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, with second line being a major commercial opportunity (DREAMM-7 and -8 trials). Other key anti-BCMA agents include the CAR-T therapies Abecma, which was approved for fifth-line or later (5L+) MM in the US and 4L+ in the EU, and 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.
- 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 September 2022, December 2022, and April 2023 for elranatamab, REGN5458, and teclistamab, respectively. Talquetamab’s pivotal data are expected in August 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 and EU), Blenrep (US and EU), and a subcutaneous formulation of Darzalex (US and EU). 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. While Pepaxto’s OCEAN study was not an outright failure, it raised safety concerns for a subgroup of patients and led to Pepaxto being removed from the market in October 2021.
- 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 have led to label expansions for the respective drugs.
- Key upcoming catalysts include the expected US approval of ciltacabtagene autoleucel (February 2022).
- Key pivotal trial readouts still 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 9.0 years from Phase I to approval, compared to 9.7 years in the overall oncology space.
CONTENTS
8 OVERVIEW
8 Latest key takeaways
11 DISEASE BACKGROUND
11 Definition
11 Risk factors
11 Presentation
12 Symptoms
13 Diagnosis
14 Patient segmentation
15 Co-morbidities
16 Subtypes
18 TREATMENT
18 Smoldering multiple myeloma
18 Active multiple myeloma
18 Active multiple myeloma: first line, SCT eligible
19 Active multiple myeloma: first line, SCT ineligible
20 Active multiple myeloma: first-line disease
21 Active multiple myeloma: relapsed/refractory
22 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 Approval Delayed, But Janssen/Legend’s Cilta-Cel May Hit Market Just In Time
56 239 Days: Oncopeptides’ Myeloma Drug Pepaxto Comes Off Market Just Months After Accelerated Approval
56 Dr Reddy’s Eyes Generic Revlimid Exclusivity With ANDA Approval
57 Further Companies Confirm Canadian Revlimid Rivals
57 Revlimid Rivals Debut In Canada
57 Will Production Bottlenecks For BMS’s Abecma Pose Problems After EU Approval?
58 Pepaxto’s Accelerated Approval In Myeloma May Sink On OCEAN Trial’s Adverse Survival Data
58 EMA OKs BMS/bluebird bio’s CAR-T Abecma For Multiple Myeloma
58 Sun Settles On Revlimid As Natco Scoops First ANDA Approval
59 Breckenridge Eyes First Kyprolis Generic With FDA Approval
59 Ciltacabtagene Autoleucel And Melflufen Among Myriad New Filings In EU
59 Pfizer’s Elranatamab Among New Entrants On EMA’s PRIME
59 BMS/Bluebird Ready Abecma, First BCMA-Targeting CAR-T, For Initial Patients
60 EU Early Access For Melphalan Flufenamide
60 Early-Stage R&D In The Spotlight As BMS Patent Expirations Approach
60 EU Fast-Track Fail For Another BMS CAR-T Cell Therapy
61 EMA PRIME Wins For Bispecific Antibodies & Another Gene Therapy
61 Janssen Wins EU Fast-Track Status For CAR-T Therapy Cilta-Cel
61 Bumpy EU Review Ends Well For Selinexor Filing
62 Early FDA Approval For Karyopharm’s Xpovio
62 Krka, Accord And Xeris Pick Up European Nods
62 PharmaMar Victory Has EU Regulators Pondering Next Move
62 NICE OKs Sarclisa & Mayzent For Funding In England, But Rejects Vindaqel
63 Mylan Obtains CHMP Backing For Revlimid Generic In Two Indications
64 PROBABILITY OF SUCCESS
65 LICENSING AND ASSET ACQUISITION DEALS
65 Bluebird Spinoff 2seventy Bio Gets Its Own Wings
65 Sanofi Gets IP From MSKCC, Eureka Applicable In Multiple Myeloma Therapy
65 AbbVie Acquires TeneoOne And Lead Multiple Myeloma Candidate
65 Alliance For CAR-T Therapy
66 Wugen Aligns With Alpha Biopharma For Asia Markets
66 SELLAS Licenses Greater China Rights For Immunotherapies To 3D
67 CLINICAL TRIAL LANDSCAPE
68 Sponsors by status
69 Sponsors by phase
70 Recent events
73 DRUG ASSESSMENT MODEL
80 MARKET DYNAMICS
81 FUTURE TRENDS
81 Genericization of key brands Velcade, Revlimid, Pomalyst, and Kyprolis will substantially slow market growth
81 New BCMA-targeted therapies will contribute to growth in the multiple myeloma market over the forecast period
82 Label expansions of marketed drugs will help balance out downturn in the market
