Disease Analysis: Multiple Myeloma
Author: David Dahan
Publisher: Datamonitor Healthcare
- Description
- Contents
- Enquire
Disease Analysis
Multiple myeloma is characterized by the infiltration of malignant, antibody-producing plasma cells in the bone marrow. Almost all cases occur in individuals aged over 40 years, and age at diagnosis has an impact on patient outcome, especially in terms of the treatment options available. Most patients will receive at least three lines of treatment, and eligible patients will receive stem cell transplantation.
Latest key takeaways
- Datamonitor Healthcare estimates that in 2018, there were 134,100 incident cases of multiple myeloma (MM) in adults aged 40 years and older worldwide, and expects that number to increase to 153,700 incident cases by 2027.
- Revlimid, an immunomodulatory drug (IMiD), and Velcade, a proteasome inhibitor (PI), play key roles as the backbone for combination regimens across various lines of therapy. These drugs have broad approvals in all markets, and the expected expiry of their patents in 2022 will exert substantial downward pressure on the MM market.
- The launch of BCMA-targeted therapies will play a pivotal part in future market dynamics over the next decade. The antibody-drug conjugate (ADC) Blenrep is approved for triple-class exposed patients that have been treated with at least four prior therapies including a PI, an IMiD, and an anti-CD38 monoclonal antibody (MAb). Blenrep is also being evaluated in Phase III trials for earlier lines of therapy. Other key anti-BCMA agents include the CAR-T therapies Abecma, which was approved for fifth-line or later (5L+) MM, and JNJ-4528, which is under regulatory review for triple-refractory MM. Given the unmet need for effective therapies for heavily pretreated patients, uptake is expected to be rapid.
- Darzalex, the first MAb approved for MM, has experienced steady uptake and has become a new standard of care based on impressive trial results in the relapsed/refractory MM (RRMM) setting. The drug, a CD38-targeted MAb, will experience continual commercial success due to several label expansions in the newly diagnosed MM and RRMM settings, as well as the recent approval of a more convenient subcutaneous formulation.
- Sarclisa, another CD38-directed MAb, is expected to face intense in-class competition from Darzalex. The combination of Sarclisa, Pomalyst, and dexamethasone (dex) was approved by the FDA for 3L+ patients in March 2020. EMA approval followed shortly after in June 2020. In March and April 2021, Sarclisa combined with Kyprolis and dex was approved by the FDA and EMA, respectively, as a treatment for 2L+ patients. Sarclisa is currently being evaluated in Phase III trials in the front-line setting. Sarclisa will compete with Darzalex in these markets, though its second-to-market status will be difficult to overcome.
- Bristol Myers Squibb, which also markets Revlimid, has positioned Pomalyst as a subsequent therapy option. Pomalyst, another IMiD, adds a treatment option to Bristol Myers Squibb’s MM portfolio. Generic versions of Pomalyst received final approval from the FDA in October 2020, but patent litigation continues and it is not yet clear when these generics will launch. Pomalyst has regulatory exclusivity until 2023 in the EU and until 2025 in Japan.
- Second-generation PI Kyprolis is approved for the treatment of RRMM as a monotherapy and in combination with either dex, Darzalex and dex, or Revlimid and dex. Kyprolis remains the favored PI in the RRMM setting as it demonstrated improved safety and efficacy over Velcade, another PI, in the Phase III ENDEAVOR trial. However, unlike Velcade, Kyprolis does not offer a subcutaneous formulation. In the front-line setting, a Kyprolis regimen (Kyprolis, Revlimid and dex; KRd) failed to show superiority to a Velcade regimen (VRd). Nevertheless, the KRd regimen will likely continue to see some off-label use in the front-line setting due to KRd and VRd having different toxicity profiles.
- In combination with Revlimid and dex, Ninlaro, the first oral PI approved by the FDA, is part of an all-oral regimen approved for the treatment of 2L+ patients. Ninlaro has seen consistent sales in the MM market due to its convenient administration, a competitive price, and the combination’s relatively favorable safety profile.
- Empliciti, the only SLAMF7-targeted MAb approved for MM, has seen moderate uptake since the combination of Empliciti, Revlimid, and dex (ERd) was approved for the treatment of MM patients who have received one to three prior lines of therapy. A label expansion in combination with Pomalyst and dex for the treatment of 3L+ patients expanded options for the use of Empliciti in the treatment of RRMM, but did not significantly improve the drug’s commercial potential in this crowded treatment space.
