Timing of Transplant for Multiple Myeloma

Robert Z. Orlowski, Ph.D., M.D.Director, Myeloma Section

Professor, Departments of Lymphoma/Myeloma & Experimental Therapeutics

Principal Investigator, M. D. Anderson SPORE in Multiple Myeloma

Chair, Southwest Oncology Group Myeloma Committee

Chemotherapy vs. Transplant

• Not all randomized studies, however, have shown a benefit

San-Miguel, JF & Mateos, M-V. Hematology 2009, ASH Education Book.

Autologous SCT vs. CCT

• Progression-free survival is improved by autologous stem-cell transplantation vs. conventional chemotherapy

Koreth, J et al. Biol Blood Marrow Transplant. 13: 183, 2007.

Overall Survival Impact

• Survival benefit is less impressive in this meta-analysis

Koreth, J et al. Biol Blood Marrow Transplant. 13: 183, 2007.

Single or Double ASCT ?

• Double autologous stem cell transplantation provides advantages over single transplantation

Attal, M et al. N Engl J Med. 349: 2495, 2003.

Subgroup Benefits

• Benefits were especially notable in patients who did not achieve a CR or VGPR after their first autologous stem cell transplant

Attal, M et al. N Engl J Med. 349: 2495, 2003.

Consolidation Therapy

• Post-transplant consolidation with 4 cycles of VTD

• CR 15% 49%

• Molecular CR 3% 18%

• Tumor burden reduced 4.14 logs

Ladetto, M et al. J Clin Oncol. 28: 2077, 2010.

Lenalidomide Maintenance : CALGB 100104

McCarthy, P et al. N Engl J Med. 366:1770, 2012.

• TTP 46 mos. with len vs. 27 mos. for placebo

• 35 deaths on len arm vs. 53 on placebo arm

Early vs. Salvage Transplant

Fermand, JP et al. Blood 92: 3131, 1998.

Successful PBSC

collection(N = 185)

Early HDT1 Induction VAMP x 3-4 cycles

Preparatory lomustine, VP-16, cyclophosphamide, melphalan at 140

mg/m2 + TBIThen auto-PBSCT

(n = 91)

Late HDT1

Monthly VMCPFor patients ≥PR continue to plateau

Transplant as per above if progression, resistance after 6 cycles, or in relapse

(n = 94)

Untreated, symptomatic patients < 56

(N = 202)

Consort Chart

Fermand, JP et al. Blood 92: 3131, 1998.

Overall Survival

Fermand, JP et al. Blood 92: 3131, 1998.

• No difference in overall survival at median follow-up of 58 months

80%

78%

73%

71%

66%

61%

Quality of Life

Fermand, JP et al. Blood 92: 3131, 1998.

• Longer time without symptoms, treatment, and treatment toxicity (TwiSTT)– 27.8 months for early

HDT, vs. 22.3 months for salvage HDT

Data After Longer Follow-up

• Comparable OS (A; 47.8 vs. 47.6 mos.) and EFS (B; 25.3 vs. 18.7 mos.) with median follow-up of 120 months

Fermand, J-P et al. J Clin Oncol. 23: 9227, 2005.

Improved Quality of Life

• Maintained longer time without symptoms, treatment, and treatment toxicity (TwiSTT)

Fermand, J-P et al. J Clin Oncol. 23: 9227, 2005.

Early Harvest and Late Transplant

• Stem cells collected within 6 mos. of diagnosis

• Received VAD

• Transplant at progression– Median 38 mos.

Gertz, MA et al. Bone Marrow Transplant. 23: 221, 1999.

Concluded Late Transplant Feasible

• Median survival 58.5 months

Gertz, MA et al. Bone Marrow Transplant. 23: 221, 1999.

• “Underlying biology of the disease has a greater impact on survival than the timing of transplant”

E4A03 Study Design

REGISTRATION

Lenalidomide25 mg po days 1-21

+ High dose Dex40 mg days 1-4, 9-12, 17-20

x 4 cycles

CR/PR/Stable

Less thanPR

SCT possibleas early

as 4 months

Thal/dexx 4 cycles

Lenalidomide25 mg po days 1-21

+ Low dose Dex40 mg days 1, 8, 15, 22

x 4 cycles

445 patients

Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.

RD vs. Rd

Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.

• More is not necessarily better in the novel agent era

Stopped early; recommendation

of IDMC; median follow-up

of 12.5 months

96%

87%

87%

75%

With Longer Follow-up

Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.

Landmark Analysis

Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.

