Post on 23-Jan-2018
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Relapsed and Refractory Multiple Myeloma:
Unmet Need
Multiple Myeloma 2
Multiple myeloma (MM) is a clonal plasma cell disorder that accounts for 1.5% of all cancers1,2
It is the second-most common hematological2 malignancy
Incidence in the US is estimated at 24,000 people annually2
11,000 deaths expected in 2014
1. Moreau P and Touzeau C. Am Soc Clin Oncol Educ Book. 2015;35:e504-11. doi: 10.14694/EdBook_AM.2015.35.e504. 2. Sugumar D et al. Pharmgenomics Pers Med. 2015; 8:23–33.
History of Multiple Myeloma Treatment
Adapted from: Durie BGM. Concise Review of the Disease and Treatment Options: Multiple Myeloma. International Myeloma Foundation. 2011/2012 edition.
1960s 1970s 1980s 1990s 2003 2006-‐ 2007
VBMCP: Vincristine, carmustine, melphalan, cyclophosphamide, prednisone. BMCP: Carmustine, melphalan, cyclophosphamide, prednisone. VAD: Vincristine, doxorubicin, dexamethasone.
2012 Ongoing clinical investigations with novel agents and combinations
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Clinical Use of Approved Drugs in MM 4
Drug Front Line Relapsed Relapsed and Refractory
Alkylating agents Melphalan Cyclophosphamide
✔ ✓ ✓
Anthracyclines Liposomal doxorubicin
✔
Nitrosoureas Carmustine
IMiDs Thalidomide Lenalidomide
✓ ✔ ✔ ✔
Proteasome inhibitor Bortezomib
✔ ✔ ✔
Adapted from: Durie BGM. Concise Review of the Disease and Treatment Options: Multiple Myeloma. International Myeloma Foundation. 2011/2012 edition.
The Proteasome: Key to Protein Regulation 5
Timed degradation/recycling of proteins is essential for viability
Proteins conjugated to multiple units of the polypeptide ubiquitin are degraded by the proteasome
Cancer cells are more dependent upon the proteasome due to their genetic instability and rapid proliferation
Accumulation of ubiquitinated proteins and/or mis-folded can proteins lead to apoptosis
Teicher BA and Tomaszewski JE. Biochem Pharmacol. 2015: doi: 10.1016/j.bcp.2015.04.008.
Proteasome Inhibitor: Bortezomib 6
SUMMIT Study Design: Single arm, Phase 2 N=202 patients; 193
analyzed for efficacy Relapsed myeloma,
refractory to last prior therapy
Primary endpoint: Response Rate
Statistical design: lower limit of 90% CI > 10% defined activity
Patient Characteristics
N=202
Median prior regimens, n
6
Stem cell transplant 64%
Bortezomib 0%
IMiD Lenalidomide Thalidomide
83% 0% 83%
Corticosteroids >99%
Alkylating agent Cyclophosphamide Melphalan
92% - -
Anthracycline 81%
Richardson PG et al. N Engl J Med. 2003;348(26):2609-17.
Bortezomib: Efficacy 7
Efficacy N = 193 ORR (≥ PR) 27% CBR (≥ MR) 35% Duration of response, median 15 months Overall survival, median 16 months
Richardson PG et al. N Engl J Med. 2003;348(26):2609-17.
ORR=overall response rate, CBR=clinical benefit response, DOR=duration of response
• The SUMMIT trial supported the accelerated approval of Bortezomib
• Clinical activity confirmed in the subsequent Phase 3 APEX trial
Current Therapies Have Serious Side Effects 8
Drug Class Limiting Toxicities Alkylating agents Myelosuppression Anthracyclines Cardiotoxicity, myelosuppression Nitrosoureas Pulmonary disease,
myelosuppression Corticosteroids Hypertension, hyperglycemia, mood
disorders IMiDs Thromboembolic events,
myelosuppression, peripheral neuropathy
Bortezomib Neuropathy, GI disorders, myelosuppression
Adapted from: Durie BGM. Concise Review of the Disease and Treatment Options: Multiple Myeloma. International Myeloma Foundation. 2011/2012 edition.
Limitations of Current Treatment Approaches 9
Response rate decreases with increasing lines of therapy
Retrospective cohort study by IMWG* (2007-10) 383 patients in 1st relapse identified ORR following each subsequent relapse
Relapse Line of Therapy
Patients Treated
Response Rate %
1st 2nd 383 58 2nd 3rd 207 45 3rd 4th 86 30 4th 5th 27 15
*Adapted from Durie B et al, J Clin Oncol 30, 2012 (suppl); Abstract 8095.