- The XPO1 inhibitor Xpovio was the first novel mechanism approved for MM since the approval of the anti-SLAMF7 antibody Empliciti. Xpovio in combination with dex received accelerated approval in the US (2019) and EU (March 2021) for the treatment of patients with RRMM who have received at least four prior therapies and whose disease is refractory to PIs, IMiDs, and an anti-CD38 MAb. In December 2020 Xpovio was approved by the FDA as part of a triple combination with Velcade and dex in the second- to fourth-line settings. A European regulatory filing was submitted in April 2021 and approval is expected in late 2021 or early 2022. This label expansion should help to increase Xpovio’s commercial potential, but it will still face significant competition from established brands.
- Pepaxto is a novel dipeptide prodrug of the alkylating agent melphalan. Pepaxto in combination with dex is approved in the US for triple-refractory MM patients who have received at least four prior therapies. In this setting, Pepaxto will compete with Xpovio combined with dex and with Blenrep monotherapy. Pepaxto may be preferred for patients with extramedullary disease as they comprised 41% of patients in the registrational trial (compared to 22% for Xpovio and 20% for Blenrep). Pepaxto is also being developed for earlier lines of therapy, which will increase its commercial potential.
- There are four bispecific antibodies being evaluated in pivotal Phase II trials for fourth-line or later multiple myeloma: Pfizer’s elranatamab, Regeneron’s REGN5458, and Johnson & Johnson’s teclistamab and talquetamab. Three of the bispecifics target BCMA x CD3, while talquetamab is specific for CD3 and the novel target GPRC5D. Pivotal data are expected in January 2022 for teclistamab, while elranatamab and REGN5458 are expected to read out in June 2022 and December 2022, respectively. Talquetamab’s pivotal data are expected in September 2023.
- Iberdomide is a next-generation IMiD being developed by Bristol Myers Squibb, and binds the E3 ligase cereblon with higher affinity than Revlimid and Pomalyst. A pivotal Phase II cohort is evaluating iberdomide combined with dex in triple-refractory 4L+ patients, and data are expected in H2 2021.
- Venclexta is positioned to be approved for a limited subset of RRMM patients. The FDA placed a clinical hold on all Venclexta trials in MM after the Phase III BELLINI study showed a higher mortality rate in the Venclexta, Velcade, and dex arm compared to patients in the Velcade/dex arm. However, the FDA lifted the partial clinical hold exclusively for the Phase III CANOVA study of Venclexta in combination with dex for RRMM patients positive for the translocation (11;14) abnormality. Topline results from the trial are expected during 2021.
- Key recent events include the approvals of Abecma (US), Blenrep (US and EU), a subcutaneous formulation of Darzalex (US and EU), and Pepaxto (US). There were two Phase III failures: Ninlaro in the induction setting (TOURMALINE-MM2), and Kyprolis in an ECOG study comparing Kyprolis or Velcade combined with Revlimid and dex (KRd vs VRd) in front-line MM.
- Other key recent events include two Phase III successes for second-line or later MM: Sarclisa’s success in IKEMA in combination with Kyprolis and dex, and Xpovio’s success in BOSTON in combination with Velcade and dex. Both of these successes have led to label expansions for their respective drugs.
- Key upcoming catalysts for 2021 include the expected EU approval of Abecma and the US approval of JNJ-4528 (November 2021). Subcutaneous Darzalex combined with Pomalyst and dex is expecting a supplementary approval for second-line or later MM in the US (September 2021) and EU (H2 2021).
- Key pivotal trial readouts expected in 2021 include Phase III trials for Venclexta (CANOVA), subcutaneous Darzalex (CEPHEUS), Sarclisa (IMROZ) and Pepaxto (OCEAN), and a Phase II readout for iberdomide.
- The overall likelihood of approval of a Phase I MM asset is 6.6%, and the average probability a drug advances from Phase III is 56%. MM drugs, on average, take 9.1 years from Phase I to approval, compared to 9.6 years in the overall oncology space.