• 90 patients went off LD or Ld after 4 cycles for SCT• OS 92% at 3 years

• 248 patients continued on therapy past the initial 4 cycles• 79% 3-year overall survival

• PFS at 3 years 46% for RD vs. 50% for Rd

Off after 4No SCT

Off after 4+ SCT

Continued past4 cycles

2010 ASH Abstract 38

Outcome with Lenalidomide Plus Dexamethasone Followed by Early Autologous Stem Cell

Transplantation In the ECOG E4A03 Randomized Clinical Trial

David Samuel diCapua Siegel, Susanna Jacobus, S. Vincent Rajkumar, Rafat Abonour, Natalie Scott Callander, Michael S Katz, Rafael Fonseca, David H. Vesole,

and On behalf of the Eastern Cooperative Oncology Group

Landmark Analysis

431 patients alive at 4 cycles

Off therapy at 4 cycles

n=183

Primary therapy beyond 4 cycles

n=248

no transplantN=93

(median age 68)

Transplant n=90

(median age 57)

Ldn=140

(median age 66)

LDn=108

(median age 65)

Outcomes in Younger Patients (<65)

Progression Free Survival Overall Survival

Outcomes in Older Patients (≥70)

Progression Free Survival Overall Survival

Case Control Study

Kumar, SK et al. Cancer 118: 1585, 2012.

• 290 patients treated with an IMiD-based induction regimen prior to transplant• 123 got TD, 167 got LD

• Late transplant: occurred after 12 months• 42 had gotten SCT; median 44.5 mos.

• Early transplant: within 2 months of harvest, 12 months of diagnosis• Median 5.3 mos. to SCT

Outcomes

Kumar, SK et al. Cancer 118: 1585, 2012.

• Four year overall survival was identical in the two groups (73%)• TD 68% vs. 64%• LD 82% vs. 86%

• Time to progression after transplant similar

• 20 mos. (early) vs. 16 mos. (late)

IFM/DFCI 2009 Study

RVDx3

RVD x 2

RVD x 5

Lenalidomide 18 mos

Melphalan 200mg/m2 + ASCT

Induction

Consolidation

Maintenance

CY (3 g/m2) MOBILIZATION

Goal: 5 x 106 cells/kg

RVDx3

CY (3 g/m2) MOBILIZATION

Goal: 5 x 106 cells/kg

Randomize

Collection

Lenalidomide 18 mos SCT at relapse

Is Achieving CR the Key ?

• GEM2000 trial– 1,075 pts enrolled

– 632 response-assessable

• Uniform induction – VBMCP followed by

VBAD

Lahuerta, JJ et al. J Clin Oncol. 26: 5775, 2008.

Value of CR Post-transplant

• After induction, patients went on to single or tandem high dose chemotherapy with autologous stem cell rescue

Lahuerta, JJ et al. J Clin Oncol. 26: 5775, 2008.

Value of CR in IFM Studies

• IFM 99-02 and 99-04 trials– VAD, then

tandem ASCT

• Best post-ASCT data available for 802 pts

Harousseau, J-L et al. J Clin Oncol. 27: 5720, 2009.

Value of CR in Asia

• Korean Multiple Myeloma Working Party study of 197 chemosensitive patients who received a single SCT

• CR prior to transplant (upper panel) and after transplant (lower panel) predicted a better outcome

Kim, JS et al. Biol Blood Marrow Transplant. 15: 463, 2009.

Role of CR in Total Therapy 3

Barlogie, B et al. Br J Haematol. 138: 176, 2007.

Achieving and Maintaining CR

Barlogie, B et al. Cancer 113: 355, 2008.

• Sustaining CR within a 3-year landmark from treatment initiation was associated with a highly superior survival (P <0.0001)• Achieving and losing

CR worse than no CR

M. D. Anderson Data

• Retrospective analysis of 758 patients with newly-diagnosed myeloma

• Received dex-based induction -/+ high-dose therapy (+ in 395) within 1 year

• Groups were comparable in 2m, SCr, ISS stage

Wang, M et al. Bone Marrow Transpl. 45: 498, 2010.

SCT in CR

• High dose therapy did not improve outcomes for patients already in CR

Wang, M et al. Bone Marrow Transpl. 45: 498, 2010.

Other Considerations

• Access to novel agents– SCT may best achieve cytoreduction/CR if

novel agent access is limited

• Cost of chemotherapy vs. transplant– SCT is a cost-effective way to achieve rapid

cytoreduction vs. long-term novel drugs– Allows novel agents to be reserved for the time

of relapse, thereby saving healthcare resources

Conclusions

• Randomized trials are needed in the novel agent era comparing the effectiveness of early vs. delayed transplant

• Available (albeit limited) data do not suggest that patient outcomes are compromised by reserving transplant until first relapse

• Possibility remains that relapse after novel agent induction/consolidation/maintenance may be less sensitive to melphalan-based approaches