed multiple myeloma, the 3-year OS from the time of relapse were similar across the four treatment groups

Adverse effects:• induction phase: the most frequent grade 3 or 4 adverse events were

neutropenia (in 8.5% of the patients), anemia (in 6.3%), infection (in 6.0%), and dermatologic events (in 4.8%); one death occurred as a result of arrhythmia.

• consolidation therapy,:hematologic adverse events HD melphalan >MPR. These events were mainly grade 3 or 4 neutropenia (94.3% vs. 51.5%, P<0.001) and thrombocytopenia (93.6% vs. 8.3%, P<0.001) .Other grade 3 or 4 adverse events that were more common in patients who received HD melphalan were gastrointestinal events (18.4% vs. 0%, P<0.001), infections (16.3% vs. 0.8%, P<0.001), and systemic events (12.8% vs. 1.5%, P<0.001).

• Maintenance Phase, the most frequent grade 3 or 4 adverse events were neutropenia (in23.3% of patients who received lenalidomide maintenance therapy vs. 0% of patients who received nomaintenance therapy, P<0.001), infections (in 6.0% vs. 1.7%, P=0.09), and dermatologic events (in 4.3% vs. 0%, P=0.03)

• Eleven patients (2.8%) had a second primary cancer: lung cancer in one patient during induction; prostate cancer in two patientsand breast cancer in three patients during lenalidomide maintenance therapy

Grade 3 and 4 Adverse Events Occurring in at Least 2% of the Safety Population.

Grade 3 or 4 adverse event

DISCUSSION

HD Mel vs MPR

• The standard high-dose consolidation therapy followed by stem-cell transplantation, as compared with MPR, was associated with a significant reduction in the risk of progression or death (hazard ratio, 0.44) and prolonged overall survival (hazard ratio for death, 0.55).

• Adverse events were more frequent with high-dose melphalan than with MPR. It did not affect the rate of early death or treatment discontinuation or patients’ ability to proceed to the maintenance or no-maintenance phase

Maintenance Lenalidomide• The clinical benefit associated with lenalidomide maintenance was

independent of the consolidation regimen.

• Response rates improved during maintenance therapy in both the high-dose melphalan and MPR groups.

• As compared with no maintenance,low-dose lenalidomidemaintenance delayed relapse by approximately 2 years.

• lenalidomide maintenance, as compared with no maintenance, was associated with significantly prolonged progression-free survival; no significant improvement in overall survival was noted

LIMITATIONS OF THE STUDY

A. Only 68% of the enrolled patients were eligible to undergo the first randomization; the main reasons for discontinuation during the induction phase were disease progression and the patient’s decision to choose an alternative therapy because of a suboptimal response after induction.

B. Bortezomib-based induction and consolidation regimens in combination with alkylating or immunomodulatory agents have been associated with unprecedented rates of high-quality response and a positive effect on outcomes in patients, regardless of whether they are eligible for stem-cell transplantation.

C. Placebo was not administered in the group of patients who did not receive maintenance therapy, and a blind assessment of progression was not made.

D. Quality-of-life assessments were not performed

Yet to proved!!!!!!

• The response was assessed with the use of standard laboratory tests, and minimal residual disease was not monitored with immunophenotypic or molecular techniques, which might have revealed more subtle differences in the response, as reported in similar studies.

• Proteasome inhibitor versus autologous stem-cell transplantation

• The benefit of early versus late transplantation

• Duration of maintenance therapy

TAKE HOME MESSAGE

• The best treatment strategy (induction followed by high-dose melphalanand lenalidomide maintenance) was associated with a 5-year rate of progression-free survival from the time of diagnosis of approximately 48% and an overall survival rate of 78% among all patients

• consolidation therapy with high-dose melphalan, as compared with MPR, improved progression-free and overall survival, although at a cost of increased toxicity.

• lenalidomide, as compared with no maintenance therapy, significantly reduced the risk of disease progression

THANK YOU