CONTENTS
9 OVERVIEW
9 Latest key takeaways
12 DISEASE BACKGROUND
12 Definition
12 Risk factors
12 Presentation
13 Symptoms
14 Diagnosis
15 Patient segmentation
16 Co-morbidities
17 Subtypes
19 TREATMENT
19 Smoldering multiple myeloma
19 Active multiple myeloma
19 Active multiple myeloma: first line, SCT eligible
20 Active multiple myeloma: first line, SCT ineligible
21 Active multiple myeloma: first-line disease
22 Active multiple myeloma: relapsed/refractory
23 Active multiple myeloma: progressive or relapsed disease
24 Approvals for key multiple myeloma regimens
27 EPIDEMIOLOGY
27 Incidence methodology
31 MARKETED DRUGS
36 PIPELINE DRUGS
56 KEY REGULATORY EVENTS
56 Pfizer’s Elranatamab Among New Entrants On EMA’s PRIME
56 BMS/Bluebird Ready Abecma, First BCMA-Targeting CAR-T, For Initial Patients
56 EU Early Access For Melphalan Flufenamide
56 Early-Stage R&D In The Spotlight As BMS Patent Expirations Approach
57 EU Fast-Track Fail For Another BMS CAR-T Cell Therapy
57 EMA PRIME Wins For Bispecific Antibodies & Another Gene Therapy
57 Janssen Wins EU Fast-Track Status For CAR-T Therapy Cilta-Cel
58 Bumpy EU Review Ends Well For Selinexor Filing
58 Early FDA Approval For Karyopharm’s Xpovio
58 Krka, Accord And Xeris Pick Up European Nods
59 PharmaMar Victory Has EU Regulators Pondering Next Move
59 NICE OKs Sarclisa & Mayzent For Funding In England, But Rejects Vindaqel
59 Mylan Obtains CHMP Backing For Revlimid Generic In Two Indications
60 Approval Of BMS/Bluebird’s Ide-Cel May Come Just In Time
60 Kyprolis+Darzalex Offers Relapsed Myeloma Patients An IMiD-Free Regimen
60 GSK To Address Multiple Myeloma With First-In-Class Blenrep In EU
60 GSK’s Blenrep Wins BCMA Race, Carries Ocular Toxicity Warning
61 EMA Says Yes To GSK’s Belantamab
61 GSK’s Myeloma Drug Gets AdComm Backing, But Limitations Remain Clear
61 Concerns About Eye Toxicity Could Limit GSK’s Myeloma Drug Potential
61 Sanofi Is ‘Working On’ Resolving England’s Sarclisa Funding Concerns
62 New EU Approvals
62 Manufacturing Issues Ground bluebird/Bristol ‘Ide-Cel’ CAR-T
62 Approval For New Darzalex Dosing
62 Xpovio Avoided Complete Response Letter Through Late-Cycle Submission Of BOSTON Data
64 PROBABILITY OF SUCCESS
65 LICENSING AND ASSET ACQUISITION DEALS
65 Wugen Aligns With Alpha Biopharma For Asia Markets
65 SELLAS Licenses Greater China Rights For Immunotherapies To 3D
65 Kiadis And Sanofi Sign Natural Killer Cell Therapy Pact
65 Bluebird Revises Business Priorities And Secures Upfront Cash From Bristol
67 CLINICAL TRIAL LANDSCAPE
68 Sponsors by status
69 Sponsors by phase
70 Recent events
74 DRUG ASSESSMENT MODEL
81 MARKET DYNAMICS
82 FUTURE TRENDS
82 Genericization of key brands Velcade, Revlimid, and Pomalyst will substantially slow market growth
82 New BCMA-targeted therapies will contribute to growth in the multiple myeloma market over the forecast period
83 Label expansions of marketed drugs will help balance out downturn in the market
84 Drugs with a novel mechanism of action, such as Xpovio, Pepaxto, and Blenrep, will move into earlier lines of therapy
85 CONSENSUS FORECASTS
88 RECENT EVENTS AND ANALYST OPINION
88 Darzalex for Multiple Myeloma (December 7, 2020)
89 bb21217 for Multiple Myeloma (December 5, 2020)
90 CT053 for Multiple Myeloma (December 5, 2020)
91 JNJ-4528 for Multiple Myeloma (December 5, 2020)
