Disease Analysis: Multiple Myeloma

Disease Analysis

Multiple myeloma (MM) is a hematological malignancy characterized by the infiltration of malignant, antibody-producing plasma cells in the bone marrow. The disease represents approximately 1% of all cancers, and 10% of hematological cancers. The hallmarks of MM are high levels of monoclonal (M-) protein, high levels of clonal plasma cells in the bone marrow, and organ damage. Plasma cells normally produce antibodies in response to infection or allergens, but in MM a plasma cell clone starts to proliferate and produce excessive amounts of one type of abnormal antibody, referred to as M-protein or paraprotein. In addition to high levels of M-protein, most patients with active MM have some form of organ damage caused by the proliferation of plasma cells and the high levels of protein in the blood and urine. Typical signs of organ damage include hypercalcemia, renal insufficiency, anemia, and bone lesions.

Latest key takeaways

• Datamonitor Healthcare estimates that in 2021, there were 140,300 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 launch of generics in 2022 will exert substantial downward pressure on the MM market.
• The launches 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 who 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 CAR-T therapies Abecma and Carvykti, which are approved for fifth-line or later MM in the US and at fourth-line or later in the EU. Given the unmet need for effective therapies for heavily pretreated patients, uptake is expected to be rapid.
• Teclistamab, a bispecific antibody targeting BCMA and CD3, is under regulatory review for heavily pretreated MM, with an approval expected by August 2022. Two other BCMA-targeted bispecific antibodies, Pfizer’s elranatamab and Regeneron’s REGN5458, are expecting Phase II pivotal trial data in September 2022 and December 2022, respectively. Both teclistamab and elranatamab are currently in Phase III trials in combination with Darzalex. These trials are enrolling second-line or later patients and have estimated primary completion dates in 2024.
• 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 approval of a more convenient subcutaneous (SC) 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 third-line or later patients in March 2020, and EMA approval followed shortly after in June 2020. In March 2021 and April 2021, Sarclisa combined with Kyprolis and dex was approved by the FDA and EMA, respectively, as a treatment for second-line or later patients. Sarclisa is currently being evaluated in Phase III trials in the front-line setting and will compete with Darzalex, 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, was originally approved for the third-line or later setting, but in 2019 it received a label expansion in the EU and Japan to the second-line setting. In the US, approval for the second-line or later setting in combination with SC Darzalex and dex is noted in the FDA label for SC Darzalex. Pomalyst has regulatory exclusivity until June 2025 in the US, May 2024 in the EU, and June 2026 in Japan. Following a settlement with Dr. Reddy’s Laboratories, the first US pomalidomide generics are expected to launch in Q1 2026.
• 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 an SC 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 second-line or later 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 third-line or later 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 following Empliciti. Xpovio in combination with dex received accelerated approval in the US (in 2019) and EU (in 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 an opinion is expected during Q2 2022. This label expansion should help to increase Xpovio’s commercial potential, but it will still face significant competition from established brands.
• Talquetamab is a bispecific antibody targeting CD3 and GPRC5D. Talquetamab’s pivotal data for fourth-line or later patients are expected in August 2023, with regulatory submissions expected later in 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 Phase III trial (EXCALIBER-RRMM) is expected to initiate during Q2 2022 and will compare iberdomide combined with Darzalex and dex versus Darzalex combined with Velcade and dex in second-line and third-line MM patients. The trial has an estimated primary completion date of April 2026.
• 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 during 2022, with regulatory submissions expected in 2023.
• Key recent events include the approvals of Abecma (US, EU, and Japan), Blenrep (US and EU), Carvykti (US), and an SC formulation of Darzalex (US and EU). There have been two recent 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 Oncopeptides has halted marketing of the drug pending further discussions with the FDA.
• 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 teclistamab (August 2022), and an EU decision for Pepaxto.
• Key pivotal trial readouts expected during 2022 include Phase III trials for SC Darzalex (CEPHEUS), Sarclisa (IMROZ), Blenrep (DREAMM-3), and Venclexta (BELLINI), as well as pivotal Phase II readouts for elranatamab and REGN5458.
• The overall likelihood of approval of a Phase I multiple myeloma asset is 6.4%, and the average probability a drug advances from Phase III is 55.6%. Multiple myeloma drugs, on average, take 8.8 years from Phase I to approval, compared to 9.7 years in the overall oncology space.