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The Multiple Myeloma Drug Market Paul Wilcock and Rachel Webster Credit: Gino De Graaf/Alamy Stock Photo

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The Multiple Myeloma Drug Market Paul Wilcock and Rachel Webster Credit: Gino De Graaf/Alamy Stock Photo NEWS & ANALYSIS FROM THE ANALYST’S COUCH The multiple myeloma drug market Paul Wilcock and Rachel Webster Credit: Gino de Graaf/Alamy Stock Photo Multiple myeloma, the second most common (Empliciti; Bristol- Myers Squibb/AbbVie) Drug pipeline haematological malignancy after non-Hodgkin targets signalling lymphocytic activation The multiple myeloma pipeline is one of lymphoma, is characterized by the abnormal molecule F7 (SLAMF7; encoded by CS1). the most diverse in oncology (TABLE 1). proliferation of plasma cells in the bone It was initially approved in combination Biopharma is heavily investing in drugs that marrow. The malignant plasma cells crowd with lenalidomide and dexamethasone target B cell maturation antigen (BCMA), out normal blood cells, which can lead to low (ERd) for R/R multiple myeloma, but a cell- surface receptor universally expressed blood counts, bone destruction and renal is also approved in combination with on myeloma cells. damage. New drugs for multiple myeloma pomalidomide and dexamethasone (EPd). have transformed treatment in the past ERd is also being evaluated in newly BCMA. There are several approaches to decade and agents in the pipeline promise diagnosed transplant- ineligible patients. target BCMA. Autologous BCMA-targeted further advances. Daratumumab (Darzalex; Janssen) targets chimeric antigen receptor (CAR)-T cell CD38 and was initially approved as a therapies are under investigation for Current treatment monotherapy for heavily pretreated R/R heavily- pretreated R/R multiple myeloma; The main approaches to multiple myeloma multiple myeloma. The label has expanded to bluebird bio/Celgene’s bb2121 is the most treatment include chemotherapy, non- include other combinations. Daratumumab advanced. Celgene anticipates filing of chemotherapy, corticosteroids and stem is being evaluated in numerous other patient bb2121 in 2020 based on the pivotal cell transplantation (if eligible). In the populations, including transplant-eligible phase II KarMMa trial. A phase III past decade there have been extraordinary patients, and as a novel subcutaneous (KarMMa-3) trial is also ongoing. bb2121 advances in treatment, largely owing to formulation. has demonstrated impressive efficacy the proteasome inhibitor bortezomib (Velcade; Takeda/Janssen) and the Table 1 | Selected therapies in the pipeline for multiple myeloma immunomodulatory agent lenalidomide (Revlimid; Celgene). Bortezomib and Product Companies Target or mechanism Development lenalidomide are cornerstone drugs in of action status (phase) numerous doublet and triplet regimens. Selinexor Karyopharm SINE Pre- registration Excellent clinical activity has supported Therapeutics/ Ono Pharmaceutical the approval of these agents across multiple treatment settings. These agents can be bb2121 bluebird bio/Celgene BCMA III individually prescribed in combination Isatuximab Sanofi/ImmunoGen CD38 III with dexamethasone (BD and Rd, Pembrolizumab Merck & Co. PD1 III respectively) or together in combination with dexamethasone (VRd; ‘D’ indicates a Nivolumab Bristol–Myers Squibb/ PD1 III Ono Pharmaceutical higher dose of dexamethasone than ‘d’). Other proteasome inhibitors and Venetoclax Roche/Genentech/ BCL2 III AbbVie immunomodulatory agents have been added to the armamentarium. Carfilzomib Melphalan flufenamide Oncopeptides AB Alkylating agent III (Kyprolis; Amgen/Ono Pharmaceutical) GSK2857916 GlaxoSmithKline BCMA II and ixazomib (Ninlaro; Takeda) are both Eltanexor Karyopharm SINE I/II approved for relapsed or refractory (R/R) Therapeutics/ multiple myeloma. Both agents exhibit Ono Pharmaceutical a lower risk of peripheral neuropathy AUTO2 Autolus Therapeutics BCMA and TACI I/II than bortezomib. The third-generation LCAR- B38M Nanjing Legend/ BCMA I/II immunomodulatory agent pomalidomide Johnson & Johnson (Pomalyst/Imnovid; Celgene) is approved bb21217 bluebird bio/Celgene BCMA I for R/R multiple myeloma in combination with dexamethasone (Pd). All three of these JCARH125 Celgene BCMA I agents are also being investigated in expanded AMG-420 Amgen BCMA and TCR I patient populations. P- BCMA-101 Poseida Therapeutics BCMA I Two monoclonal antibodies that Pembrolizumab, nivolumab and venetoclax are already approved for other indications. BCL2, B cell target cell- surface antigens are approved lymphoma 2; BCMA , B cell maturation antigen; SINE, selective inhibitor of nuclear export; TACI, to treat multiple myeloma. Elotuzumab transmembrane activator and calcium modulator and cyclophilin ligand interactor ; TCR , T cell receptor. NatURE REVIEWS | DRUG DISCOVERY VOLUME 18 | AUGUST 2019 | 579 NEWS & ANALYSIS 35 BCMA-targeted with antibodies are favourable. CAR-T cells assess isatuximab in combination with VRd 30 agents will be more amenable to younger, healthier for newly diagnosed transplant-ineligible SINE patients who have slowly progressing disease and transplant- eligible multiple myeloma, ) 25 Apoptosis- and for potential long-term remissions. respectively. It is also being assessed for inducing agents 20 Cell-surface- Amgen is developing a bispecific T cell the treatment of R/R multiple myeloma in billions $ targeted agents engager (BiTE) that targets BCMA and combination with Pd (ICARIA-MM) and 15 Proteasome T cells (AMG-420). In a phase I dose- carfilzomib and dexamethasone (IKEMA). 