92 MEDI2228 for Multiple Myeloma (December 5, 2020)
93 Multiple Drugs for Multiple Myeloma (December 5, 2020)
94 RG6160 for Multiple Myeloma (December 5, 2020)
95 Teclistamab for Multiple Myeloma (December 5, 2020)
96 Talquetamab for Multiple Myeloma (December 5, 2020)
98 UCARTCS1 for Multiple Myeloma (November 17, 2020)
98 Darzalex Faspro for Multiple Myeloma (July 31, 2020)
99 Blenrep for Multiple Myeloma (July 14, 2020)
100 Blenrep for Multiple Myeloma (July 10, 2020)
102 UCARTCS1 for Multiple Myeloma (July 6, 2020)
103 Sarclisa for Multiple Myeloma (June 2, 2020)
104 CC-92480 for Multiple Myeloma (May 31, 2020)
106 Kyprolis for Multiple Myeloma (May 31, 2020)
107 Sarclisa for Multiple Myeloma (May 31, 2020)
109 Orvacabtagene Autoleucel for Multiple Myeloma (May 30, 2020)
111 Teclistamab for Multiple Myeloma (May 29, 2020)
113 Xpovio for Multiple Myeloma (May 28, 2020)
115 Blenrep for Multiple Myeloma (May 27, 2020)
117 Abecma for Multiple Myeloma (May 13, 2020)
118 Sarclisa for Multiple Myeloma (May 12, 2020)
120 Pepaxto for Multiple Myeloma (March 26, 2020)
121 Ninlaro for Multiple Myeloma (March 10, 2020)
123 Empliciti for Multiple Myeloma (March 9, 2020)
124 Xpovio for Multiple Myeloma (March 2, 2020)
127 KEY UPCOMING EVENTS
128 KEY OPINION LEADER INSIGHTS
130 UNMET NEEDS
131 BIBLIOGRAPHY
133 APPENDIX
LIST OF FIGURES
29 Figure 1: Trends in incident cases of multiple myeloma, 2018–27
36 Figure 2: Overview of pipeline drugs for multiple myeloma in the US
36 Figure 3: Pipeline drugs for multiple myeloma, by company
37 Figure 4: Pipeline drugs for multiple myeloma, by drug type
37 Figure 5: Pipeline drugs for multiple myeloma, by classification
64 Figure 6: Probability of success in the multiple myeloma pipeline
67 Figure 7: Clinical trials in multiple myeloma
67 Figure 8: Top 10 drugs for clinical trials in multiple myeloma
68 Figure 9: Top 10 companies for clinical trials in multiple myeloma
68 Figure 10: Trial locations in multiple myeloma
69 Figure 11: Multiple myeloma trials status
70 Figure 12: Multiple myeloma trials sponsors, by phase
74 Figure 13: Datamonitor Healthcare’s drug assessment summary for multiple myeloma
81 Figure 14: Market dynamics in multiple myeloma
82 Figure 15: Future trends in multiple myeloma
92 Figure 16: JNJ-4528 for Multiple Myeloma (December 5, 2020): Phase Ib/II – CARTITUDE-1 (Dose Finding)
104 Figure 17: Sarclisa for Multiple Myeloma (June 2, 2020): Phase III – IKEMA (w/Carfilzomib+Dex)
107 Figure 18: Kyprolis for Multiple Myeloma (May 31, 2020): Phase III – ECOG Study – w/Bortezomib/Lenalidomide/Dexamethasone (VRd)
109 Figure 19: Sarclisa for Multiple Myeloma (May 31, 2020): Phase II – GMMG-CONCEPT
111 Figure 20: Orvacabtagene Autoleucel for Multiple Myeloma (May 30, 2020): Phase I/II – EVOLVE
113 Figure 21: Teclistamab for Multiple Myeloma (May 29, 2020): Phase I – CR108206
115 Figure 22: Xpovio for Multiple Myeloma (May 28, 2020): Phase III – BOSTON
117 Figure 23: Blenrep for Multiple Myeloma (May 27, 2020): Phase II – DREAMM-6 (w/ Vd or Rd)
120 Figure 24: Sarclisa for Multiple Myeloma (May 12, 2020): Phase III – IKEMA (w/Carfilzomib+Dex)
121 Figure 25: Pepaxto for Multiple Myeloma (March 26, 2020): Phase II – HORIZON
123 Figure 26: Ninlaro for Multiple Myeloma (March 10, 2020): Phase III – TOURMALINE-MM2 (w/Len/Dex (First Line))
