FROM THE ANALYST'S COUCH

The multiple myeloma drug market

Decision Resources Group, London, UK

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Multiple myeloma, the second most common haematological malignancy after non-Hodgkin lymphoma, is characterized by the abnormal proliferation of plasma cells in the bone marrow. The malignant plasma cells crowd out normal blood cells, which can lead to low blood counts, bone destruction and renal damage. New drugs for multiple myeloma have transformed treatment in the past decade and agents in the pipeline promise further advances.

Current treatment

The main approaches to multiple myeloma treatment include chemotherapy, non-chemotherapy, corticosteroids and stem cell transplantation (if eligible). In the past decade there have been extraordinary advances in treatment, largely owing to the proteasome inhibitor bortezomib (Velcade; Takeda/Janssen) and the immunomodulatory agent lenalidomide (Revlimid; Celgene). Bortezomib and lenalidomide are cornerstone drugs in numerous doublet and triplet regimens. Excellent clinical activity has supported the approval of these agents across multiple treatment settings. These agents can be individually prescribed in combination with dexamethasone (BD and Rd, respectively) or together in combination with dexamethasone (VRd; 'D' indicates a higher dose of dexamethasone than 'd').

Other proteasome inhibitors and immunomodulatory agents have been added to the armamentarium. Carfilzomib (Kyprolis; Amgen/Ono Pharmaceutical) and ixazomib (Ninlaro; Takeda) are both approved for relapsed or refractory (R/R) multiple myeloma. Both agents exhibit a lower risk of peripheral neuropathy than bortezomib. The third-generation immunomodulatory agent pomalidomide (Pomalyst/Imnovid; Celgene) is approved for R/R multiple myeloma in combination with dexamethasone (Pd). All three of these agents are also being investigated in expanded patient populations.

Two monoclonal antibodies that target cell-surface antigens are approved to treat multiple myeloma. Elotuzumab (Empliciti; Bristol-Myers Squibb/AbbVie) targets signalling lymphocytic activation molecule F7 (SLAMF7; encoded by CS1). It was initially approved in combination with lenalidomide and dexamethasone (ERd) for R/R multiple myeloma, but is also approved in combination with pomalidomide and dexamethasone (EPd). ERd is also being evaluated in newly diagnosed transplant-ineligible patients. Daratumumab (Darzalex; Janssen) targets CD38 and was initially approved as a monotherapy for heavily pretreated R/R multiple myeloma. The label has expanded to include other combinations. Daratumumab is being evaluated in numerous other patient populations, including transplant-eligible patients, and as a novel subcutaneous formulation.

Drug pipeline

The multiple myeloma pipeline is one of the most diverse in oncology (Table 1). Biopharma is heavily investing in drugs that target B cell maturation antigen (BCMA), a cell-surface receptor universally expressed on myeloma cells.

Table 1 | Selected therapies in the pipeline for multiple myeloma

Product

Companies

Target or mechanism of action

Development status (phase)

Selinexor

Karyopharm Therapeutics/Ono Pharmaceutical

SINE

Pre-registration

bb2121

bluebird bio/Celgene

BCMA

III

Isatuximab

Sanofi/ImmunoGen

CD38

III

Pembrolizumab

Merck & Co.

PD1

III

Nivolumab

Bristol–Myers Squibb/Ono Pharmaceutical

PD1

III

Venetoclax

Roche/Genentech/AbbVie

BCL2

III

Melphalan flufenamide

Oncopeptides AB

Alkylating agent

III

GSK2857916

GlaxoSmithKline

BCMA

II

Eltanexor

Karyopharm Therapeutics/Ono Pharmaceutical

SINE

I/II

AUTO2

Autolus Therapeutics

BCMA and TACI

I/II

LCAR-B38M

Nanjing Legend/Johnson & Johnson

BCMA

I/II

bb21217

bluebird bio/Celgene

BCMA

I

JCARH125

Celgene

BCMA

I

AMG-420

Amgen

BCMA and TCR

I

P-BCMA-101

Poseida Therapeutics

BCMA

I

BCMA. There are several approaches to target BCMA. Autologous BCMA-targeted chimeric antigen receptor (CAR)-T cell therapies are under investigation for heavily-pretreated R/R multiple myeloma; bluebird bio/Celgene’s bb2121 is the most advanced. Celgene anticipates filing of bb2121 in 2020 based on the pivotal phase II KarMMa trial. A phase III (KarMMa-3) trial is also ongoing. bb2121 has demonstrated impressive efficacy (94% objective response rate (ORR)) and is well tolerated. Celgene is developing two other BCMA-targeted T cell therapies: bb21217, designed to improve persistence and produce more durable responses, and JCARH125, from its acquisition of Juno Therapeutics. Other BCMA-targeted CAR-T cell therapies include LCAR-B38M (Nanjing Legend/Johnson & Johnson) and P-BCMA-101 (Poseida Therapeutics). LCAR-B38M has achieved a high ORR (88%) in patients with R/R multiple myeloma. A global phase I/II trial is currently recruiting. A similar ORR (100%) has been reported for P-BCMA-101, albeit in a small number of evaluable patients. A pivotal trial for P-BCMA-101 is planned for early 2019. Autolus Therapeutics is developing a novel dual targeted CAR-T cell therapy (AUTO2).

