Mayo Clinic College of MedicineMayo Clinic Comprehensive Cancer Center

Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida

Pomalidomide, Bortezomib and Dexamethasone (PVD) for Patients with Relapsed Lenalidomide Refractory

Multiple Myeloma (MM)MQ. Lacy, B. LaPlant., P. Richardson, A. Jakubowiak, K. Laumann, S. Kumar, M.A. Gertz, S.R. Hayman, F. Buadi, A. Dispenzieri, J.A. Lust, P. Kapoor, N. Leung, S.J.

Russell, D. Dingli, R. Go, Y. Lin, W. Gonsalves, R. Fonseca, P.L. Bergsagel, V. Roy, T. Sher, A. Chanan Khan, A.K. Stewart, C. Reeder, S.V. Rajkumar, J.R. Mikhael

Mayo Clinic; Dana Farber Cancer Center; University of Chicago

Background

• Pomalidomide and dexamethasone (Pom/dex) has been extensively studied and has response rates of 25-35% in patients with lenalidomide refractory myeloma

• The combination of IMiDs and proteasome inhibitors have potential for deeper and more durable responses

• The MM005 trial phase I study of twice weekly bortezomib with pomalidomide and dexamethasone and reported with promising results. ORR of 75% and 30% ≥ VGPR. (Richardson, ASH 2013)

• This trial was designed to evaluate the safety and efficacy of the combination of pomalidomide, once weekly bortezomib and dexamethasone – Pom-Bor-Dex or “PVD.” Results of the phase I portion were reported (Mikhael, ASH 2013)

Goals This study was activated on March 21, 2012. A total of 50 patients have been accrued (dose level (DL)1: 3, DL 2: 6, Phase II: 41). This summary will focus on patients treated at the MTD (DL2 and Phase II)

• Primary:• Phase II: To evaluate the confirmed response rate (PR,

VGPR, or CR) of pomalidomide, bortezomib and dexamethasone in patients with lenalidomide refractory relapsed myeloma

• Secondary:• Overall survival, progression-free survival, and

duration of response• To assess the toxicity of pomalidomide, bortezomib

and dexamethasone in this patient population

Eligibility

• Previously treated, relapsed MM

• 1-4 prior regimens.

• Resistant/refractory to lenalidomide. Refractory defined as progression on or within 60 days of stopping RX

• Prior bortezomib was allowed but patients could not have been refractory

• Measurable disease (one of the following) :• Serum M-spike 1.0 g/dL• 24-hour Urine M-spike >200 mg • Serum immunoglobulin FLC > 10 mg/dL with abnormal ratio• Measurable soft tissue plasmacytoma• > 30% plasma cells in bone marrow

• ANC 1000/μL and PLT 75,000/μL

• Creatinine 3 mg/dL

• ECOG PS 0, 1, or 2.

Treatment

Pomalidomide 4 mg daily days 1-21

Bortezomib 1.3 mg/m2 (IV or SC)

Dexamethasone 40 mg

Thromboprophylaxis was given to all patients as either aspirin or full dose anticoagulation

Responses assessed by IMWG criteria; Toxicity assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

28 day cycle

days 1, 8, 15, 22

After 8 cycles, dex and BTZ were stopped and pom continued until progression

N=47

Age, median (range) 66 (45-83)

Gender, male 49% 

Months from Diagnosis to On Study, median (range) 49 (15-142)

ECOG Performance Score 0/1/2 62% / 36% / 2%

Prior treatment disease status

Relapsed off treatment 18 (38%)

Relapsed on treatment 28 (60%)

Refractory (never responded) 1 (2%)

Refractory to immediate prior therapy, yes 13 (28%) 

Patient Characteristics

N=47Prior regimens

IMIDs Thalidomide 8 (18%) Lenalidomide 47 (100%) Bortezomib 27 (57%) Other proteosome inhibitors 17 (36%) Alkylators 25 (53%)Autologous SCT 32 (68%)

Number of prior regimens

1 28%

2 25%

3 28%

4 17%

5 2%

Median 2

Prior Regimens

Risk Factors  Total (N=47)Cytogenetics      Normal 60%    Abnormal 36%    Not Available 4%   