10 inhibitors escalation trial, the optimal dose yielded an ICARIA- MM met the primary end point Sales (US Immuno- ORR of 70%. AMG-420 is also an off-the- of prolonged progression-free survival in 5 modulatory shelf drug; however, the need for 4-week February 2019. agents 0 continuous intravenous infusion via a pump 2017 2022 2027 and the high incidence of cytokine release Market indicators syndrome are drawbacks. In 2017, sales of key branded agents for Fig. 1 | Major- market sales of key drug classes multiple myeloma across the major markets in multiple myeloma. The figure shows the 2017–2027 forecast for the seven major markets: SINE. Karyopharm Therapeutics and totalled US$13.9 billion. Although multiple the United States, France, Germany , Italy , Ono Pharmaceutical’s selinexor is a first- myeloma accounts for less than 2% of Spain, the United Kingdom and Japan. in-class selective inhibitor of nuclear export cancers in the United States, sales of multiple Immunomodulatory agents: thalidomide, (SINE). This small molecule is being myeloma drugs are among the highest, lenalidomide and pomalidomide. Proteasome trialled in combination with Bd (BOSTON) owing to the availability of premium-priced inhibitors: bortezomib, carfilzomib and ixazomib. or dexamethasone only (STORM) for branded agents prescribed in doublet and Cell- surface-targeted agents: daratumumab, R/R multiple myeloma. Selinexor is triplet regimens. Long treatment durations elotuzumab and isatuximab. Apoptosis-inducing under priority review with the FDA; the and prolonged survival also contribute agents: venetoclax. Selective inhibitors Prescription Drug User Fee Act date is in to high sales. We forecast sales to double of nuclear export (SINE): selinexor. B cell April 2019. Karyopharm also has a second- by 2027, reaching $28.7 billion; however, maturation antigen (BCMA)-targeted agents: bb2121 and GSK2857916. generation SINE therapy (eltanexor) in its peak- year sales of key branded agents early- phase pipeline. (~$33 billion) are expected in 2023 (Fig. 1). The fall in sales after 2023 is a result of (94% objective response rate (ORR)) and PD1. The development of PD1 inhibitors generic erosion of lenalidomide, bortezomib is well tolerated. Celgene is developing in combination with immunomodulatory and pomalidomide sales. two other BCMA-targeted T cell therapies: agents has been plagued by safety issues. Sales will be driven by the label bb21217, designed to improve persistence Two phase III trials set out to assess expansion of marketed therapies and the and produce more durable responses, and pembrolizumab (Keytruda; Merck & Co.) potential launch of five novel therapies JCARH125, from its acquisition of Juno in combination with Pd (KEYNOTE-183) (venetoclax, selinexor, isatuximab, bb2121 Therapeutics. Other BCMA-targeted and Rd (KEYNOTE-185), but unexpected and GSK2857916). Immunomodulatory CAR- T cell therapies include LCAR-B38M deaths in the experimental arms of the agents are expected to be the sales-leading (Nanjing Legend/Johnson & Johnson) trials resulted in termination of these drug class throughout the forecast period, and P- BCMA-101 (Poseida Therapeutics). arms. The phase III (CheckMate-602) earning peak sales of almost $19 billion LCAR- B38M has achieved a high ORR trial assessing nivolumab (Opdivo; in 2023. These sales will be predominantly (88%) in patients with R/R multiple Bristol- Myers Squibb/Ono Pharmaceutical) driven by lenalidomide’s high penetration myeloma. A global phase I/II trial is in combination with pomalidomide was across treatment settings. Sales of currently recruiting. A similar ORR (100%) placed on a partial clinical hold, but the hold proteasome inhibitors and cell-surface has been reported for P-BCMA-101, albeit was lifted with a modified protocol. targeted agents will grow substantially, in a small number of evaluable patients. largely driven by prescriptions of carfilzomib A pivotal trial for P-BCMA-101 is planned Apoptosis- inducing agents. Two apoptosis- and ixazomib (for proteasome inhibitors) and for early 2019. Autolus Therapeutics is inducing agents, venetoclax (Venclexta/ daratumumab (for cell-surface-targeted developing a novel dual targeted CAR-T cell Venclyxto; AbbVie/Roche/Genentech)
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