1. A Phase I/II Trial of Bendamustine and Pomalidomide with Dexamethasone (BPd) in Patients with Relapsed/Refractory Multiple Myeloma
Duke University
Cristina Gasparetto MD

2. PI Disclosures Cristina Gasparetto MD Research Funding: Celgene (Inst)
Consulting or Advisory Role: Celgene, Takeda Oncology, Janssen, Bristol-Myers Squibb
Presented by:

3. Learning Objectives
After reading and reviewing this material, the participant should be able to:
Evaluate the safety, efficacy, and maximum tolerated dose (MTD) of the combination of bendamustine and pomalidomide with dexamethasone (BPd) in patients with relapsed or refractory multiple myeloma (RRMM)
Assess overall response rate (ORR), toxicity profile, and progression free survival (PFS)
Presented by:

4. Background
Bendamustine: A bifunctional mechlorethamine derivative with alkylating properties1,2
Single agent activity in the relapsed/refractory setting is 30% in patients having received prior therapies that included steroids, alkylators, IMiDs, and proteasome inhibitors3
Pomalidomide: the third drug in the immunomodulatory agent (IMiD) class with anti-angiogenic, anti-proliferative, and immunomodulatory activity4,5
Single agent activity is percent6
Carfilzomib/Pom/Dex (n=32)7
ORR: 50%, CBR: 66%
In combination with dex
Maybe delete carf pom dex
Presented by:

5. Background (cont.)
Preclinical and clinical data support the hypothesized synergy between bendamustine and the IMiDs -thalidomide and lenalidomide- and the proteasome inhibitors, -bortezomib and carfilzomib- 8,9
We hypothesized that the combination of bendamustine and pomalidomide with dexamethasone (BPd) would be highly efficacious in patients with RRMM
Phase I data presented at ASH 2015 established the maximum tolerated dose (MTD) of bendamustine (120 mg/m2), pomalidomide (3mg), and dexamethasone (40mg) in heavily treated RRMM with a median of 5 lines of prior therapy10
Presented by:

6. Phase 1: Dosing Cohorts (3+3 design)
Dose Escalation
Bendamustine
Pomalidomide
Dexmethasone
Cohort -1
120 mg/m2
2 mg
40 mg**
Cohort 1
(Initial Dose Level)
3 mg
40 mg
Cohort 2
4 mg
Cohort 3
Cohort 4
Bendamustine was administered IV over 30 minutes; pomalidomide was administered orally; dexamethasone was administered either IV or orally.
*Dosing of dexamethasone may be adjusted at any point during the trial at the discretion of the PI
Presented by:

7. Phase 1: Maximum Tolerated Dose (MTD)
Cohort level 1 (bendamustine 120mg/m2, pomalidomide 3mg, dexamethasone 40mg)
1 of 6 patients experienced a dose-limiting toxicity (DLT) of grade 3 nausea, diarrhea, and mucositis.
Cohort level 2 (bendamustine 120mg/m2, pomalidomide 4mg, dexamethasone 40mg)
Initial 2 patients enrolled experienced DLTs consisting of grade 4 rash and grade 3 febrile neutropenia
The MTD was established as bendamustine 120mg/m2, pomalidomide 3mg, dexamethasone 40mg (Cohort 1)
Presented by:

8. Treatment Schema
Total target accrual (n = 56)
Patients with RRMM
Prior Len with ≤25% response/progression during Tx or ≤60 d after completion of regimen containing Len at full dose or MTD for ≥2 cycles
Pomalidomide naïve
Cycles 1-12: 28-day cycles
Cycles ≥13: Discontinue Bendamustine. Maintenance cycles with pomalidomide/ dexamethasone unchanged.
REDO THIS FIGURE
Presented by:

9. Phase II Study Objectives
Primary Objectives:
To evaluate the overall response rate (ORR) of BPd
Safety
Secondary Objectives:
Time to Progression (TTP)
Progression-free survival (PFS)
Overall Survival (OS)
Presented by:

10. Phase II: Study Design
Phase II portion: planned enrollment of up to 38 efficacy-evaluable patients in two stages.
The study was designed to detect an improvement in response rate from 20% to 40% with 81% power and a Type I error rate of .05
Simon’s optimal two-stage design:
First stage: 14 patients enrolled (4 / 14 responses needed)
Second stage: 24 additional patients accrued (12 / 38 responses needed)
The significance level of this design is and the power is 0.815
Look this up in the protocol
Presented by:

11. Treatment Schema (cont.)
Bendamustine given via IV infusion on day 1 of each cycle
Cycle 13+: Maintenance cycles initiated. Discontinue Bendamustine and continue with Pom/dex as per regular dosing
Concomitant medications included proton pump inhibitor and defined anticoagulation therapies
Primary endpoint: Overall response rate (ORR) and safety
Presented by:

12. Key Inclusion Criteria
Relapsed and/or refractory multiple myeloma w/ measurable disease
ECOG 0-2
Adequate hematologic, renal, liver, and cardiac function
All patients must have been refractory to prior full or maximally tolerated dose of lenalidomide, as well as be pomalidomide naïve
Additionally, they must have relapsed or have been refractory to their most recent therapy
Refractory defined as < 25% response or progression during therapy or within 60 days after completion of a regimen.
Presented by:

13. Patient Demographics Characteristic N = 38 Prior Stem Cell Transplant
Sex, n (%)
Male
Female
17 (45%)
21 (55%)
ECOG performance status, n (%) 1 2
7 (18%)
25 (66%)
6 (16%)
Prior Stem Cell Transplant
Prior Bortezomib
Prior Carfilzomib
Prior Lenalidomide
Lenalidomide Refractory
31 (82%)
38 (100%)
12 (32%)
Median age, years (range)
67 years ( )
Number of prior regimens, median (range)
5 (3 - 8)
Median time since initial diagnosis, years (range)
3.6 years (.75 – 9.86)
Presented by:

14. Baseline FISH/Cytogenetics
FISH/Cytogenetics, n (%)
N=38
Hypodiploid
1 (3%)
Hyperdiploid
12 (31%)
Del(13) by FISH
7 (18%)
Del(17p)
6 (15%)
t(4;14)
4 (10%)
t(11;14)
+1q
* According to mSMART risk classification: high risk, 17p-positive/t(14;16); intermediate risk, t(4;14)-positive/hypodiploid; standard risk, hyperdiploid/t(11;14); FISH/cytogenetic data missing for 1 patient
Presented by:

15. Treatment-Related Hematologic Adverse Events (N = 34)
Grade 1, n
Grade 2, n
Grade 3, n
Grade 4, n
All grades, n (%)
Anemia 6 11 10
27 (79%)
Thrombocytopenia 9 4
21 (62%)
Neutropenia 5
28 (82%)
Febrile Neutropenia 1
6 (18%)
Leukopenia 8 2
15 (44%)
Lymphopenia
10 (29%)
Presented by:

16. Major Treatment-Related Non-Hematologic Adverse Events (N=34)
Grade 1, n
Grade 2, n
Grade 3, n
Grade 4, n
All grades, n
Diarrhea 5 2
9 (27%)
Nausea 8 1
11 (32%)
Fatigue 12 3
20 (59%)
Dyspnea 9
15 (44%)
Rash
10 (29%)
Hypomagnesemia 10
Hypoalbuminemia
Pneumonia
7 (21%)
Hypokalemia 11
Hypocalcemia
14 (41%)
Hyponatremia 7
Fever
12 (35%)
Presented by:

17. Clinical Activity: Response Rates
Best overall response
N = 32 (efficacy evaluable patients)
ORR
23 (72%)
Stringent Complete Response (sCR)
3 (9%)
Very good partial response (VGPR)
Partial response (PR)
17 (50%)
Stable disease (SD)
7 (25%)
Progressive disease (PD)
2 (6%)
ORR
Overall Response Rate: 72%
median 5 lines of prior therapy
UNFINISHED SLIDE
Presented by:

