Disease Analysis: Multiple Myeloma
Author: David Dahan
Publisher: Datamonitor Healthcare
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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 (ciltacabtagene autoleucel), 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, but while the OCEAN study met its PFS primary endpoint, Pepaxto’s advantage over Pomalyst was limited to about half of the patients extensively pretreated with the Pomalyst analog Revlimid.
- 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 and December 2022 for teclistamab and REGN5458, respectively. Elranatamab was expected to read out in June 2022, however, in May 2021, the FDA paused recruitment after three cases of peripheral neuropathy were reported in a Phase I study. 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 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 in 2022, with regulatory submissions in 2023.
- 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).
- Key pivotal trial readouts expected in 2021 include Phase III trials for subcutaneous Darzalex (CEPHEUS) and Sarclisa (IMROZ), and a Phase II readout for iberdomide.
- The overall likelihood of approval of a Phase I multiple myeloma asset is 6.0%, and the average probability a drug advances from Phase III is 53.8%. Multiple myeloma 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
54 KEY REGULATORY EVENTS
54 EMA OKs BMS/bluebird bio’s CAR-T Abecma For Multiple Myeloma
54 Sun Settles On Revlimid As Natco Scoops First ANDA Approval
54 Breckenridge Eyes First Kyprolis Generic With FDA Approval
54 Ciltacabtagene Autoleucel And Melflufen Among Myriad New Filings In EU
55 Pfizer’s Elranatamab Among New Entrants On EMA’s PRIME
55 BMS/Bluebird Ready Abecma, First BCMA-Targeting CAR-T, For Initial Patients
55 EU Early Access For Melphalan Flufenamide
56 Early-Stage R&D In The Spotlight As BMS Patent Expirations Approach
56 EU Fast-Track Fail For Another BMS CAR-T Cell Therapy
56 EMA PRIME Wins For Bispecific Antibodies & Another Gene Therapy
57 Janssen Wins EU Fast-Track Status For CAR-T Therapy Cilta-Cel
57 Bumpy EU Review Ends Well For Selinexor Filing
57 Early FDA Approval For Karyopharm’s Xpovio
58 Krka, Accord And Xeris Pick Up European Nods
58 PharmaMar Victory Has EU Regulators Pondering Next Move
58 NICE OKs Sarclisa & Mayzent For Funding In England, But Rejects Vindaqel
59 Mylan Obtains CHMP Backing For Revlimid Generic In Two Indications
59 Approval Of BMS/Bluebird’s Ide-Cel May Come Just In Time
59 Kyprolis+Darzalex Offers Relapsed Myeloma Patients An IMiD-Free Regimen
59 GSK To Address Multiple Myeloma With First-In-Class Blenrep In EU
60 GSK’s Blenrep Wins BCMA Race, Carries Ocular Toxicity Warning
60 EMA Says Yes To GSK’s Belantamab
60 GSK’s Myeloma Drug Gets AdComm Backing, But Limitations Remain Clear
60 Concerns About Eye Toxicity Could Limit GSK’s Myeloma Drug Potential
62 PROBABILITY OF SUCCESS
63 LICENSING AND ASSET ACQUISITION DEALS
63 Sanofi Gets IP From MSKCC, Eureka Applicable In Multiple Myeloma Therapy
63 AbbVie Acquires TeneoOne And Lead Multiple Myeloma Candidate
63 Alliance For CAR-T Therapy
63 Wugen Aligns With Alpha Biopharma For Asia Markets
64 SELLAS Licenses Greater China Rights For Immunotherapies To 3D
64 Kiadis And Sanofi Sign Natural Killer Cell Therapy Pact
65 CLINICAL TRIAL LANDSCAPE
66 Sponsors by status
67 Sponsors by phase
68 Recent events
71 DRUG ASSESSMENT MODEL
78 MARKET DYNAMICS
79 FUTURE TRENDS
79 Genericization of key brands Velcade, Revlimid, and Pomalyst will substantially slow market growth
79 New BCMA-targeted therapies will contribute to growth in the multiple myeloma market over the forecast period
80 Label expansions of marketed drugs will help balance out downturn in the market
81 Drugs with a novel mechanism of action, such as Xpovio, Pepaxto, and Blenrep, will move into earlier lines of therapy
82 CONSENSUS FORECASTS
86 RECENT EVENTS AND ANALYST OPINION
86 Pepaxto for Multiple Myeloma (July 8, 2021)
87 Darzalex for Multiple Myeloma (June 12, 2021)
89 Ciltacabtagene Autoleucel for Multiple Myeloma (June 1, 2021)
91 Pepaxto for Multiple Myeloma (May 25, 2021)
93 Darzalex for Multiple Myeloma (December 7, 2020)
94 bb21217 for Multiple Myeloma (December 5, 2020)
96 CT053 for Multiple Myeloma (December 5, 2020)
96 JNJ-4528 for Multiple Myeloma (December 5, 2020)
98 MEDI2228 for Multiple Myeloma (December 5, 2020)
99 Multiple Drugs for Multiple Myeloma (December 5, 2020)
100 RG6160 for Multiple Myeloma (December 5, 2020)
101 Teclistamab for Multiple Myeloma (December 5, 2020)
102 Talquetamab for Multiple Myeloma (December 5, 2020)