124 Figure 27: Empliciti for Multiple Myeloma (March 9, 2020): Phase III – ELOQUENT-1
126 Figure 28: Xpovio for Multiple Myeloma (March 2, 2020): Phase III – BOSTON
127 Figure 29: Key upcoming events in multiple myeloma
LIST OF TABLES
13 Table 1: Diagnostic criteria for MGUS and smoldering multiple myeloma
14 Table 2: Symptoms of advanced multiple myeloma
16 Table 3: ISS criteria for multiple myeloma
16 Table 4: R-ISS criteria for multiple myeloma
17 Table 5: Common co-morbidities associated with multiple myeloma
18 Table 6: Common cytogenetic abnormalities associated with multiple myeloma
22 Table 7: Recommended front-line pharmacological therapies for multiple myeloma
23 Table 8: NCCN recommended treatment regimens for previously treated multiple myeloma
24 Table 9: ESMO recommended treatment regimens for previously treated multiple myeloma
25 Table 10: Approvals for key multiple myeloma regimens, by country
28 Table 11: Incident cases of multiple myeloma, 2018–27
30 Table 12: Incident cases of multiple myeloma, by gender, 2018
32 Table 13: Marketed drugs for multiple myeloma
38 Table 14: Pipeline drugs for multiple myeloma in the US
86 Table 15: Historical global sales, by drug ($m), 2016–20
87 Table 16: Forecasted global sales, by drug ($m), 2021–25
88 Table 17: Darzalex for Multiple Myeloma (December 7, 2020)
89 Table 18: bb21217 for Multiple Myeloma (December 5, 2020)
90 Table 19: CT053 for Multiple Myeloma (December 5, 2020)
91 Table 20: JNJ-4528 for Multiple Myeloma (December 5, 2020)
93 Table 21: MEDI2228 for Multiple Myeloma (December 5, 2020)
94 Table 22: Multiple Drugs for Multiple Myeloma (December 5, 2020)
95 Table 23: RG6160 for Multiple Myeloma (December 5, 2020)
96 Table 24: Teclistamab for Multiple Myeloma (December 5, 2020)
97 Table 25: Talquetamab for Multiple Myeloma (December 5, 2020)
98 Table 26: UCARTCS1 for Multiple Myeloma (November 17, 2020)
99 Table 27: Darzalex Faspro for Multiple Myeloma (July 31, 2020)
100 Table 28: Blenrep for Multiple Myeloma (July 14, 2020)
101 Table 29: Blenrep for Multiple Myeloma (July 10, 2020)
102 Table 30: UCARTCS1 for Multiple Myeloma (July 6, 2020)
103 Table 31: Sarclisa for Multiple Myeloma (June 2, 2020)
105 Table 32: CC-92480 for Multiple Myeloma (May 31, 2020)
106 Table 33: Kyprolis for Multiple Myeloma (May 31, 2020)
108 Table 34: Sarclisa for Multiple Myeloma (May 31, 2020)
110 Table 35: Orvacabtagene Autoleucel for Multiple Myeloma (May 30, 2020)
112 Table 36: Teclistamab for Multiple Myeloma (May 29, 2020)
114 Table 37: Xpovio for Multiple Myeloma (May 28, 2020)
115 Table 38: Blenrep for Multiple Myeloma (May 27, 2020)
117 Table 39: Abecma for Multiple Myeloma (May 13, 2020)
119 Table 40: Sarclisa for Multiple Myeloma (May 12, 2020)
120 Table 41: Pepaxto for Multiple Myeloma (March 26, 2020)
122 Table 42: Ninlaro for Multiple Myeloma (March 10, 2020)
123 Table 43: Empliciti for Multiple Myeloma (March 9, 2020)
125 Table 44: Xpovio for Multiple Myeloma (March 2, 2020)
© Informa UK Ltd. This document is a licensed product and is not to be reproduced or redistributed
Do you have a subscription to Datamonitor Healthcare, Biomedtracker or Meddevicetracker? You may already have access to these reports, contact your account manager or email pharma@informabi.com for further help or assistance.
Market Spotlight: Gastrointestinal Stromal Tumor (GIST) 
Sign up to the