Unmet Need in MM Treatment 10
Frontline Relapsed
Treatment
Relapsed Refractory or Intolerant
Expected survival (months)
20-50 14-16 6-10
Sensitivity to therapy
Sensitive Less Sensitive/Resistant
Resistant
Treatment limitations/ comorbidities
Peripheral neuropathy (~15% at diagnosis)
>80% incidence of Peripheral neuropathy; Compromised marrow reserve; Cytopenia
Intolerant to or ineligible for available therapy
Elderly population are at risk for heart, lung, renal, liver dysfunction and diabetes2
1. Adapted from: Durie BGM. Concise Review of the Disease and Treatment Options: Multiple Myeloma. International Myeloma Foundation. 2011/2012 edition. 2. Jagannath S. Clin Lymphoma Myeloma. 2008;8 (Suppl 4):S149-S156.
Unmet Medical Need in Relapsed and Refractory MM 11
No standard of care and few options Trials of repeat single agent/combination novel
agents Transient and diminishing responses Short progression-free survival and overall survival
Urgent need for additional novel agents Clinically meaningful responses Durability of response Associated clinical benefit
Carfilzomib represents a promising next generation proteasome inhibitor in this clinical setting
Teicher BA and Tomaszewski JE. Biochem Pharmacol. 2015: doi: 10.1016/j.bcp.2015.04.008.
Carfilzomib (KYPROLIS™): A Novel Proteasome Inhibitor
Carfilzomib induces irreversible proteasome inhibition lasting ≥48 hours
In 2012, carfilzomib was approved for the treatment of patients with multiple myeloma Who have received at least
two prior therapies including bortezomib and an immunomodulatory agent
And have demonstrated disease progression on or within 60 days of completion of the last therapy
KYPROLIS [prescribing Information]. South San Francisco, CA: Onyx Pharmaceuticals Inc; 2013.
• Potent and prolonged inhibition • Irreversible and highly specific
Carfilzomib is a modified tetrapeptidyl epoxide proteosome inhibitor
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Carfilzomib Does Not Induce Neurodegeneration 13
Bortezomib induces significant neurite degeneration in vitro No neurodegeneration seen with carfilzomib
Does not inhibit serine protease critical to neuronal cell survival
Consistent with results from chronic dosing studies in animals
Arastu-Kapur S et al. Clin Cancer Res. 2011;17(9):2734-2743.
Key Inclusion Criteria • Received ≥ 2prior
therapies including Bortezomib and thalidomide and/or lenalidomide
• ≤25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy
Primary Endpointb
• Overall Response Rate (ORR)
Secondary Endpoint • Duration of
Response (DOR) • Safety
• All cycles=28 days • 6 doses per cycle • Administered on
consecutive days each week for 3 weeks followed by 12-day rest period
Cycle 2-12a
27 mg/m2
aUntil disease progression, unacceptable toxicity, or for a maximum of 12 cycles
Cycle 1 KYPROLIS 20 mg/m2
bAssessed by an Independent Review Committee using International Myeloma Working Group criteria. ORR = stringent complete response (sCR) + complete response (CR) + very good partial response (VGPR) + partial response (PR).
Siegel DS et al. Blood. 2012;120(14):2817-25.
Pivotal Phase 2 Study (003A1) of Single-agent Carfilzomib in Relapsed Multiple Myeloma
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Pivotal Phase 2 Study (003A1): Efficacy
0.4% N=1
4.9% N=13
17.7% N=47
0
5
10
15
20
CR VGPR PR Perc
enta
ge o
f Pat
ient
s (%
)
• ORR=22.9% (95% CI: 18.0, 28.5) • DOR=7.8 months (95% CI: 5.6, 9.2)
ORR=22.9% (N=61)
Patients with high unmet medical need
Actively progressing, multiply relapsed, and refractory myeloma
Objective, durable, and clinically meaningful benefit ORR by IRC and investigator
highly concordant CBR 35.7%, median DOCBR
of 8.3 months Consistent benefit in clinically
important subgroups Benefit replicated in
supportive Phase 2 myeloma trials
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Siegel DS et al. Blood. 2012;120(14):2817-25.
Pivotal Phase 2 Study (003A1): Safety
Patients with comorbidities can be safely treated with carfilzomib
Low discontinuation rate Serious cardiac event and
mortality rates comparable to literature
Carfilzomib can be used for long-term treatment, even in patients with peripheral neuropathy
No cumulative toxicity
Deaths due to all causes (7%)
Serious Adverse Reactions (ARs) (45%) • Pneumonia (10%) • Acute renal failure (4%) • Pyrexia (3%) • Congestive heart failure (3%)
ARs leading to discontinuation (15%)
• Congestive heart failure (2%) • Cardiac arrest, dyspnea, increased blood
creatinine, and acute renal failure (1% each)
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Siegel DS et al. Blood. 2012;120(14):2817-25.
Challenges for Relapsed and Refractory Patients with Multiple Myeloma
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Reuse of agents but with lower ORR and shorter duration
Combination regimens needed to achieve efficacy but are poorly tolerated
Supportive, palliative care and hospice