This document summarizes a debate on the role of autologous stem cell transplant (ASCT) in the treatment of multiple myeloma in the era of novel agents. It presents results from several randomized controlled trials comparing ASCT plus standard therapy to standard therapy alone. While some trials showed a progression-free survival benefit to ASCT, most did not show an overall survival benefit. Additionally, novel agent combinations like daratumumab-lenalidomide-dexamethasone have shown high rates of minimal residual disease negative responses without ASCT. Therefore, the presenter concludes that ASCT is not always needed, particularly not upfront, given the potent induction regimens now available and lack of clear overall survival improvement with AS

1. Debate: Role of Transplant in Myeloma
Professor Chng Wee Joo
Director
National University Cancer Institute of Singapore (NCIS)
National University Health System (NUHS)

2. My Arguing Position:
High-dose Therapy with Autologous Stem
Cell Transplant is not needed in the era of
novel agents

3. Phases of Treatment
InductionInduction
Stem cell
Transplant
Stem cell
Transplant
ConsolidationConsolidation MaintenanceMaintenance

4. Results: PFS Benefit
Hazard Ratio of Progression
.1 .5 1 5 10
Combined
IFM9906*
M97G*
HOVON*
PETHEMA*
S9321
MRC7
MAG91
MAG90*
IFM90
Excluding Non-Standard RCTs
RCTs preferring PBSCs
RCTs with Longer Follow-up
RCTs with Lower Crossover‡
Favors HDT Favors SDT PFS (95%CI)
0.61 ( 0.42, 0.89)
0.42 ( 0.30, 0.58)
0.76 ( 0.57, 1.02)
0.68 ( 0.54, 0.85)
0.87 ( 0.72, 1.06)
0.85 ( 0.60, 1.22)
0.85 ( 0.63, 1.14)
0.48 ( 0.34, 0.66)
1.80 ( 1.30, 2.50)
0.75 ( 0.59, 0.96)
0.75 ( 0.65, 0.87)
0.77 ( 0.59, 1.00)
0.70 ( 0.51, 0.96)
0.72 ( 0.62, 0.83)
Sensitivity/Sub-group Analyses

5. Hazard Ratio of Death
.1 .5 1 5 10
Combined
IFM9906*
M97G*
HOVON*
PETHEMA*
S9321
MRC7
MAG91
MAG90*
IFM90
Using Adjusted HR
Adding ‘HDT better’ CIAM
Excluding Non-Standard RCTs
RCTs preferring PBSCs
RCTs with Longer Follow-up
RCTs with Lower Crossover‡
Sensitivity/Sub-group Analyses
Favors HDT Favors SDT OS (95%CI)
0.68 ( 0.49, 0.94)
0.99 ( 0.71, 1.38)
1.02 ( 0.75, 1.39)
0.75 ( 0.57, 0.99)
0.97 ( 0.77, 1.21)
0.98 ( 0.65, 1.48)
1.17 ( 0.80, 1.72)
0.40 ( 0.24, 0.67)
1.70 ( 1.20, 2.60)
0.92 ( 0.74, 1.13)
0.92 ( 0.75, 1.13)
0.89 ( 0.73, 1.09)
0.85 ( 0.71, 1.03)
0.95 ( 0.76, 1.19)
0.92 ( 0.80, 1.06)
0.83 ( 0.69, 1.01)
Results: OS Benefit

6. Induction Consolidation Maintenance Salvage
Induction Consolidation Salvage
PFS versus OS
PFS
OS
Continuous
Treatment Free Period
Non-continuous
PFS
OS
Important Consideration
1) No Drug free period with the first model
2) More Toxicity with the first Model?
3) Is the cost of these 2 treatment different?

