This document summarizes research on small molecule drugs for multiple myeloma, including Carfilzomib, Bortezomib, and Pomalidomide. It discusses the incidence and market size of multiple myeloma, providing market evaluations and clinical trial summaries for each drug. Key points include: the global multiple myeloma drug market is expected to reach $6.2 billion by 2017 and grow at 9.2% annually; Carfilzomib, Bortezomib, and Pomalidomide are top drugs to treat multiple myeloma; and clinical trials are exploring these drugs' efficacy in combination with other treatments.

1. Research Report On
Small Molecules In Multiple Myeloma
Abdul Muheem
M.Pharm (Jamia Hamdard), PGDPRA, PGDIPR (NALSAR)
5 years of experience in IPR and secondary market research
Cell no:+91-9704227105; Email id: muheem.abdul985@gmail.com

2. – Introduction
– Incidence rates
– Drug market
– Top drugs
• Carfilzomib
– Market Research
– Products
– IP insights
– Clinical Trials
• Bortezomib
– Market Research
– Products
– IP insights
– Clinical Trials
• Pomalidomide
– Market Research
– Products
– IP insights
– Clinical Trials
Contents

3. Introduction
• Multiple myeloma (MM) is a plasma cell neoplasm with substantial morbidity and mortality.
• Worldwide in 2016 there were 138 509 incident cases of MM
with an age-standardized incidence rate (ASIR) of 2.1 cases per
100 000 persons (95% uncertainty interval [UI], 1.8-2.3).
• Incident cases from 1990 to 2017 increased by 132% globally
and by 106% to 192% for all sociodemographic index (SDI)
quintiles.
• Highest ASIR of MM is in Australasia, North America, and
Western Europe.
• Multiple myeloma caused 2.2 million disability-adjusted life-
year(DALYs)
globally in 2017.
• By 2016, Lenalidomide and Bortezomib was approved in 73
and 103 countries.
Incidence rates of multiple myeloma
Age-Standardized Incidence Rate of Multiple MyelomaAge-standardized incidence rate of multiple
myeloma, both sexes. ATG indicates Antigua and Barbuda; BRB, Barbados; COM, Comoros; DMA,
Dominica; FJI, Fiji; FSM, Federated States of Micronesia; GRD, Grenada; KIR, Kiribati; LCA, Saint Lucia;
MDV, Maldives; MHL, Marshall Islands; MLT, Malta; MUS, Mauritius; TLS, Timor-Leste; TON, Tonga;
TTO, Trinidad and Tobago; SGP, Singapore; SLB, Solomon Islands; SYC, Seychelles; VCT, Saint Vincent
and the Grenadines; VUT, Vanuatu; and WSM, Samo (Formerly Western Samoa). (Source)

4. Market Information: multiple myeloma
Lenalidomide and Bortezomib Approval, 2016ATG indicates Antigua and Barbuda; BRB, Barbados; COM, Comoros;
DMA, Dominica; FJI, Fiji; FSM, Federated States of Micronesia; GRD, Grenada; KIR, Kiribati; LCA, Saint Lucia; MDV,
Maldives; MHL, Marshall Islands; MLT, Malta; MUS, Mauritius; TLS, Timor-Leste; TON, Tonga; TTO, Trinidad and
Tobago; SGP, Singapore; SLB, Solomon Islands; SYC, Seychelles; VCT, Saint Vincent and the Grenadines; VUT,
Vanuatu; and WSM, Samo (Formerly Western Samoa).
• According to Thomson Reuters, the market for multiple myeloma
drugs in the US is expected to reach up to $6.2bn by 2017. In global
market, multiple myeloma to grow with a CAGR of 9.2% over the
forecast period of 2018-2024.
• Kyprolis is also expected to occupy a major part of the US market
share by obtaining about $570m.
• Furthermore FDA approved three novel multiple myeloma treatments
last year: Novartis’ Farydak (panobinostat), which was the first
histone deacetylases (HDAC) inhibitor, Johnson & Johnson’s Darzalex
(daratumumab), the first monoclonal antibody, and Bristol-Myers
Squibb’s immunotherapy treatment Empliciti (elotuzumab).
• Major companies in this space:
• Celgene Corporation
• Takeda Pharmaceuticals
• Amgen Inc
• Bristol-Myers Squibb
• Novartis
• Pfizer
• Johnson and Johnson