However, BCMA-targeted CAR-T cell therapies might be usurped by antibodies that target BCMA. GlaxoSmithKline’s BCMA-targeted antibody–drug conjugate GSK2857916 has achieved an ORR of 66% in heavily pretreated R/R multiple myeloma and, although numerically lower than that of bb2121, this ORR is considerably higher than that of carfilzomib and daratumumab monotherapy (20–30%). GSK2857916 requires more frequent administration than one-time CAR-T cell treatment; however, its off-the-shelf formulation and physicians’ familiarity with antibodies are favourable. CAR-T cells will be more amenable to younger, healthier patients who have slowly progressing disease and for potential long-term remissions. Amgen is developing a bispecific T cell engager (BiTE) that targets BCMA and T cells (AMG-420). In a phase I dose-escalation trial, the optimal dose yielded an ORR of 70%. AMG-420 is also an off-the-shelf drug; however, the need for 4-week continuous intravenous infusion via a pump and the high incidence of cytokine release syndrome are drawbacks.

SINE. Karyopharm Therapeutics and Ono Pharmaceutical’s selinexor is a first-in-class selective inhibitor of nuclear export (SINE). This small molecule is being trialled in combination with Bd (BOSTON) or dexamethasone only (STORM) for R/R multiple myeloma. Selinexor is under priority review with the FDA; the Prescription Drug User Fee Act date is in April 2019. Karyopharm also has a second-generation SINE therapy (eltanexor) in its early-phase pipeline.

PD1. The development of PD1 inhibitors in combination with immunomodulatory agents has been plagued by safety issues. Two phase III trials set out to assess pembrolizumab (Keytruda; Merck & Co.) in combination with Pd (KEYNOTE-183) and Rd (KEYNOTE-185), but unexpected deaths in the experimental arms of the trials resulted in termination of these arms. The phase III (CheckMate-602) trial assessing nivolumab (Opdivo; Bristol-Myers Squibb/Ono Pharmaceutical) in combination with pomalidomide was placed on a partial clinical hold, but the hold was lifted with a modified protocol.

Apoptosis-inducing agents. Two apoptosis-inducing agents, venetoclax (Venclexta/Venclyxto; AbbVie/Roche/Genentech) and melphalan flufenamide (Ygalo; Oncopeptides AB), are in phase III trials for R/R multiple myeloma. Venetoclax is being evaluated in combination with dexamethasone with (M14-031) or without (CANOVA) bortezomib, and melphalan flufenamide is being assessed in combination with dexamethasone (OCEAN).

CD38. With a shorter infusion time than daratumumab, Sanofi and ImmunoGen’s isatuximab is being assessed in combination with current standard therapies in several patient populations. The IMROZ and GMMG HD7 trials will assess isatuximab in combination with VRd for newly diagnosed transplant-ineligible and transplant-eligible multiple myeloma, respectively. It is also being assessed for the treatment of R/R multiple myeloma in combination with Pd (ICARIA-MM) and carfilzomib and dexamethasone (IKEMA). ICARIA-MM met the primary end point of prolonged progression-free survival in February 2019.

Market indicators

In 2017, sales of key branded agents for multiple myeloma across the major markets totalled US$13.9 billion. Although multiple myeloma accounts for less than 2% of cancers in the United States, sales of multiple myeloma drugs are among the highest, owing to the availability of premium-priced branded agents prescribed in doublet and triplet regimens. Long treatment durations and prolonged survival also contribute to high sales. We forecast sales to double by 2027, reaching $28.7 billion; however, peak-year sales of key branded agents (~$33 billion) are expected in 2023 (Fig. 1). The fall in sales after 2023 is a result of generic erosion of lenalidomide, bortezomib and pomalidomide sales.

Fig. 1 | Major-market sales of key drug classes in multiple myeloma. The figure shows the 2017–2027 forecast for the seven major markets: the United States, France, Germany, Italy, Spain, the United Kingdom and Japan. Immunomodulatory agents: thalidomide, lenalidomide and pomalidomide. Proteasome inhibitors: bortezomib, carfilzomib and ixazomib. Cell-surface-targeted agents: daratumumab, elotuzumab and isatuximab. Apoptosis-inducing agents: venetoclax. Selective inhibitors of nuclear export (SINE): selinexor. B cell maturation antigen (BCMA)-targeted agents: bb2121 and GSK2857916.

Sales will be driven by the label expansion of marketed therapies and the potential launch of five novel therapies (venetoclax, selinexor, isatuximab, bb2121 and GSK2857916). Immunomodulatory agents are expected to be the sales-leading drug class throughout the forecast period, earning peak sales of almost $19 billion in 2023. These sales will be predominantly driven by lenalidomide’s high penetration across treatment settings. Sales of proteasome inhibitors and cell-surface targeted agents will grow substantially, largely driven by prescriptions of carfilzomib and ixazomib (for proteasome inhibitors) and daratumumab (for cell-surface-targeted agents). Market penetration will be difficult for the five novel emerging therapies, which are expected to produce comparatively modest sales. In 2027, these five therapies are forecasted to collectively garner $2.9 billion, accounting for 10% of major-market sales.

doi: 10.1038/d41573-019-00031-w
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