Debate: Is transplant a necessity or a choice? Focus on the necessity for CR and MRD. Answer: NO

Transcription

1 Debate: Is transplant a necessity or a choice? Focus on the necessity for CR and MRD. Answer: NO Tomer M. Mark Department of Medicine, Division of Hematology / Oncology Weill-Cornell Medical College / New York Presbyterian Hospital, New York, NY, USA 1

2 Disclosures Research Funding: Celgene Inc.; Amgen. Speakers Bureau: Celgene; Takeda; Amgen. Membership on an entity's advisory committees: Celgene Corp., Millenium Inc. Off-label usage of bortezomib, lenalidomide, and carfilzomib are discussed. 2

3 Is Transplant a Necessity of a Choice: Focus on CR and MRD. Answer: NO 3

4 Breaking the question down: Should we transplant patients who achieve CR or MRD negative status? No Must we use transplant as a means to get people into CR or MRD negative status? No 4

5 Treatment Paradigm for MM Induction Transplant eligible? Comorbidities? Lifestyle / Social Factors? How long to treat? Transplant Delayed vs upfront? One or two? Maintenance Necessary? Which agent(s)?

6 M Protein (g/l) Natural History of MM: 100 Asymptomatic Active Myeloma Symptomatic 50 Relapse 20 MGUS or Smoldering Myeloma Plateau Remission Refractory Relapse Therapy Therapy Therapy ~11,000 Annual deaths in U.S. 2

7 Tumor Volume Pathway to cure one hypothesis Ineffective treatment Dexamethasone Alkylators High-Dose Therapy Limit of detection Goal of newer therapy options Time Ultimate goal: Cure

8 Should we transplant patients who achieve CR or MRD negativity? 8

9 Not for debate: People in CR do better People with MRD- status do better 9

10 Survival Distribution Function (%) Survival Distribution Function (%) Deeper Responses are Better: Impact of CR + VGPR on Outcome IFM90 IFM99 Double ASCT % (n = 51) 50% (n = 81) < 50% (n = 46) p =.0007 PR: 290 CR + VGPR: 440 EFS p = 7 x ,000 1,2501,500 1,750 2,000 2,250 p = 7 x 10-5 EFS = event-free survival. Moreau et al, 2008; Attal et al, 1996, PR: 290 CR + VGPR: ,000 1,2501,500 1,750 2,000 2,250 OS

11 Importance of MRD status Paiva, B. et al. J Clin Oncol; 29:

12 Survival Benefit for MRD status*: Andy C. Rawstron et al. Blood 2015;125:

13 Why is stem cell transplant still recommended for patients in CR? Stem cell transplant has a OS benefit Caveat: data is old; very few patients achieved CR (5-10%). Fewer treatment options available Stem cell transplant deepens treatment response Does a remission deeper than CR matter for transplant? 13

14 Do you need a transplant if you achieve CR with induction therapy? Chemo-alone ASCT within 1 yr Wang et al., 2010, Bone Marrow Transplant, 45, Retrospective look at 758 consecutive patients at MDACC undergoing induction followed by ASCT within 1 year of dx. Landmark analysis based on response at 2 years after start of tx. Patients who upgraded their response with ASCT obtained a OS benefit. Patients at CR prior to ASCT did not achieve a longer OS. 14

15 Impact of Response To Induction Therapy Lahuerta, J. J. et al. J Clin Oncol 26:

16 Significance of Depth of Response Lahuerta, J. J. et al. J Clin Oncol 26:

17 Do we need transplant to get people in CR or MRD-? It is now possible to achieve CR and MRDwith chemo alone in an increasing fraction of people. Proven to be possible with BiRd, KRD, and certainly will become more the norm 17

18 Maximum Response to BiRD (n = 72, 69 evaluable) Median time on treatment: 368 days (29-944) Niesvizky et al. Blood. 2008;111:

19 Sustained Responses to BiRD over Time PR% VGPR% CR% SCR%

20 PCR Analysis Pt. #15 Pt. #40 Pt. #43 Pt. #59 pre post pre post pre post pre post Primary clone lost on 5/7 testing patients in CR on BiRD

21 MRD with carfilzomib induction combination Jakubowiak: 20/22 patients in ncr/cr were MRD negative Patients with scr and MRD negative: 3 yr OS 100%, PFS 89% Jakubowiak et al. Blood. 2012;120(9),

22 MRD with carfilzomib induction combination Korde: 29/30 pts in ncr/cr were MRD negative Overall 18-month PFS: 91% Korde N. et al. JAMA Oncol. 2015;1(6),

23 Do you need ASCT if you continue GOOD induction instead? (i.e. BIRD) P=0.64 Adriana Rossi et al. Blood 2013;121:

24 The Ideal Study: Observe? ASCT Maintain? MRD- Observe No ASCT Maintain CR? Best Induction Tx MRD+ ASCT Observe Maintain Everyone else Off study No ASCT Observe Maintain 24

25 Conclusions CR and MRD- is the goal for all patients. Increasingly more patients can reach MRD- status without the use of ASCT. Achievement of CR prior to transplant gives an equal outcome to CR post-transplant Transplant studies with MRD detection may strengthen / disprove this conclusion Continuing induction chemo may be all some people need Transplant will still be needed to get some people into CR / MRD- *(for now). 25

26 Thank you CR 26