Multiple Myeloma Market Will Expand With Launch of Monoclonal Antibodies

Abstract

Analysts foresee substantial growth in the multiple myeloma market in the next decade, driven mainly by the monoclonal antibodies elotuzumab and daratumumab.

In multiple myeloma (MM), abnormal plasma cells (myeloma cells) accumulate in the bone marrow, forming tumors that may prevent the marrow from producing enough healthy blood cells. As myeloma cells proliferate, fewer leukocytes, erythrocytes, and platelets are made. Myeloma cells also weaken and damage the bone. The signs and symptoms of MM include bone pain, bones that break easily, fever for no known reason, easy bruising or bleeding, and trouble breathing.¹

MM is the third most common blood cancer in the U.S. (after lymphoma and leukemia). Men have a higher incidence than women, and African-Americans have more than twice the incidence and mortality rates of whites. In 2014, it was estimated that more than 24,000 people would be diagnosed with MM in the U.S. and that more than 11,000 would die from it.²

MM treatments include chemotherapy and other drugs (Table 1), biologic therapy, radiation, surgery, stem-cell transplant (SCT), bisphosphonates, and plasmapharesis.³ In drug therapy, the immunomodulatory agent lenalidomide (Revlimid, Celgene) dominates the MM market in the U.S., where it is included in all lines of MM therapy either as monotherapy or in combination with other drugs. For newly diagnosed patients who are eligible for SCT, the most commonly used regimens are the RD (Revlimid and dexamethasone) and RVD (Revlimid, Velcade [bortezomib, Takeda], and dexamethasone) combinations. Newly diagnosed, SCT-ineligible patients are commonly treated with the same combinations. For consolidation therapy, patients usually receive either lenalidomide monotherapy or lenalidomide-containing regimens.⁴

Table 1.

Key FDA-Approved Treatments for Multiple Myeloma^a

Drug Manufacturer	Initial MM Approval Date	Description	MM Dosage and Administrationb	Cost of 24 Weeks of Treatmentc
Immunomodulatory Drugs
Daratumumab (Darzalex) Genmab/Janssen	November 16, 2015	Anti-CD38 monoclonal antibody	16 mg/kg IV infused once weekly for 8 weeks, then every 2 weeks for 16 weeks, then every 4 weeks thereafter. Administered with bortezomib and DX.	M: $123,034d F: $103,680
Elotuzumab (Empliciti) Bristol-Myers Squibb/AbbVie	November 30, 2015	Anti-CS1 monoclonal antibody	10 mg/kg IV infused on days 1, 8, 15, and 22 of first two 28-day cycles and days 1 and 15 of later cycles. Administered with lenalidomide and DX.	M: $101,161d F: $85,248
Lenalidomide (Revlimid) Celgene	June 29, 2006	Thalidomide analog with antiangiogenic and anti-neoplastic properties	25 mg QD orally on days 1–21 of repeated 28-day cycles. Administered with DX.	$76,007
Pomalidomide (Pomalyst) Celgene	February 8, 2013	Thalidomide analog with antineoplastic activity	4 mg QD orally on days 1–21 of repeated 28-day cycles. May be administered with DX.	$88,032
Thalidomide (Thalomid) Celgene	May 26, 2006	Immunomodulatory agent with anti-inflammatory and anti-angiogenic properties	200 mg QD orally. Administered with DX in repeated 28-day cycles.	$63,673
Proteasome Inhibitors
Bortezomib (Velcade) Takeda Oncology	June 23, 2008	26S proteasome inhibitor with anti-neoplastic activity	1.3 mg/m2 IV or SC for nine 6-week cycles on days 1, 4, 8, 11, 22, 25, 29, and 32 in cycles 1–4 and days 1, 8, 22, and 29 of cycles 5–9. Administered with oral melphalan and prednisone.	M: $45,926e F: $41,334
Carfilzomib (Kyprolis) Onyx Pharmaceuticals/Amgen	July 24, 2015	26S proteasome inhibitor with anti-neoplastic activity	20 mg/m2 IV on days 1 and 2 of first 28-day cycle. If tolerated, escalate to target dose of 27 mg/m2 on days 8, 9, 15, and 16 of cycle 1. From cycle 13, omit day 8 and 9. Discontinue after cycle 18. Administered with lenalidomide and DX.	M: $71,350e F: $64,215
Ixazomib (Ninlaro) Millennium Pharmaceuticals/Takeda	November 20, 2015	20S proteasome inhibitor	4 mg orally on days 1, 8, and 15 of 28-day cycle. Administered with lenalidomide and DX.	$62,424
Histone Deacetylase Inhibitor
Panobinostat (Farydak) Novartis	February 23, 2015	HDAC inhibitor induces cell-cycle arrest and apoptosis	20 mg orally on days 1, 3, 5, 8, 10, and 12 of weeks 1 and 2 of each 21-day cycle for 8 cycles. Administered with DX.	$65,856
Traditional Chemotherapy
Doxorubicin liposome injection (Doxil) Janssen Products	May 17, 2007	Anthracycline topoisomerase II inhibitor prevents nucleic acid synthesis	30 mg/m2 IV over 60 minutes on day 4 of each 21-day cycle for 8 cycles or until disease progression or unacceptable toxicity. Administered with bortezomib.	M: $31,044e F: $27,939

^aThis list is not all-inclusive; additional therapies may be available.