18. Progression-Free Survival
Median PFS
9.6 months
95% CI
Median Cycles of Therapy
7.8
range (2-31)
Median Follow-up
12.0 months
Presented by:

19. Median Cycles of Therapy
Overall Survival
Median OS
21.3 months
95% CI
12.3 – N/A
Median Cycles of Therapy
7.8
range (2-31)
Median Follow-up
12.0 months
Presented by:

20. Responses by Cytogenetics/FISH
Response category,
n (%)
Hyperdiploid (n=12)
Del(13) (n=7)
Del(17p) (n=6)
t(11;14) (n=7)
ORR
6 (50%)
3 (43%)
4 (67%)
2 (29%)
sCR
1 (14%)
1 (17%)
VGPR
2 (17%) PR
4 (33%)
3 (50%) SD
2 (33%) PD
3 (25%)
Presented by:

21. Survival by Genetic Risk Status
No significant difference in PFS and OS between intermediate/high risk and standard risk groups (established at diagnosis) via cytogenetic and FISH analysis
Presented by:

22. Conclusions
The combination of Bendamustine, Pomalidomide, and Dexamethasone (BPd) is relatively tolerable and achieves a promising overall response rate in this heavily pretreated, lenalidomide-refractory patient population
Patients had prior bortezomib exposure and received a median of 5 prior lines of therapy
>VGPR
19%
ORR
72%
median PFS
9.6 months
median OS
21.3 months
Enrollment is complete in this phase I/II trial, however 7 patients are still receiving therapy on study
Presented by:

23. Acknowledgments Celgene Collaboration with pharmaceutical company
Patients/Caregivers/Families
Research Staff
Special thanks to
Beth Mancuso
Kelly Corbet
Stacy Murray
Presented by:

24. References
Rummel MJ, Gregory SA. Bendamustine’s emerging role in the management of lymphoid malignancies. Semin Hematol. 2011;48 Suppl 1:S24-S36. doi: /j.seminhematol
Leoni LM. The evolving role of bendamustine in lymphoid malignancy: understanding the drug and its mechanism of action--introduction. Semin Hematol. 2011;48 Suppl 1:S1-S3. doi: /j.seminhematol
Damaj G, Gressin R, Bouabdallah K, et al. Results from a prospective, open-label, phase II trial of bendamustine in refractory or relapsed T-cell lymphomas: the BENTLY trial. J Clin Oncol. 2013;31(1): doi: /JCO
Lacy MQ, McCurdy AR. Pomalidomide. Blood. 2013;122(14): doi: /blood
Richardson PG, Mark TM, Lacy MQ. Pomalidomide: new immunomodulatory agent with potent antiproliferative effects. Crit Rev Oncol Hematol. 2013;88 Suppl 1:S36-S44. doi: /j.critrevonc
Lacy MQ, Rajkumar SV. Pomalidomide: a new IMiD with remarkable activity in both multiple myeloma and myelofibrosis. Am J Hematol. 2010;85(2): doi: /ajh
Shah JJ, Stadtmauer EA, Abonour R, et al. Carfilzomib, pomalidomide, and dexamethasone (CPD) in patients with relapsed and/or refractory multiple myeloma. Blood. January 2015:blood doi: /blood
Ramasamy K, Hazel B, Mahmood S, Corderoy S, Schey S. Bendamustine in combination with thalidomide and dexamethasone is an effective therapy for myeloma patients with end stage renal disease. Br J Haematol. 2011;155(5): doi: /j x.
Pönisch W, Heyn S, Beck J, et al. Lenalidomide, bendamustine and prednisolone exhibits a favourable safety and efficacy profile in relapsed or refractory multiple myeloma: final results of a phase 1 clinical trial OSHO - #077. Br J Haematol. 2013;162(2): doi: /bjh
Gasparetto C, Green M, Srinivasan A, et al. A Phase I-II Study of the Combination of Bendamustine and Pomalidomide with Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma. Blood. 2015;126(23):
Presented by:

25. Thank You Duke University Medical Center
Should we add a comparison to Ben/Len/Dex and Carf/Pom/Dex?
Presented by: