Single-agent Bortezomib in previously
untreated, symptomatic Multiple Myeloma
(MM): Results of a Phase 2 Multi-center Study
Paul G Richardson,1 Asher Chanan-Khan,2 Robert Schlossman,1 Nikhil
Munshi,1 Anne Louise Oaklander,3 L Thompson Heffner,4 Hani Hassoun,5
David Avigan,6 Anthony Amato,1 Kenneth C Anderson1
1Dana-Farber Cancer Institute, Boston, MA; 2Roswell Park Cancer
Institute, Buffalo, NY; 3Massachusetts General Hospital, Boston, MA;
4Emory University, Atlanta, GA; 5Memorial Sloan-Kettering Cancer Center,
New York, NY; 6Beth Israel Deaconess Medical Center, Boston, MA
Study Rationale
Bortezomib (BZ): active in relapsed, refractory MM13
In APEX, BZ monotherapy had greater efficacy in patients
(pts) who received 1 prior line of therapy, vs >1 prior line1
BZ-based combinations active in frontline MM412
Peripheral neuropathy (PN): may require dose modification
and/or discontinuation13,13
Evaluate baseline PN, as part of MM14,15
Assess incidence during BZ treatment, manage
appropriately
1. Richardson et al. N Engl J Med 2005;352:248798.
9. Orlowski et al. Haematologica 2005;90:151 (Abstract).
2. Richardson et al. N Engl J Med 2003;348:260917.
10. Wang et al. Blood 2005;106:Abstract 784.
3. Jagannath et al. Br J Haematol 2004;127:16572.
11. Badros et al. Blood 2005;106:Abstract 2747.
4. Mateos et al. Blood 2005;106:Abstract 786.
12. Barlogie et al. Blood 2005;106:Abstract 1154.
5. Jagannath et al. Br J Haematol 2005;129:77683.
13. San Miguel et al. Blood 2005;106:Abstract 366.
6. Jagannath et al. Blood 2005;106:Abstract 783.
14. Dispenzieri et al. Best Pract Res Clin Haematol 2005;
7. Harousseau et al. J Clin Oncol 2005;23:Abstract 6653.
18:67388.
8. Oakervee et al. Br J Haematol 2005;129:75562.
15. Ropper et al. N Engl J Med 1998;338:16017.
Objectives
Primary
Overall Response Rate (ORR; complete response [CR] +
partial response [PR], European Group for Blood and
Marrow Transplant [EBMT] criteria1) to BZ monotherapy
in newly diagnosed, symptomatic MM
Secondary
Time to progression
Safety
Incidence and severity of PN
Impact of dose modifications on PN
Effect of pharmacologic interventions on PN
1. Bladé et al. Br J Haematol 1998;102:111523.
Patient Eligibility
Inclusion criteria:
Previously untreated, measurable MM
Nonsecretory or oligosecretory MM if measurable
No previous chemotherapy
Karnofsky Performance Status 60%
Platelets 50 x 109/L (or 30 x 109/L if extensive bone
marrow infiltration)
Adequate liver function
Exclusion criteria:
POEMS syndrome
Secondary malignancy requiring active treatment
HIV positive or active hepatitis
Grade > 2 PN
Steroids > 10mg daily of prednisone or equivalent
Study Design
Open-label, phase 2 study at 6 centers (USA)
BZ 1.3 mg/m2 IV
Cycles 18
Long-term
follow-up
ologic
10-d rest
Neur evaluation
End of
Registration
D1
D4
D8
D11
treatment visit
Study Design
Tumor response assessed by EBMT criteria1 every 2
cycles (6 wks)