^bBased on prescribing information; doses and schedules may vary based on patient-specific requirements.

^cCosts calculated using average wholesale price and regimen provided for initial 24 weeks of treatment, rounded to the nearest dollar. Costs do not include coadministered medications.

^dPrice calculated using weights of 88 kg for men and 75 kg for women.

^ePrice calculated using body surface areas of 2.0 for men and 1.8 for women.

DX = dexamethasone; F = female; HDAC = histone deacetylase; IV = intravenous; M = male; MM = multiple myeloma; QD = once daily.

Sources: FDA, National Cancer Institute, American Cancer Society, International Myeloma Foundation, product prescribing information, Red Book online

For the treatment of first relapse, the most popular choices are RD and RVD. For second relapse, several regimens are used, with approximately 20% of clinicians choosing either RD or RVD. For patients at third relapse, pomalidomide (Pomalyst, Celgene) is the preferred treatment, followed by the RVD regimen.⁴

Analysts foresee substantial growth in the MM market into the next decade, driven primarily by the launch of two injectable monoclonal antibodies, elotuzumab (Empliciti, Bristol-Myers Squibb/AbbVie) and daratumumab (Darzalex, Genmab/Janssen) (Table 1). Both are expected to lengthen the time between relapses. Their favorable efficacy and safety will also mean that more MM patients will ultimately receive drug treatment.⁴

It is believed that elotuzumab will be preferred over daratumumab for use in combination with lenalidomide/dexamethasone because of the synergistic effects of elotuzumab and lenalidomide on the immune system. In November 2015, elotuzumab was approved for use with this combination in patients who have received one to three prior therapies, whereas daratumumab was approved as monotherapy in patients who have received at least three prior lines of therapy or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.^5–8 Elotuzumab is forecast to reach blockbuster status by 2018, with peak sales in 2022 at $4.2 billion, and daratumumab is anticipated to achieve peak sales of $3.7 billion in 2023.⁴

Another recent addition to the MM armamentarium is the 20S proteasome inhibitor ixazomib (Ninlaro, Millennium Pharmaceuticals/Takeda), also approved in November 2015. Like elotuzumab, it is indicated for use in combination with lenalidomide and dexamethasone (Table 1). Unlike both elotuzumab and daratumumab, ixazomib is an oral medication, available in capsule form.^9,10

Treatment options for MM patients will be further increased by label extensions to elotuzumab, daratumumab, and ixazomib, as well as to the currently marketed, second-generation proteasome inhibitor carfilzomib (Kyprolis, Onyx Pharmaceuticals/Amgen). In addition, several promising agents are in clinical development, including two 20S proteasome inhibitors, marizomib (Triphase Accelerator Corporation) and oprozomib (Onyx Pharmaceuticals), and a new monoclonal antibody, SAR650984 (Sanofi) (Table 2).⁴

Table 2.

Promising Multiple Myeloma Drugs in Clinical Development

Drug Developer	Status	Therapeutic Class	Treatment Regimen
Evofosfamide (TH-302) Threshold Pharmaceuticals/Merck	Phase2	Tumor hypoxia-activated prodrug	Best-tolerated IV dosage in clinical trials: 380 mg/m2 biweekly with DX.
Filanesib (ARRY-520) Array BioPharma	Phase 2	KSP inhibitor	In phase 2 trial: 1.25 mg/m2/day IV on days 1, 2, 15, and 16 of 28-day cycle with prophylactic filgrastim.
LGH447 Novartis	Phase 1 and phase 2	Specific pan-PIM kinase inhibitor	In phase 1 dose-ranging trial: 70–700 mg/day orally; maximum tolerated dosage: 500 mg/day.
Marizomib (NPI-0052) Triphase Accelerator Corporation	Phase 1/2 and phase 2	20S proteasome inhibitor	In phase 1 dose-ranging trial: 0.075–0.6 mg/m2 IV over 1 to 200 minutes on days 1, 4, 8, and 11 of 21-day cycle with DX.
Oprozomib (ONX-0912) Onyx Pharmaceuticals	Phase 1B/2; FDA filing in July 2015	20S proteasome inhibitor	In clinical trials: 240 mg orally on days 1–5 of 14-day cycle or 240 mg on days 1, 2, 8, and 9 of 14-day cycle.
Plitidepsin (Aplidin) PharmaMar	Phase 3	Antitumor and immunosuppressive natural product; original molecule isolated from sea squirt	In phase 3 trial: 5 mg/m2 IV over 3 hours on days 1 and 15 every 4 weeks. Administered with DX.
SAR650984 Sanofi	Phase 1 and phase 2	Anti-CD38 monoclonal antibody	In phase 1 dose-ranging trial: 0.3, 1, 3, 5, 10, and 20 mg/kg IV every 2 weeks and 10 mg/kg IV weekly.
Selinexor (KPT-330) Karyopharm Therapeutics	Phase 2	CRM1 inhibitor	Best response in phase 1 trial: 45 mg/m2 IV with DX twice weekly.

CRM1 = chromosome region maintenance 1; DX = dexamethasone; IV = intravenous; KSP = kinase spindle protein; PIM = serine/threonine protein kinase subfamily.

Sources: FDA, GlobalData, company websites

Analysts expect the new MM drugs to come with hefty price tags, but the patent expirations of lenalidomide and bortezomib may alleviate spending.⁴