5. Multiple
Myeloma
Carfilzomib
Bortezomib
PomalidomideIxazomib
Lenalidomide

6. Small molecule
Target Site
Inhibitory
pathway/
Mechanism
Adverse
reactions
Recent
clinical trials
Carfilzomib
20S proteasome
Arrest cell cycle/
apoptosis tumor growth
Heart failure
Shortness of breath
Thrombocytopenia,
anemia, WBC disorder
ASPIRE trial---> comparing
carfilzomib, lenalidomide &
dexamethasone vs.
lenalidomide &
dexamethasone for relapsed
multiple myeloma
Bortezomib
26S proteasome
Degradation of
ubiquitylated proteins ---
-> triggering
programmed cell death
Peripheral neuropathy,
thrombocytopenia ,
acute interstitial
nephritis
Bortezomib has been
trialled for systemic
lupus erythematosus
(SLE)
Pomalidomide
IL-2, IL-6, IL-10
Upregulation of IL-2 & IL-
10 and down-regulation
of IL-6
Blood clots forming in
the legs or lung,
shortness of breath,
chest pain or arm or leg
swelling
Phase II: myelofibrosis.
Phase III: taking
pomalidomide &
dexamethasone vs.
dexamethasone shows
improved survival rate
Ixazomib
Proteasome subunit beta
type-5
Proteasome subunit beta
type-5 ----> Apoptosis/
programmed cell death
Diarrhoea and low
platelet count
Phase III: for the
treatment of AL
amyloidosis and
plasmacytoma of the
bones
Lenalidomide
Ubiquitin E3 ligase
cereblon
Gegrade the Ikaros
transcription factors
IKZF1 and IKZF3
Venous
thromboembolism,
Stevens-Johnson
syndrome
NA
Top drugs in multiple myeloma treatment
IP Ownership Amgen Takeda Celgene Takeda Celgene

7. Pomalidomide

8. Pomalidomide- Market Evaluation
Orange book_Approved drug product
• Combination of Pomalidoamide
(Pomalyst) and low dose
dexamethasone may be advantageous
for some patients with MM that has
worsened despite other treatments.
• Pomalidomide market is segmented, by
geographical region into North America,
China, Europe, Japan, Southeast Asia,
and India.
• Celegene marketed product (pomalyst) per unit price Unit Price for 1mg Capsule is $949.99.
• Celgene hiked the list prices of key cancer meds Pomalyst by 9% this month.
• The company has also raised prices on Pomalyst twice so far in 2017, amounting to a 17.7%
jump year to date. The multiple myeloma drug brought in $1.3 billion last year.
• Kyprolis (carfilzomib) from Onyx Pharmaceuticals was approved 7 months earlier. Both drugs
won orphan drug designation and both come with significant price tags. Celgene priced
Pomalyst at $10,500 monthly, slightly higher than the $9,950 per month charged for Kyprolis.
• Both drugs have also been selling well in a market that is slated to only get bigger, powered in
part by their approvals. The market has been forecast to grow 60% by 2021, reaching more than
$7 billion from about $4.4 billion.

9. Pomalidomide- IP Insights
IP ownership IP Protection
Orange book_Patents linked with approved drug products
• Celgene holds the ownership of the molecule patents, whereas top assignees such as Calithera Biosciences, Arvinas, Celularity and GSK have patents disclosing the
formulation patents in which, pomalidomide is used in combination with other drugs(Evorilimus, monoclonal antibodies etc.) for the multiple myeloma or other cancer
treatments.

