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, over time, exert substantial downward pressure on the MM market.
• Darzalex, the first monoclonal antibody (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.
• The launches of BCMA-targeted therapies will play a pivotal part in future market dynamics over the next decade. Key anti-BCMA agents include the CAR-T therapies Abecma and Carvykti, which are approved for fifth-line or later MM in the US and for fourth-line or later MM in the EU. Given the unmet need for effective therapies for heavily pretreated patients, demand has been high and manufacturing has struggled to keep pace.
• Several Phase III trials are evaluating CAR-T therapies for earlier lines of therapy, which represents a major commercial opportunity. Abecma’s KarMMa-3, a head-to-head trial against standard of care doublet or triplet therapy, met its primary endpoint, and regulatory submissions for third-line or later MM are expected by the end of 2022. Carvykti’s CARTITUDE-4, another head-to-head trial, is expecting topline data by the end of 2022, and if the data are positive, this could support approval for second-line or later MM, one line ahead of Abecma. Looking further into the future, in the first-line setting, KarMMa-9 will evaluate Abecma in patients who have a suboptimal response to transplant. In contrast, Carvykti has two ongoing Phase III trials in the first-line setting, with CARTITUDE-5 evaluating Carvykti as a replacement for Revlimid maintenance following induction therapy in patients not suited for transplant, and CARTITUDE-6 evaluating Carvykti as a replacement for transplant in transplant-eligible patients.
• Arcellx’s CART-ddBCMA is positioned to be the third BCMA CAR-T to enter the market, but it lags significantly behind its competitors in development. While Abecma and Carvykti were first approved in 2021 and 2022, respectively, CART-ddBCMA is only set to begin its pivotal trial, iMMagine-1, in late 2022.
• There are currently three BCMA x CD3 bispecific antibodies that are either approved or are in late-phase development. First-to-market was Tecvayli, which is approved in the US for fifth-line or later patients and in the EU for fourth-line or later patients. Elranatamab has released overall response rate data from a pivotal Phase II trial, with additional data expected before the end of 2022. Pivotal data from REGN5458 are also expected in late 2022. While bispecific antibodies have the advantage of off-the-shelf availability, there has been some concern over high levels of infections.
• Both Tecvayli and elranatamab are in Phase III trials evaluating a combination with Darzalex. The trials are enrolling second-line or later patients and have estimated primary completion dates (EPCDs) in 2024. Tecvayli is the first bispecific to initiate a Phase III trial in the first-line setting; MajesTEC-7 has an EPCD of July 2029 and is an add-on trial comparing Tecvayli combined with Darzalex and lenalidomide to Darzalex, lenalidomide, and dex in transplant-ineligible newly diagnosed patients.
• The antibody-drug conjugate (ADC) Blenrep received accelerated approval for triple-class exposed patients who have been treated with at least four prior therapies including a PI, an IMiD, and an anti-CD38 mAb. However, in November 2022 it was announced that a confirmatory Phase III trial, DREAMM-3, had failed to meet its primary endpoint of PFS. Blenrep’s continued approval now depends on results from two additional Phase III trials, DREAMM-7 and DREAMM-8, which are expected to read out in H1 2023.
• 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. While the target patient population for the doublet is limited, Xpovio is now also approved in the US (December 2020) and EU (July 2022) as part of a triple combination with Velcade and dex for second- to fourth-line MM. 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 comparing iberdomide combined with Darzalex and dex versus Darzalex combined with Velcade and dex in second-line and third-line MM patients and has an EPCD of April 2026. Two additional Phase III trials for newly diagnosed patients are expected to initiate in 2023: EXCALIBER-NDMM will compare iberdomide combined with Velcade and dex, or combined with Darzalex and dex, versus RVd in non-transplant-eligible patients, while the second Phase III trial will be a head-to-head comparison of iberdomide versus Revlimid in the post-transplant maintenance setting.
• Just as Pomalyst was developed for patients who progress on Revlimid, Bristol Myers Squibb is developing mezigdomide (CC-92480), an IMiD even more potent than iberdomide, for second-line or later patients who progress on iberdomide. SUCCESSOR-1 (which has an EPCD of November 2025) is a head-to-head Phase III trial comparing mezigdomide combined with Velcade and dex to Pomalyst combined with Velcade and dex. A second Phase III trial, SUCCESSOR-2 (EPCD of February 2026), is an add-on trial comparing mezigdomide combined with Kyprolis and dex to Kyprolis and dex.
• 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 and 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 are expected by the end of 2022, with regulatory submissions expected in 2023.
• Key recent events include the approvals of three additional anti-BCMA agents: Abecma (US, EU, and Japan), Carvykti (US, EU and Japan), and Tecvayli (US and EU).
• Other key recent events include positive Phase III data for Abecma in third-line or later patients, and positive pivotal Phase II data for elranatamab, with additional details for both drugs expected in late 2022. Meanwhile, Blenrep failed its confirmatory Phase III trial, DREAMM-3. Additional key pivotal trial readouts expected before the end of 2022 include Phase III trials for SC Darzalex (CEPHEUS) and Venclexta (CANOVA), as well as a pivotal Phase II readout for REGN5458.
• Two drugs with accelerated approval have been removed from the US market: Pepaxto, which reported a negative OS signal in its Phase III trial, and Farydak, which did not complete a required post-approval clinical study. Both drugs continue to be marketed in the EU.
• The overall likelihood of approval of a Phase I multiple myeloma asset is 5.7%, and the average probability a drug advances from Phase III is 55.6%. Multiple myeloma drugs, on average, take 8.6 years from Phase I to approval, compared to 9.9 years in the overall oncology space.