Pts achieving CR received additional 2 cycles
beyond confirmation of CR
Pts with progressive disease (PD) or unacceptable
toxicity discontinued treatment
Candidates for SCT could proceed to SCT at
investigator's discretion
Planned treatment duration: up to 8 cycles
Dexamethasone- free approach
1. Bladé et al. Br J Haematol 1998;102:111523.
Neurologic Assessments (All Sites):
Pts underwent neurologic examination by a
neurologist at screening, at the end of the study,
during therapy if screening results were abnormal,
or if clinically indicated (i.e. development of PN)
In addition, pts completed the Functional
Assessment of Cancer Therapy/Gynecologic
Oncology Group neurotoxicity (FACT/GOG-Ntx)
questionnaire on D 1 and 8 of each treatment cycle,
at end of study
Neurologic Assessments (DFCI):
Motor, sensory nerve conduction studies (NCS):
ˇ Sural NCS
ˇ Peroneal, posterior tibial motor NCS
ˇ Radial, ulnar sensory NCS + ulnar motor NCS
Quantitative sensory testing (QST) to assess small-fibers
Autonomic testing to assess small myelinated,
unmyelinated nerve fibers:
ˇ Quantitative sudomotor axon reflex testing (QSART)
ˇ Assessment of cardiovagal function by HR
variability to deep breathing, Valsalva maneuver
ˇ Assessment of sympathetic skin responses
ˇ QST to assess temperature, light touch,
vasodilation
Skin biopsies at screening, on development of PN, end of
treatment
Dose Modifications, Pharmacologic
Intervention for PN:
Bortezomib dose modifications for PN:
Severity of PN
Modification
G 1 without pain/loss of function
No action
G 1 with pain or G2
Reduce dose from 1.3 to 1.0
mg/m2
G 2 with pain or G3
Withhold until PN resolves,
reinitiate at 0.7 mg/m2 once wkly
G 4
Discontinue
Interventions for G 1 PN, neuropathic pain
Step 1: daily vitamins and/or nutritional supplements
Step 2: add gabapentin 300mg TID; titrate as tolerated up
to 1,200mg TID
Step 3: add nortryptiline 25mg qhs, increase up to 50mg
after 2 wks, then increase by 25mg monthly as tolerated
up to 100mg qhs; add duloxetine 2060mg QD
Results: Pt Demographics,
Baseline Characteristics (N=66)
Median age, yrs (range)
60 (3377)
Male, n (%)
45 (68)
Myeloma type, n (%)
IgG
28 (42)
IgG
8 (12)
IgA
7 (11)
Free light chain
2 (3)
Free light chain
2 (3)
light chain
1 (2)
Other/unknown
18 (27)
ISS myeloma stage, n (%)
I
21 (32)
II
14 (21)
III
31 (47)
Ig = immunoglobulin; ISS = International Staging System
Results: Pt Disposition
N (%)
Pts enrolled
66 (100)
Completed therapy (8 cycles)
30 (45)
Discontinued*
35 (52)
Evaluable for response
63 (95)
Evaluable for safety
65 (98)
Underwent neurophysiologic testing
34 (52)
*PD (9 pts), adverse events (8 pts, incl 2 for PN), CR (3 pts), other (14 pts)
One pt had screening visit only
Efficacy (N=63*)
Best Response to BZ treatment
n (%)
(EBMT)
CR
6 (10)
PR
19 (30)
ORR (CR + PR)
25 (40)
MR
14 (22)
CR + PR + MR
39 (62)
Stable disease (SD)
20 (32)
PD
4 (6)
*3 pts not evaluable
Time-to-event Analysis: DFCI
(n = 34)
32/34 (94%) responded (CR + PR + MR)
DOR (defined as time from best response to progression):
8.5 mos (range 1-19 mos)
14/32 responders progressed
18/34 (53%) progressed; 9 during treatment
Median TTP: 6 mos (range 1-24 mos)
Safety (n=54*)
Adverse Events (all grades)
n (%)
PN
38/65* (58)
Constipation
31 (57)
Nausea
26 (48)
Fatigue
23 (43)
Rash
18 (33)
Upper respiratory infection
9 (17)
Varicella zoster virus infection
3
(5)
*PN reported for all study centers: data collection for other adverse events
ongoing at one study center (RPCI)
All AE's were G 12 in severity except:
1 G3 event: PN
1 G4 event: fluid overload
1 G5 event: bacterial meningitis
PN: Grade, Dose Modifications and
Reversibility
PN reported in 38/65 (58%) pts:
24 G1
13 G2
1 G3
Dose reductions, discontinuations:
4 pts with G1 reduction from 1.3 to 1.0 mg/m2; 3 further
reduction to 0.7 mg/m2
9 pts with G2 reduction from 1.3 to 1.0 mg/m2; 2 further
reduction to 0.7 mg/m2
1 pt with grade 3 PN discontinued
Preliminary analysis shows PN improved or
resolved in 6/8 pts (75%) with dose reduction
PN: Characteristics from
Neurophysiologic Testing (N=34)
n/N*
(%)
Baseline:
Small-fiber PN at baseline
17/34 (50)
Large-fiber PN at baseline
3/34 (9)
Post-treatment:**
New small-fiber PN
9/28 (32)
Worsened small-fiber PN
7/17 (41)
New large-fiber PN
4/25 (16)
*34 pts @ DFCI; 1 pt had screening visit only; some pts declined
post-treatment neurologic analysis
Small-fiber PN based on QST, autonomic studies, or both
Large-fiber PN based on abnormal sural sensory nerve action potential
**Preliminary Analysis (n=28)
Conclusions:
Single-agent BZ is active in pts with newly
diagnosed MM:
10% CR
40% ORR (CR + PR)
22% MR
6% PD
Toxicities manageable:
No unexpected AE's; no DVT's reported
Safety profile similar to previous studies
Varicella zoster virus infection noted prior to
prophylaxis with acyclovir, other anti-viral
therapy
"Steroid-sparing" approach
Conclusions:
Treatment-emergent PN (58%) manageable:
- lower grades noted (only 1 G3)
- reversibility c/w other studies
Underlying small-fiber PN appears more
common in MM than previously appreciated:
Evidence of small-fiber PN observed >50% of
pts with neurophysiologic testing at baseline
Small-fiber PN may emerge or worsen during BZ
treatment
Future Directions
Combination Therapy
Risk-adapted Approach
Optimal Sequence of Treatments
Further Evaluation of PN,
Characterization, Effect of Interventions
Acknowledgments: Study Teams
Dana-Farber Cancer Institute
Roswell Park Cancer Institute
Massachusetts General Hospital
Emory University
Memorial Sloan-Kettering Cancer Center
Beth Israel Deaconess Medical Center
Millennium Pharmaceuticals, Inc.
The Patients and their Families