8. Is ASCT still needed in Era of
Novel Agents

9. Significant improvement in post-induction and post-
transplant CR/nCR and VGPR rates with bortezomib-
based induction regimens

10. 10

11. 11

12. IFM 2009: Phase 3 Trial of RVd ± ASCT
Study Design1-3
ASCT, autologous stem cell transplant; BORT, bortezomib; CR, complete response; CYC, cyclophosphamide; DEX, dexamethasone; G-CSF, granulocyte colony-stimulating factor; GEP, gene
expression profiling; HR, hazard ratio; IFM, Intergroupe Francophone du Myelome; ISS, International Staging System; LEN, lenalidomide; MEL, melphalan; MRD, minimal residual disease;
NDMM, newly diagnosed multiple myeloma; ORR, overall response rate; PFS, progression-free survival; PO, oral administration; pt, patient; RVd, lenalidomide, bortezomib, and low-dose
dexamethasone; SC, stem cell; TTP, time to progression; VGPR, very good partial response.
1. Attal M et al. Blood. 2015;126:391. 2. Avet-Loiseau H et al. Blood. 2015;126:191. 3. https://clinicaltrials.gov/ct2/show/NCT01191060.

13. IFM 2009: Phase 3 Trial of RVd ± ASCT
Patient Disposition
RVd + ASCT
(n = 350)
RVd, no ASCT
(n = 350)
3-yr PFS, % 61 48
HR 1.5 (95% CI, 1.2-1.9)
Stratified log-rank P < .0002
3-yr OS, % 88 88
Stratified log-rank P = .25
CR, % 58 46
P < 0.01
SPM, n (%) 23 (6.6) 18 (5.1)
ASCT, autologous stem cell transplant; CR, complete response; HR, hazard ratio; IFM, Intergroupe Francophone du Myelome; Ig, immunoglobulin; ISS, International Staging System; OS, overall
survival; PFS, progression-free survival; RVd, lenalidomide, bortezomib, and low-dose dexamethasone; SPM, second primary malignancy.
1. Attal M et al. Blood. 2015;126:391.
• PFS benefit of ASCT was consistent across subgroups including age (≤ or > 60 yrs),
sex, Ig isotype (IgG or others), ISS stage (I or II or III), cytogenetics (standard or high
risk), and response after 3 cycles of RVd (CR or not)

14. Response and Survival
14

19. An Open-label, Randomised, Phase 3 Study of
Daratumumab, Lenalidomide, and
Dexamethasone (DRd) Versus Lenalidomide and
Dexamethasone (Rd) in Relapsed or Refractory
Multiple Myeloma (RRMM): POLLUX*
Meletios A. Dimopoulos, Albert Oriol, Hareth Nahi, Jesus San Miguel, Nizar
J. Bahlis, Neil Rabin, Robert Z. Orlowski, Mieczyslaw Komarnicki, Kenshi
Suzuki, Torben Plesner, Olga S. Samoilova, Sung-Soo Yoon, Dina Ben
Yehuda, Paul G. Richardson, Hartmut Goldschmidt, Donna Reece, Nushmia
Khokhar, Lisa O’Rourke, Christopher Chiu, Xiang Qin, Mary Guckert,
Tahamtan Ahmadi, Philippe Moreau, on behalf of the POLLUX investigators
*NCT02076009

20. POLLUX: Study Design
Cycles: 28 days
DRd (n = 286)
Daratumumab 16 mg/kg IV
•Qw in Cycles 1-2, q2w in Cycles 3-6, then q4w
until PD
R 25 mg PO
• Days 1-21 of each cycle until PD
d 40 mg PO
•40 mg weekly until PD
Rd (n = 283)
R 25 mg PO
• Days 1-21 of each cycle until PD
d 40 mg PO
•40 mg weekly until PD
Primary endpoint
•PFS
Secondary endpoints
•TTP
•OS
•ORR, VGPR, CR
•MRD
•Time to response
•Duration of response
a
On daratumumab dosing days, dexamethasone was administered 20 mg premed on Day 1 and 20 mg on Day 2; RRMM, relapsed or refractory multiple myeloma; ISS, international staging system; R, lenalidomide; DRd,
daratumumab/lenalidomide/dexamethasone; IV, intravenous; qw, once weekly; q2w, every 2 weeks; q4w, every 4 weeks; PD, progressive disease; PO, oral; d, dexamethasone; Rd, lenalidomide/dexamethasone; TTP, time to
progression; MRD, minimal-residual disease.
Key eligibility criteria
•RRMM
•≥1 prior line of therapy
•Prior lenalidomide
exposure, but not refractory
•Patients with creatinine
clearance ≥30 mL/min
20
Multicenter, randomized (1:1), open-label, active-controlled phase 3 study
Stratification factors
•No. prior lines of therapy
•ISS stage at study entry
•Prior lenalidomide
R
A
N
D
O
M
I
Z
E
1:1
Pre-medication for the DRd treatment group consisted of dexamethasone 20 mga
,
paracetamol, and an antihistamine
Statistical analyses
•295 PFS events: 85% power for 7.7
month PFS improvement
•Interim analysis: ~177 PFS events

