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Dr. Jesus San Miguel- Patient outcomes by prior therapies and depth of response: analysis of MM-003, a phase III study comparing pomalidomide + low-dose dexamethasone vs high-dose dexamethasone in relapsed/refractory MM

Prof. Jesus San Miguel, MD
Director of Clinical and Translational Medicine, Universidad de Navarra
Pamplona, Spain


Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation II

Monday, December 9, 2013: 4:45 PM, 393-394 (Ernest N. Morial Convention Center)

Jesús F. San Miguel, MD, PhD1, Katja Weisel, MD2*, Kevin W. Song, MD, FRCPC3, Michel Delforge, MD, PhD4, Lionel Karlin, MD5*, Hartmut Goldschmidt, MD6, Philippe Moreau, MD7*, Anne Banos, MD8*, Albert Oriol, MD9*, Laurent Garderet, MD10, Michele Cavo, MD11*, Valentina Ivanova, MD, PhD12*, Adrian Alegre, MD13, Joaquin Martinez-Lopez14*, Christine I. Chen, MD15, Christoph Renner, MD16*, Nizar J. Bahlis, MD17, Xin Yu, PhD18*, Terri Teasdale, MS18*, Lars Sternas, MD18*, Christian Jacques, MD18, Mohamed H. Zaki, MD, PhD18 and Meletios A. Dimopoulos, MD19

1Hematology, Hospital Universitario de Salamanca, Salamanca, Spain
2Hematology & Oncology, Department of Medicine, University Hospital Tübingen, Tübingen, Germany, Tübingen, Germany
3Vancouver General Hospital, Vancouver, BC, Canada
4Department of Hematology, University Hospital Leuven, Leuven, Belgium
5Centre Hospitalier Lyon Sud/Hospices Civils de Lyon, Pierre-Benite, France
6University Hospital Heidelberg and German Cancer Research Center, Heidelberg, Germany
7Hematology, University Hospital Hôtel-Dieu, Nantes, France
8Hematology, Centre Hospitalier de la Côte Basque, Bayonne, France
9Institut Catala d'Oncologia, HGTiP, Barcelona, Spain
10Hopital Saint Antoine, Paris, France
11Institute of Hematology and Medical Oncology, Bologna University School of Medicine, Bologna, Italy
12GUZ Moscow City Clinical Hospital S.P.Botkin, Moscow, Russia
13Hematology, Hospital Universitario de la Princesa, Madrid, Spain
14Hospital Universitario 12 de Octubre, Madrid, Spain
15Princess Margaret Hospital, Toronto, ON, Canada
16University Hospital Zurich, Zurich, Switzerland
17University of Calgary, Calgary, AB, Canada
18Celgene Corporation, Summit, NJ
19Alexandra Hospital, Athens, Greece


Background: Patient (pt) survival after becoming refractory/intolerant to novel agent treatment (Tx) is short (Kumar 2012). Depth of response has been shown to predict favorable outcomes (Harousseau, 2010). POM is a distinct oral IMiD® immunomodulatory agent with 3 primary activities: direct anti-myeloma activity, stromal cell-support inhibition, and immune modulation (Quach, 2010). POM has been approved by the US FDA for RRMM pts with ≥ 2 prior Tx, including lenalidomide (LEN) and bortezomib (BORT), and progressive disease (PD) on or within 60 days of completion of the last line of Tx. The randomized phase 3 trial MM-003 demonstrated significantly longer progression-free survival (PFS) and overall survival (OS) with an acceptable tolerability profile for POM + LoDEX vs HiDEX in pts with RRMM (San Miguel, EHA 2013).

Methods: Pts must have been refractory to last prior Tx (PD during Tx or within 60 days) and exhausted BORT and LEN after ≥ 2 consecutive cycles of each (alone or in combination). Pts were randomized 2:1 to receive 28-day cycles of POM 4 mg D1-21 + DEX 40 mg (20 mg for pts aged > 75 y) weekly or DEX 40 mg (20 mg for pts aged > 75 y) D1-4, 9-12, and 17-20. HiDEX was chosen as the comparator to isolate the effects of POM as at the time of trial design it was the standard salvage Tx for heavily pretreated pts. Tx continued until PD or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included OS, time to progression (TTP), overall response rate (ORR; ≥ partial response [PR]), and safety. The current analysis describes pt outcomes by prior Tx history and depth of response.

