1. Maintenance therapies in Multiple Myeloma
Saurabh Chhabra, MD MS
Associate Professor of Medicine
Froedtert & the Medical College of Wisconsin

2. Definitions Transplant-Eligible Induction Maintenance Consolidation
Transplant-Ineligible
Continuous vs. fixed duration therapy

3. Staging Cytogenetics International Staging System
Stage I-III, based on
albumin
β2-microglobulin
Revised-International Staging System
ISS stage
lactate dehydrogenase
cytogenetics
High risk
Standard risk
Testing by:
Fluorescent In Situ Hybridization (FISH)
Karyotyping

4. Chronology of Approved Treatment for Multiple Myeloma
Monoclonal Antibodies
Autologous bone marrow transplantation
Daratumumab
High-dose therapy with autologous stem cell support
Proteasome inhibitors
Elotuzumab
VAD (Vincristine, Doxorubicin, Dexamethasone)
Bortezomib
Bisphosphonates
Carfilzomib
Oral Melphalan and Prednisone
Ixazomib
1962
1983
1984
1986
1996
1999
2003
2005
2012
2013
2015
2019
High dose Melphalan
Thalidomide
Lenalidomide
Pomalidomide
Immunomodulatory agents
Panabinostat
Selinexor
HDAC inhibitor
XPO inhibitor
Anderson KC. J Clin Oncol 2012 Feb 1;30(4):

5. Attributes of maintenance therapy for Multiple Myeloma
Effective (in preventing return of multiple myeloma)
Safe (for long-term use)
Convenient (e.g., oral >> intravenous)
Preserves quality of life

6. Drugs considered for maintenance therapy
Thalidomide (oral)
Lenalidomide (oral)
Bortezomib (injectable)
Carfilzomib (injectable)
Ixazomib (oral)
Daratumumab (injectable)
Elotuzumab (injectable) (with lenalidomide)
Immunomodulatory Drugs (IMiDs)
Proteasome Inhibitors (PIs)
Monoclonal Antibodies (MoAbs)

7. Lenalidomide as Maintenance Autologous Stem cell transplant
CALGB :
Lenalidomide as Maintenance
Placebo
Stage I-III,
<70 years
Therapy ≥2 cycles
≥Stable disease
Autologous Stem cell transplant
Response
Lenalidomide
10 mg/d
McCarthy PL, et al. N Engl J Med 2012 May 10;366(19):

8. Maintenance Len vs. placebo
Lenalidomide Maintenance until Progression Significantly Prolongs Survival
460 patients
Maintenance Len vs. placebo
Median TTP: 46 vs. 27 months
3-year OS: 88% vs. 80%
Holstein SA, et al. Lancet Haematol 2017;4: e431–42

9. Meta-analysis of 3 Phase III Lenalidomide Maintenance Trials
McCarthy PL. J Clin Oncol Oct 10;35(29):

10. Meta-analysis of 3 Phase III Lenalidomide Maintenance Trials
McCarthy PL. J Clin Oncol Oct 10;35(29):

11. HOVON-65/GMMG-HD4 Trial Newly Diagnosed MM, Transplant Eligible, N=824
MM Stage II or III, Age 18 to 65
Randomization
3 x VAD
3 x PAD
Mobilization and Leukapheresis
CAD
CAD
MEL AutoHCT
MEL AutoHCT
Thalidomide for 2 years
Bortezomib for 2 years
NDMM=Newly Diagnosed Multiple Myeloma
Sonneveld P. J Clin Oncol Aug 20;30(24):

12. Progression-Free Survival 5-year Overall Survival
HOVON-65/GMMG-HD4 Trial Newly Diagnosed MM, Transplant Eligible, N=824
Bortezomib
Thalidomide
Number of pts
413
414
Complete response
36%
24%
CR+near CR rate
49%
34%
Progression-Free Survival
35 months
28 months
5-year Overall Survival
61%
55%
Bortezomib
Thalidomide
Deletion 17p 26 12 69 17
t(4;14) 25 22 66 44
Median PFS (months)
OS at 36 months (%)
Sonneveld P. J Clin Oncol Aug 20;30(24):
Neben K et al Blood. 2012 Jan 26;119(4):940-8.

13. Bortezomib + Lenalidomide as Maintenance
Small study of 45 patients with high-risk cytogenetics
All received bortezomib weekly + lenalidomide days dexamethasone weekly in 4-weekly cycles for up to 3 years.
Progression-Free Survival was 32 months.
Overall Survival at 3 years was 93%.
Nooka AK et al. Leukemia (2014) 28, 690–693

14. Ixazomib Maintenance
Ixazomib 3-4 mg on Days 1, 8, and 15
(n = 395)
Maximum 24 months, progression, or toxicity
Newly-diagnosed myeloma after autologous transplant (N = 656)
Placebo on Days 1, 8, and 15
(n = 261)
Ixazomib
Placebo
Progression-Free survival
26.5 months
21.3 months
Upgrade in response
46%
32%
Ixazomib + Lenalidomide as maintenance in clinical trials: results awaited
Dimopoulos MA, et al. Lancet 2019; 393: 253–64

15. Daratumumab
Daratumumab is a human IgG1κ monoclonal antibody that binds to CD38+ MM cells, inducing CDC, ADCC, ADCP and apoptosis.
Tai & Anderson. Immunotherapy Sep 15

16. CASSIOPEIA: Daratumumab Maintenance
Induction 4 cycles
Consolidation 2 cycles
VTD + Dara
VTD + Dara
Dara R R
HDM
ASCT
VTD
VTD
Observation
Moreau P et al. Lancet 2019; 394: 29–38

17. MAIA
Phase III trial of daratumumab added to lenalidomide and dexamethasone in transplant-ineligible newly diagnosed MM
Daratumumab + Lenalidomide + Dex (n=368)
Transplant-ineligible newly diagnosed MM (n=737)
Until progression
Lenalidomide + Dex (n=369)
Outcome
Dara-Rd (n=368)
Rd (n=369)
30-months Progression-Free Survival
71%
56%
Overall Response Rate
Complete Response Rate
93%
47%
81%
24%
Facon T et al. ASH Abstract LBA-2.

18. Summary Maintenance is an integral part of myeloma treatment
Current recommendation is for all patients, regardless of stage, risk and response to receive maintenance.
Duration of maintenance – until progression or relapse of myeloma
Lenalidomide until progression is standard of care
High-risk patients: Bortezomib + lenalidomide
Role of MoAbs: results from trials are awaited