10. Pomalidomide- Clinical Trials
NCT Number Sponsor/ Collaborators Conditions Interventions Age Phases
NCT02071888
Calithera Biosciences, Inc Non-Hodgkin's Lymphoma (NHL)|Multiple
Myeloma|Waldenstrom's Macroglobulinemia (WM)|Other B-cell
NHL Subtypes, Including WM|T-cell NHL
Drug: CB-839|Drug: CB-839 and low dose dexamethasone|Drug:
CB-839, pomalidomide, and low dose dexamethasone
18 Years and older
 (Adult, Older Adult)
Phase 1
NCT00833833
Celgene Multiple Myeloma Drug: Pomalidomide|Drug: Dexamethasone|Drug: Aspirin 18 Years and older
 (Adult, Older Adult)
Phase 1|Phase
2
NCT01464034
Criterium, Inc.|Amgen|Celgene
Corporation
Multiple Myeloma Drug: Carfilzomib|Drug: Pomalidomide|Drug: Dexamethasone 18 Years and older
 (Adult, Older Adult)
Phase 1|Phase
2
NCT03715478
Myeloma Canada Research
Network|GlaxoSmithKline
Relapsed and/or Refractory Multiple Myeloma Drug: GSK2857916 in combination with Pomalidomide and Dex 18 Years and older
 (Adult, Older Adult)
Phase 1|Phase
2
NCT03257631
Celgene Central Nervous System Neoplasms|Medulloblastoma Drug: Pomalidomide 1 Year to 21 Years
 (Child, Adult)
Phase 2
NCT02011113
Celgene Multiple Myeloma Drug: Pomalidomide|Drug: Dexamethasone 20 Years and older
 (Adult, Older Adult)
Phase 2
NCT01559129
Celgene Scleroderma, Systemic|Sclerosis, Systemic|Systemic
Scleroderma|Systemic Sclerosis
Drug: Pomalidomide (CC-4047)|Drug: Placebo 18 Years to 80 Years
 (Adult, Older Adult)
Phase 2
NCT00463385
Celgene Myelofibrosis With Myeloid Metaplasia|Myeloid
Metaplasia|Myelofibrosis
Drug: Pomalidomide|Drug: Prednisone|Drug: Placebo to
pomalidomide|Drug: Placebo to prednisone
18 Years and older
 (Adult, Older Adult)
Phase 2
NCT00072722
Celgene Prostate Cancer Drug: CC-4047 18 Years and older
 (Adult, Older Adult)
Phase 2
NCT03567616
AbbVie|Celgene Multiple Myeloma Drug: Venetoclax|Drug: Pomalidomide|Drug: Dexamethasone 18 Years and older
 (Adult, Older Adult)
Phase 2
NCT02718833
Massachusetts General
Hospital|Celgene|BMS|Multipl
e Myeloma Research
Consortium
Multiple Myeloma Drug: Elotuzumab|Drug: Pomalidomide|Drug: Bortezomib|Drug:
Dexamethasone
18 Years and older
 (Adult, Older Adult)
Phase 2
NCT03590652
Caitlin Costello,
MD|Celgene|Takeda|Janssen,
LP|University of California
Relapsed/Refractory Multiple Myeloma Drug: Ixazomib|Drug: Pomalidomide|Drug: Dexamethasone|Drug:
Daratumumab
18 Years and older
 (Adult, Older Adult)
Phase 2
NCT01311687
Celgene Multiple Myeloma Drug: pomalidomide|Drug: Dexamethasone 18 Years and older
 (Adult, Older Adult)
Phase 3
NCT01324947
Celgene Multiple Myeloma Drug: pomalidomide 18 Years and older
 (Adult, Older Adult)
Phase 3
• Clinical trial report shows that Celgene and Calithera Biosciences are exploring other uses of pomalidomide apart from multiple myeloma. Other studies are in clinical phase-1 and 2 for treating prostrate
cancer, CNS and lymphoma.
• Clinical studies are ongoing for the combination of pomalidoamide and low dose dexamethasone.
• Celgene, Calithera Biosciences, Amgen and Criterium are performing trial with these combinations which shows advantage for some patients with MM that has worsened despite other treatments.

11. Bortezomib

12. Bortezomib- Market Evaluation
Orange book_Approved drug product
• Bortezomib is marketed as Velcade by Takeda Oncology. The cost for bortezomib intravenous powder for
injection 3.5 mg is around $1,355 for a supply of 1 powder for injection
• Velcade will cede nearly $1 billion in U.S. sales by 2022 as generics take their toll. The analysts predict
the drug will fall to $187 million in 2022, down from an estimated $1.13 billion in U.S. sales for fiscal
2016, which ends March 31. Through Takeda's third quarter, the drug had brought in 83 billion yen, or
about $732 million.
• Forecasts show that Velcade will lose further market share to Kyprolis (carfilzomib; Amgen/Ono
Pharmaceutical), which drastically improved progression-free survival when compared head-to-head
with Velcade in second-line patients in the ENDEAVOR trial (ClinicalTrials.gov identifier: NCT01568866;
Dimopoulos et al., 2015). The ongoing ECOG trial (ClinicalTrials.gov identifier: NCT01863550) is
evaluating Kyprolis head-to-head with Velcade in the first-line setting.
• Takeda’s oral second-generation proteasome inhibitor Ninlaro (ixazomib) will capture considerable
market share from Velcade in the first-line, maintenance, and second-line settings following anticipated
label expansions.
Source
Products

13. Bortezomib - IP Insights
IP ownership IP Protection
• Millenium holds the ownership of the molecule patents, whereas top assignees such as GSK, Immuonmedics, Bayer and Merck have patents disclosing
the formulation patents in which, bortezomib is used in combination with other drugs(Ixazomib, Delanzomib, other monoclonal antibodies) for the
multiple myeloma or other cancer treatments.
Orange book patents linked with approved drug products

14. Bortezomib - Clinical Trials
NCT Number Patents Conditions Interventions Sponsor/Collaborators Age Phases
NCT00920556
US9207243B2;
US9988343B2;
US9126997B1;
US9034829B1
Multiple
Myeloma Drug: 5.0g SRT501|Drug: Bortezomib
Sirtris, a GSK
Company|GlaxoSmithKline
18 Years and
older  (Adult,
Older Adult) Phase 2
NCT03544281
US9597410B2;
US9579283B2;
US9226972B2;
US8227509B2
Multiple
Myeloma
Drug: GSK2857916|Drug: Lenalidomide|Drug:
Dexamethasone|Drug: Bortezomib|Drug: RP2D of
GSK2857916 GlaxoSmithKline|IQVIA
18 Years and
older  (Adult,
Older Adult) Phase 2
NCT01497626
US20110044938A1;
US20090246169A1;
US9988343B2
Advanced
Solid Tumors Drug: Lapatinib and bortezomib
Georgetown
University|GlaxoSmithKline|Mille
nnium Pharmaceuticals, Inc.
18 Years and
older  (Adult,
Older Adult) Phase 1
NCT00479167
US9579283B2;
US20090246169A1;
US20100266674A1;
US9226972B2
Follicular
Lymphoma Drug: Bortezomib and Tositumomab I-131
Rush University Medical
Center|GlaxoSmithKline|Millenni
um Pharmaceuticals, Inc.
18 Years and
older  (Adult,
Older Adult) Phase 2
NCT01536067
US8227509B2;
US9597410B2;
US9579283B2;
US9226972B2
Waldenstra,
Macroglobulin
emia
Biological: ofatumumab|Drug: bortezomib|Other:
laboratory biomarker analysis
Roswell Park Cancer
Institute|National Cancer
Institute (NCI)|GlaxoSmithKline
18 Years and
older  (Adult,
Older Adult) Phase 2
• Clinical trial report shows that Takeda (Millennium Pharmaceutical) is exploring other uses of Bozrtezomib apart from multiple myeloma. Other studies are in
clinical phase-1 and 2 for treating of Lymphoma and solid tumors.
• Clinical studies are ongoing for the combination of Lapatinib, tositumomab, oftatumumab and low dose dexamethasone.