Results: 302 pts were randomized to POM + LoDEX and 153 pts to HiDEX. Pt characteristics were well balanced between Tx arms. The median number of prior Tx was 5 (range, 2-17). Most pts (75%) were refractory to both BORT and LEN. POM + LoDEX significantly prolonged PFS vs HiDEX regardless of type or number of prior Tx (Table). OS favored POM + LoDEX for all subgroups analyzed. Importantly, significant OS benefits were observed in pts with ≤ 3 prior Tx and in pts who were refractory to LEN as last prior Tx. The ORR was consistently and significantly higher for POM + LoDEX vs HiDEX. The TTP for POM + LoDEX pts was similar in this trial vs that seen with their last prior LEN-based line of Tx (4.8 vs 6.2 months; P =.11). Additionally, LEN as the last prior Tx did not negatively impact PFS, OS, or ORR when compared with the intent-to-treat (ITT) population. In the POM + LoDEX arm, a total of 17 pts (6%) achieved a very good partial response or better, and 78 pts (26%) achieved PR as best response. Baseline characteristics were generally similar regardless of the degree of M-protein reduction. Analyses of the correlation between M-protein reduction and PFS and OS are ongoing and will be presented at the meeting.

Conclusions: In this heavily pretreated population, POM + LoDEX provided consistent efficacy regardless of number of prior Tx or prior Tx type. Significant OS benefits were observed for pts who received POM + LoDEX earlier in Tx and immediately following the development of LEN-refractory disease. Importantly, LEN as last prior Tx did not impact response, PFS, or OS vs the overall ITT population. POM + LoDEX should be considered a standard Tx option in RRMM pts.





Patients, n (%)

PFS, mos (P value)

OS, mos (P value)

ORR,a % (P value)

All patients

302 (100) vs 153 (100)

4.0 vs 1.9 (< .001)

12.7 vs 8.1 (.03)

31 vs 10 (< .001)

≤ 3 prior Tx

69 (23) vs 33 (22)

3.7 vs 1.9 (.02)

11.1 vs 6.9 (.02)

26 vs 3 (.005)

> 3 prior Tx

233 (77) vs 120 (78)

4.4 vs 2.0 (< .001)

13.1 vs 8.7 (.19)

33 vs 12 (< .001)

Prior THAL

173 (57) vs 93 (61)

4.4 vs 2.0 (< .001)

12.3 vs 8.5 (.11)

30 vs 10 (< .001)

No prior THAL

129 (43) vs 60 (39)

3.9 vs 1.9 (< .001)

13.4 vs 8.0 (.13)

33 vs 10 (< .001)

LEN refractory

286 (95) vs 141 (92)

3.9 vs 1.9 (< .001)

12.7 vs 8.0 (.02)

30 vs 9 (< .001)

BORT refractory

238 (79) vs 121 (79)

3.9 vs 2.0 (< .001)

11.9 vs 7.7 (.07)

30 vs 12 (< .001)

LEN and BORT refractory

225 (75) vs 113 (74)

3.7 vs 2.0 (< .001)

11.1 vs 7.7 (.10)

28 vs 12 (< .001)

Refractory to LEN as last prior Tx

85 (28) vs 49 (32)

4.6 vs 1.9 (< .001)

12.3 vs 7.3 (.01)

33 vs 6 (< .001)

Refractory to BORT as last prior Tx

132 (44) vs 66 (43)

3.8 vs 1.9 (< .001)

13.1 vs 12.3 (.55)

34 vs 12 (.001)

a By IMWG criteria.
BORT, bortezomib; HiDEX, high-dose dexamethasone; LEN, lenalidomide; LoDEX, low-dose dexamethasone; ORR, overall response rate;
OS, overall survival; PFS, progression-free survival; POM, pomalidomide;  THAL, thalidomide; Tx, treatment.


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