83 Drugs with a novel mechanism of action, such as Xpovio and Blenrep, will move into earlier lines of therapy, while
talquetamab will seek its first approval
84 CONSENSUS FORECASTS
88 RECENT EVENTS AND ANALYST OPINION
88 Pepaxto for Multiple Myeloma (October 22, 2021)
89 Multiple Drugs for Multiple Myeloma (October 7, 2021)
90 Pepaxto for Multiple Myeloma (September 11, 2021)
92 Pepaxto for Multiple Myeloma (July 8, 2021)
94 Darzalex for Multiple Myeloma (June 12, 2021)
95 Ciltacabtagene Autoleucel for Multiple Myeloma (June 1, 2021)
97 Pepaxto for Multiple Myeloma (May 25, 2021)
99 Darzalex for Multiple Myeloma (December 7, 2020)
100 bb21217 for Multiple Myeloma (December 5, 2020)
102 CT053 for Multiple Myeloma (December 5, 2020)
102 Ciltacabtagene Autoleucel for Multiple Myeloma (December 5, 2020)
104 MEDI2228 for Multiple Myeloma (December 5, 2020)
105 Multiple Drugs for Multiple Myeloma (December 5, 2020)
106 RG6160 for Multiple Myeloma (December 5, 2020)
107 Teclistamab for Multiple Myeloma (December 5, 2020)
108 Talquetamab for Multiple Myeloma (December 5, 2020)
110 UCARTCS1 for Multiple Myeloma (November 17, 2020)
110 Darzalex Faspro for Multiple Myeloma (July 31, 2020)
111 Blenrep for Multiple Myeloma (July 14, 2020)
112 Blenrep for Multiple Myeloma (July 10, 2020)
114 UCARTCS1 for Multiple Myeloma (July 6, 2020)
116 KEY UPCOMING EVENTS
117 KEY OPINION LEADER INSIGHTS
119 UNMET NEEDS
120 BIBLIOGRAPHY
122 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
73 Figure 13: Datamonitor Healthcare’s drug assessment summary for multiple myeloma
80 Figure 14: Market dynamics in multiple myeloma
81 Figure 15: Future trends in multiple myeloma
92 Figure 16: Pepaxto for Multiple Myeloma (September 11, 2021): Phase III – OCEAN
94 Figure 17: Pepaxto for Multiple Myeloma (July 8, 2021): Phase III – OCEAN
95 Figure 18: Darzalex for Multiple Myeloma (June 12, 2021): Phase III – MAIA (MMY3008)
97 Figure 19: Ciltacabtagene Autoleucel for Multiple Myeloma (June 1, 2021): Phase Ib/II – CARTITUDE-1 (Dose Finding)
99 Figure 20: Pepaxto for Multiple Myeloma (May 25, 2021): Phase III – OCEAN
104 Figure 21: Ciltacabtagene Autoleucel for Multiple Myeloma (December 5, 2020): Phase Ib/II – CARTITUDE-1 (Dose Finding)
116 Figure 22: Key upcoming events in multiple myeloma
LIST OF TABLES
12 Table 1: Diagnostic criteria for MGUS and smoldering multiple myeloma
13 Table 2: Symptoms of advanced multiple myeloma
15 Table 3: ISS criteria for multiple myeloma
15 Table 4: R-ISS criteria for multiple myeloma
16 Table 5: Common co-morbidities associated with multiple myeloma
17 Table 6: Common cytogenetic abnormalities associated with multiple myeloma
21 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
85 Table 15: Historical global sales, by drug ($m), 2016–20
87 Table 16: Forecasted global sales, by drug ($m), 2021–25
88 Table 17: Pepaxto for Multiple Myeloma (October 22, 2021)
89 Table 18: Multiple Drugs for Multiple Myeloma (October 7, 2021)
90 Table 19: Pepaxto for Multiple Myeloma (September 11, 2021)
93 Table 20: Pepaxto for Multiple Myeloma (July 8, 2021)
94 Table 21: Darzalex for Multiple Myeloma (June 12, 2021)
96 Table 22: Ciltacabtagene Autoleucel for Multiple Myeloma (June 1, 2021)
98 Table 23: Pepaxto for Multiple Myeloma (May 25, 2021)
100 Table 24: Darzalex for Multiple Myeloma (December 7, 2020)
101 Table 25: bb21217 for Multiple Myeloma (December 5, 2020)
102 Table 26: CT053 for Multiple Myeloma (December 5, 2020)
103 Table 27: Ciltacabtagene Autoleucel for Multiple Myeloma (December 5, 2020)
105 Table 28: MEDI2228 for Multiple Myeloma (December 5, 2020)
106 Table 29: Multiple Drugs for Multiple Myeloma (December 5, 2020)
107 Table 30: RG6160 for Multiple Myeloma (December 5, 2020)
108 Table 31: Teclistamab for Multiple Myeloma (December 5, 2020)
109 Table 32: Talquetamab for Multiple Myeloma (December 5, 2020)
110 Table 33: UCARTCS1 for Multiple Myeloma (November 17, 2020)
111 Table 34: Darzalex Faspro for Multiple Myeloma (July 31, 2020)
112 Table 35: Blenrep for Multiple Myeloma (July 14, 2020)
113 Table 36: Blenrep for Multiple Myeloma (July 10, 2020)
114 Table 37: UCARTCS1 for Multiple Myeloma (July 6, 2020)
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