15. Carfilzomib

16. Carfilzomib - Market Evaluation
Orange book_Approved drug product
• KYPROLIS is also approved in Argentina,
Australia, Bahrain, Canada, Hong Kong,
Israel, Japan, Kuwait, Lebanon, Macao,
Mexico, Thailand, Colombia, S. Korea,
Canada, Qatar, Switzerland, United Arab
Emirates, Turkey, Russia, Brazil, India,
Oman and the U.S. Additional regulatory
applications are underway for aaproval in
the health authorities worldwide.
• In global market, Carfilzomib is
segmented, by geographical region into
North America, China, Europe, Japan,
Southeast Asia, & India.
• In 2018, FDA approves KYPROLIS(carfilzomib) once-weekly 70 mg/m2 in combination with
Dexamethasone (Kd70) for patients with relapsed or refractory multiple myeloma.
• Amgen marketed Product (Kyprolis) is used in combination Captisol, which was originally
developed by CyDex Pharmaceuticals and acquired by Ligand in 2011. Onyx agreed to pay Ligand
a milestone payment of $600,000, and Ligand, in turn, will pay CyDex $3.5m for obtaining the
formulation.
• Kyprolis is also expected to occupy a major part of the US market share by obtaining about
$570m.
• Kyprolis (carfilzomib) from Onyx Pharmaceuticals was approved as an orphan drug status.

17. Carfilzomib - IP Insights
IP ownership IP Protection
Orange book patents linked with approved drug products
• Onyx Therapeutics Inc, a wholly owned subsidiary of Amgen Inc. Amgen Inc. holds the molecule patents for the Carfilzomib, whereas GSK is tops the study with maximum number of patents disclosing
the formulation patents in which, Carfilzomib is used in combination with other for the multiple myeloma or other cancer types.
• In 2015, Amgen announces the European Medicines Agency (EMA)acceptance of Kyprolis® (Carfilzomib) marketing authorization application for the treatment of relapsed multiple myeloma

18. Carfilzomib - Clinical Trials
NCT Number Patents Conditions Interventions Sponsor/Collaborators Age Phases
NCT01949532
EP3330260A1; EP3101026A1 Relapsed Multiple Myeloma|End-
stage Renal Disease
Drug: Carfilzomib Amgen 18 Years and older  (Adult,
Older Adult)
Phase 1
NCT01987232
US9511109B2 Extensive-Stage Small-Cell Lung
Cancer
Drug: Carfilzomib|Drug:
Carboplatin|Drug: Etoposide
Amgen 18 Years and older  (Adult,
Older Adult)
Phase 1|Phase 2
NCT01660750
EP2796134B1; US9511109B2 Multiple Myeloma Drug: Carfilzomib|Drug:
Cyclophosphamide|Drug:
Dexamethasone
Criterium, Inc.|Amgen 18 Years and older  (Adult,
Older Adult)
Phase 1
NCT01464034
US10034872B2;
BR112017003620A2;
EP3182996A1; US9511109B2
Multiple Myeloma Drug: Carfilzomib|Drug:
Pomalidomide|Drug:
Dexamethasone
Criterium, Inc.|Amgen|Celgene
Corporation
18 Years and older  (Adult,
Older Adult)
Phase 1|Phase 2
NCT02415413
EP2796134B1; US9511109B2 Smoldering Multiple Myeloma Drug: carfilzomib|Drug:
Lenalidomide|Drug:
Dexamethasone|Drug:
Melphalan
PETHEMA Foundation|Celgene
Corporation|Amgen
18 Years to 70 Years  (Adult,
Older Adult)
Phase 2
• Clinical trial report shows that Amgen is exploring other uses of carfilzomib apart from multiple myeloma. Other studies are in clinical phase-1 for treating renal
disease and small cell lung cancer.
• Clinical studies are ongoing for the combination of carfilzomib and low dose dexamethasone.

19. Thank Note
Thank you for your
patience. 