21. 21
MRD-negative Rate
DRd
Rd
MRD-neg (10-4
) MRD-neg (10-5
) MRD-neg (10-6
)
30%
8%
P <0.0001
23%
5%
P <0.0001
10%
2%
P <0.0001
Response-evaluable set. Assessed by next generation sequencing in bone marrow.
Significantly higher MRD-negative rates for DRd vs Rd

22. Phase 3 Randomized Controlled Study of
Daratumumab, Bortezomib and Dexamethasone
(DVd) vs Bortezomib and Dexamethasone (Vd)
in Patients with Relapsed or Refractory Multiple
Myeloma (RRMM): CASTOR*
Antonio Palumbo, Asher Chanan-Khan, Katja Weisel, Ajay K. Nooka, Tamas
Masszi, Meral Beksac, Ivan Spicka, Vania Hungria, Markus Munder, Maria
Victoria Mateos, Tomer Mark, Ming Qi, Jordan Schecter, Himal Amin, Xiang
Qin, William Deraedt, Tahamtan Ahmadi, Andrew Spencer, and Pieter
Sonneveld on behalf of the CASTOR investigators
*NCT02136134

23. CASTOR: Study Design
• Cycles 1-8: repeat every 21 days
• Cycles 9+: repeat every 28 days
RRMM, relapsed or refractory multiple myeloma; DVd, daratumumab/bortezomib/dexamethasone; IV, intravenous; Vel, bortezomib; SC, subcutaneous; dex, dexamethasone; PO, oral;
Vd, bortezomib/dexamethasone; PFS, progression-free survival; TTP, time to progression; ORR, overall response rate; VGPR, very good partial response; CR, complete response;
MRD, minimal residual disease.
Multicenter, randomized, open-label, active-controlled phase 3 study
Primary Endpoint
•PFS
Secondary Endpoints
•TTP
•OS
•ORR, VGPR, CR
•MRD
•Time to response
•Duration of response
Key eligibility
criteria
•RRMM
•≥1 prior line of
therapy
•Prior bortezomib
exposure, but not
refractory
Daratumumab IV administered in 1000 mL to 500 mL; gradual escalation from 50 mL to 200
mL/hour permitted
1:1
R
A
N
D
O
M
I
Z
E
DVd (n = 251)
Daratumumab (16 mg/kg IV)
Every week - cycles 1-3
Every 3 weeks - cycles 4-8
Every 4 weeks - cycles 9+
Vel: 1.3 mg/m2
SC, days 1,4,8,11 - cycles 1-8
dex: 20 mg PO-IV, days 1,2,4,5,8,9,11,12 - cycles 1-8
Vd (n = 247)
Vel: 1.3 mg/m2
SC, days 1,4,8,11 - cycles 1-8
dex: 20 mg PO-IV, days 1,2,4,5,8,9,11,12 - cycles 1-8
4
Statistical analyses
•295 PFS events: 85% power
for 4.3 month PFS
improvement
•Interim analysis: ~177 PFS
events

24. Overall Response Ratea
a
Response-evaluable population.
P <0.0001
ORR ≥VGPR
P <0.0001
P = 0.0012 DVd
Vd
MRD-neg (10-4
)≥CR
11

25. Conclusion
• Few studies show improvement in OS by
ASCT
• In the era of novel agents, no randomized
study have shown improvement in OS
• With more potent agents such as Carfilzomib
and Daratumumab, and continuous
treatment, high level of MRD- remission is
achieved
• In this setting, the additional benefit of ASCT
is even less certain
25

26. Is ASCT still needed?
NO…..Not Always, Not
Upfront

27. Thank you for your attention
www.ncis.com.sg ncis@nuhs.edu.sg