Autologous Transplantation and Maintenance Therapy in Multiple Myeloma. Palumbo et al N Engl J Med 2014; 371:895-905

2. General scheme of treatment in symptomatic
myeloma requiring therapy.
Mehta J et al. How I treat Myeloma Blood 2010;116:2215-2223

3. Thalidomide maintenance after ASCT and conventional therapy
Study 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%

4. Bortezomib Maintenance
Study 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
2
,
bortezomib 1.3 mg/m
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%
2
,
bortezomib 1.3 mg/m
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
2
,
Bortezomib 1.3 mg/m
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
2
,
Bortezomib 1.3 mg/m
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%

5. 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

6. IMWG consensus on maintenance therapy in MM
Drug 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;
nd
increased 2
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..

7. 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.

8. MATERIALS AND METHODS

9. 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

10. 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

11. 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

13. 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

14. RESULTS

15. Demographic and Baseline Characteristics of the Enrolled Population
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 -- --

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

17. Results:- total enrolled population :402 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%

18. 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 = 0.02 HD-MEL 43 m 81.6%
MPR 22.4 m 65.3%;

19. 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=0.14 Len 41.9 months 88%
No Len 21.6 months 79.2%;

20. Subgroup Analysis: OS

21. Patient Responses during the Different Treatment Phases

22. 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

23. 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

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

25. DISCUSSION

26. 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

27. 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 lenalidomide
maintenance 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

28. 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

29. 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

30. TAKE HOME MESSAGE
• The best treatment strategy (induction followed by high-dose melphalan
and 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

31. THANK YOU