FISH   Normal  9% Abnormal 81%  Not done / Insufficient cells  10%

Fish Results   17p- 10 t(4;14) 5 t(14;16) 2 Del 13 8 Other 31   

mSMART Risk      High 11 (23%) Intermediate 8 (17%)    Standard 28 (60%)

High risk defined as deletion17p, t(4;14), or t(14;16) by FISH or deletion 13 by conventional cytogenetics or PCLI >3%

Follow Up  Total (N=47)

Progression Status      No Progression 22 (47%)    Progression 25 (53%)   

Follow-up Status      Alive 45 (96%)    Dead 2 (4%)   

Months of Follow-up (Alive Patients)      Median, range 12 (1.4-26)   

Last Cycle Received      Median, range 8.0 (1-22)   

Currently Receiving Treatment 20 (43%)   

Reason For Ending Treatment   Disease Progression 25 (93%) Other (MD discretion, stem cell transplant) 2 (7%)

Adverse Events

 At Least Possibly

RelatedN=47

   

Grade 3+ 39 (83%)

Grade 4+ 10 (21%)

Grade 5 0 (0%)

Heme Grade 3+ 34 (72%)

Heme Grade 4+ 9 (19%)

Non-heme grade 3+ 12 (26%)

Non-heme grade 4+ 1 (2%)

Hematologic Toxicity

Neutropenia

Thrombocytopenia

Anemia

0 5 10 15 20 25 30 35 40 45

Grade 3+ All grades

No. of Patients

89%

68%

81%

2%

70%

2%

Attributions of possible, probably or definite

Non Hematologic Toxicity

Fatigue

Diarrhea

Vomiting

Thromboembolic event

Insomnia

Constipation

Generalized muscle weakness

0 5 10 15 20 25 30 35

Grade 3+ All grades

No. of Patients

70%

45%

Attributions of possible, probably or definite

64%

Responses

Patient Outcomes   N=47Response Rate 85% No. of Responders 40 sCR 3 CR 6 VGPR 12 PR 19   

Overall Survival, median NA 

%Event Free at 6 mo 100% %Event Free at 12 mo 94%   

Progression Free Survival, median10.7 mo

(95%CI: 9.4-18.5)

 

Duration of Response, median13.7 mo

(95%CI: 8.5-16.8)

45% VGPR+

Responses in High Risk Patients

 High/Intermediate

Risk (N=19)Standard Risk (N=28)

Response Rate 16 (84%) 24 (86%)     

Overall Survival, median NA NA

%Event Free at 6 mo 100% 100% %Event Free at 9 mo 92% 95%     

Progression Free Survival, median  9.5 mo  16.3 mo

%Event Free at 6 mo 78% 85% %Event Free at 9 mo 57% 81% %Event Free at 12 mo 35% 60%

Overall and PFS

PFS by risk group

Conclusions

• PVD is a highly effective combination in patients refractory to lenalidomide with confirmed responses in 85%.

• Weekly administration of bortezomib and dex enhanced the tolerability and convenience of this regimen

• Toxicities are manageable, mostly consisting of mild cytopenias

• PVD is a highly attractive option in patients with relapsed and refractory MM

• Rochester• V. Rajkumar, MD • Francis Buadi, MD• David Dingli, MD• A Dispenzieri, MD• Morie Gertz, MD• Suzanne Hayman, MD• Shaji Kumar, MD• Robert Kyle, MD• Nelson Leung, MD• John Lust, MD• Steve Russell, MD• S Zeldenrust, MD• Prashant Kapoor, MD• Wilson Gonsalves, MD• Yi Lin, MD, PhD

• BioStats• Betsy LaPlant• Kristina Laumann

•Arizona•Joseph Mikhael, MD•Leif Bergsagel, MD•Rafael Fonseca, MD•Craig Reeder, MD•Keith Stewart, MD

•Florida•Vivek Roy, MD•Asher Chanan Khan, MD•Taimur Sher, MD•Sikander Ailawadhi, M.D.

•Dana Farber Cancer Center•Paul Richardson, MD

•University of Chicago• Andrzej Jakubowiak, MD