104 UCARTCS1 for Multiple Myeloma (November 17, 2020)
104 Darzalex Faspro for Multiple Myeloma (July 31, 2020)
105 Blenrep for Multiple Myeloma (July 14, 2020)
106 Blenrep for Multiple Myeloma (July 10, 2020)
108 UCARTCS1 for Multiple Myeloma (July 6, 2020)
109 Sarclisa for Multiple Myeloma (June 2, 2020)
110 CC-92480 for Multiple Myeloma (May 31, 2020)
112 Kyprolis for Multiple Myeloma (May 31, 2020)
113 Sarclisa for Multiple Myeloma (May 31, 2020)
115 Orvacabtagene Autoleucel for Multiple Myeloma (May 30, 2020)
117 Teclistamab for Multiple Myeloma (May 29, 2020)
119 Xpovio for Multiple Myeloma (May 28, 2020)
121 Blenrep for Multiple Myeloma (May 27, 2020)
123 Abecma for Multiple Myeloma (May 13, 2020)
124 Sarclisa for Multiple Myeloma (May 12, 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
62 Figure 6: Probability of success in the multiple myeloma pipeline
65 Figure 7: Clinical trials in multiple myeloma
65 Figure 8: Top 10 drugs for clinical trials in multiple myeloma
66 Figure 9: Top 10 companies for clinical trials in multiple myeloma
66 Figure 10: Trial locations in multiple myeloma
67 Figure 11: Multiple myeloma trials status
68 Figure 12: Multiple myeloma trials sponsors, by phase
71 Figure 13: Datamonitor Healthcare’s drug assessment summary for multiple myeloma
78 Figure 14: Market dynamics in multiple myeloma
79 Figure 15: Future trends in multiple myeloma
87 Figure 16: Pepaxto for Multiple Myeloma (July 8, 2021): Phase III – OCEAN
89 Figure 17: Darzalex for Multiple Myeloma (June 12, 2021): Phase III – MAIA (MMY3008)
91 Figure 18: Ciltacabtagene Autoleucel for Multiple Myeloma (June 1, 2021): Phase Ib/II – CARTITUDE-1 (Dose Finding)
93 Figure 19: Pepaxto for Multiple Myeloma (May 25, 2021): Phase III – OCEAN
98 Figure 20: JNJ-4528 for Multiple Myeloma (December 5, 2020): Phase Ib/II – CARTITUDE-1 (Dose Finding)
110 Figure 21: Sarclisa for Multiple Myeloma (June 2, 2020): Phase III – IKEMA (w/Carfilzomib+Dex)
113 Figure 22: Kyprolis for Multiple Myeloma (May 31, 2020): Phase III – ECOG Study –
w/Bortezomib/Lenalidomide/Dexamethasone (VRd)
115 Figure 23: Sarclisa for Multiple Myeloma (May 31, 2020): Phase II – GMMG-CONCEPT
117 Figure 24: Orvacabtagene Autoleucel for Multiple Myeloma (May 30, 2020): Phase I/II – EVOLVE
119 Figure 25: Teclistamab for Multiple Myeloma (May 29, 2020): Phase I – CR108206
121 Figure 26: Xpovio for Multiple Myeloma (May 28, 2020): Phase III – BOSTON
123 Figure 27: Blenrep for Multiple Myeloma (May 27, 2020): Phase II – DREAMM-6 (w/ Vd or Rd)
126 Figure 28: Sarclisa for Multiple Myeloma (May 12, 2020): Phase III – IKEMA (w/Carfilzomib+Dex)
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
83 Table 15: Historical global sales, by drug ($m), 2016–20
85 Table 16: Forecasted global sales, by drug ($m), 2021–25
86 Table 17: Pepaxto for Multiple Myeloma (July 8, 2021)
88 Table 18: Darzalex for Multiple Myeloma (June 12, 2021)
90 Table 19: Ciltacabtagene Autoleucel for Multiple Myeloma (June 1, 2021)
92 Table 20: Pepaxto for Multiple Myeloma (May 25, 2021)
94 Table 21: Darzalex for Multiple Myeloma (December 7, 2020)
95 Table 22: bb21217 for Multiple Myeloma (December 5, 2020)
96 Table 23: CT053 for Multiple Myeloma (December 5, 2020)
97 Table 24: JNJ-4528 for Multiple Myeloma (December 5, 2020)
99 Table 25: MEDI2228 for Multiple Myeloma (December 5, 2020)
100 Table 26: Multiple Drugs for Multiple Myeloma (December 5, 2020)
101 Table 27: RG6160 for Multiple Myeloma (December 5, 2020)
102 Table 28: Teclistamab for Multiple Myeloma (December 5, 2020)
103 Table 29: Talquetamab for Multiple Myeloma (December 5, 2020)
104 Table 30: UCARTCS1 for Multiple Myeloma (November 17, 2020)
105 Table 31: Darzalex Faspro for Multiple Myeloma (July 31, 2020)
106 Table 32: Blenrep for Multiple Myeloma (July 14, 2020)
107 Table 33: Blenrep for Multiple Myeloma (July 10, 2020)
108 Table 34: UCARTCS1 for Multiple Myeloma (July 6, 2020)
109 Table 35: Sarclisa for Multiple Myeloma (June 2, 2020)
111 Table 36: CC-92480 for Multiple Myeloma (May 31, 2020)
112 Table 37: Kyprolis for Multiple Myeloma (May 31, 2020)
114 Table 38: Sarclisa for Multiple Myeloma (May 31, 2020)
116 Table 39: Orvacabtagene Autoleucel for Multiple Myeloma (May 30, 2020)
118 Table 40: Teclistamab for Multiple Myeloma (May 29, 2020)
120 Table 41: Xpovio for Multiple Myeloma (May 28, 2020)
121 Table 42: Blenrep for Multiple Myeloma (May 27, 2020)
123 Table 43: Abecma for Multiple Myeloma (May 13, 2020)
125 Table 44: Sarclisa for Multiple Myeloma (May 12, 2020)
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