The United States Food and Drug Admin­istra­tion (FDA) has approved elotuzumab for the treat­ment of mul­ti­ple myeloma.

The drug will be sold under the brand name Empliciti, and it will be mar­keted by the U.S. pharma­ceu­tical com­pany Bristol-Myers Squibb. The com­pany said in a press re­lease issued this Monday that it will begin shipping Empliciti “within the next 48 hours.”

Empliciti’s ap­prov­al is for use in com­bi­na­tion with Revlimid (lena­lido­mide) and dexamethasone (Decadron) in mul­ti­ple myeloma patients who have re­ceived one to three prior ther­a­pies.

There is no re­quire­ment that treat­ment with Empliciti be preceded by any par­tic­u­lar prior ther­apy or class of ther­a­pies.

Empliciti is the third new mul­ti­ple myeloma ther­apy the FDA has approved within two weeks, and the fourth this year.

The federal regulator approved Farydak (panobinostat) in Feb­ru­ary, Darzalex (dara­tu­mu­mab) on No­vem­ber 16, Ninlaro (ix­az­o­mib) on No­vem­ber 20, and then Empliciti this Monday.

As was the case with Darzalex and Ninlaro, the FDA approved Empliciti sev­er­al months earlier than ex­pected given U.S. drug review guidelines. In addi­tion, the agency made its de­ci­sion without formally con­sult­ing with its Oncologic Drugs Advisory Com­mit­tee of outside experts.

These as­pects of the drug’s ap­prov­al sug­gest that the FDA did not have any sig­nif­i­cant con­cerns about Empliciti’s safety and ef­fec­tiveness, and that the agency be­lieves the drug meets an im­por­tant med­i­cal need.

That said, the Empliciti pre­scrib­ing in­for­ma­tion approved by the FDA in­cludes a couple safety warnings that may surprise some physicians and patients.

The warnings are not the serious, “black box” warnings found in the pre­scrib­ing in­for­ma­tion of some myeloma ther­a­pies. The warnings do note, how­ever, that Empliciti can cause liver damage, and that treat­ment with the drug has been asso­ci­ated with an in­creased risk of patients devel­op­ing a sec­ond cancer.

Empliciti also is being reviewed by the Euro­pean Medicines Agency (EMA), and its mar­ket­ing appli­ca­tion was granted ac­cel­er­ated assess­ment this past July (see re­lated press re­lease from Bristol-Myers Squibb and AbbVie). A de­ci­sion on the appli­ca­tion is ex­pected by early next year.

Second Monoclonal Anti­body Approved For Multiple Myeloma

Empliciti belongs to a class of drugs known as mono­clonal anti­bodies. It binds to a pro­tein known as SLAMF7, which is commonly found on the surface of myeloma cells. Once bound to a myeloma cell, Empliciti signals and stim­u­lates the patient's im­mune sys­tem to act against the myeloma cells.

Empliciti is the sec­ond mono­clonal anti­body approved for the treat­ment of mul­ti­ple myeloma. Darzalex was the first. Darzalex, how­ever, works by targeting a pro­tein known as CD38, which is dif­fer­en­t than the SLAMF7 pro­tein targeted by Empliciti.

Although both Empliciti and Darzalex are mono­clonal anti­bodies, only Empliciti is described in its pre­scrib­ing in­for­ma­tion as an "immunostimulatory" anti­body. This description emphasizes that the drug not only signals the im­mune sys­tem to act against myeloma cells, but also stim­u­lates the im­mune sys­tem to act against a patient’s myeloma.

Basis For The FDA Approval

Empliciti’s FDA ap­prov­al is based on data from the ELOQUENT-2 clin­i­cal trial. The Phase 3 trial in­cluded 646 patients with re­lapsed / refractory mul­ti­ple myeloma who had re­ceived a median of two prior ther­a­pies, in­clud­ing Velcade (bor­tez­o­mib) (70 per­cent), thalidomide (48 per­cent), and Revlimid (6 per­cent). Over­all, 35 per­cent of patients were resistant (refractory) to their most recent ther­apy.

Patients in the trial were ran­dom­ized to re­ceive either the three-drug com­bi­na­tion of Empliciti, Revlimid and dex­a­meth­a­sone, or Revlimid and dex­a­meth­a­sone alone. Treatment in both groups of patients was ad­min­is­tered until dis­ease pro­gres­sion or unacceptable toxicity.

Among the patients treated with Empliciti, Revlimid, and dex­a­meth­a­sone, 79 per­cent achieved at least a partial re­sponse to treat­ment, com­pared to 66 per­cent of the patients who re­ceived Revlimid and dex­a­meth­a­sone alone.

The median pro­gres­sion-free sur­vival was 19.4 months for patients who re­ceived the Empliciti regi­men versus 14.9 months for patients who re­ceived Revlimid and dex­a­meth­a­sone alone.

At the time of the most recent analysis of the trial’s re­­sults, the share of patients who were still alive was higher in the Empliciti-treated group of patients than in the group treated with just Revlimid and dexa­metha­sone (71 per­cent versus 64 per­cent). Neither the FDA nor the trial in­ves­ti­ga­tors, how­ever, have reported whether these re­­sults reflect a statistically sig­nif­i­cant dif­fer­ence in over­all sur­vival be­tween the two groups of patients.

Patients in the trial who were treated with Empliciti, Revlimid, and dexa­meth­a­sone were more likely to ex­peri­ence cer­tain side effects than the patients treated with just Revlimid and dexa­metha­sone. These side effects in­cluded coughing, fever, diarrhea, fatigue, con­sti­pa­tion, de­creased appetite, headache, and weight loss.

Ten per­cent of patients re­ceiv­ing Empliciti had in­fusion site reac­tions, the majority of which were mild in nature.

Warnings And Precautions

The FDA-approved pre­scrib­ing in­for­ma­tion for Empliciti in­cludes warnings that treat­ment with the drug may lead to in­fusion-related reac­tions, an in­creased risk of in­fec­tion, and possible inter­fer­ence with serum pro­tein electrophoresis (SPEP) and serum immuno­fix­a­tion electrophoresis (IFE) tests used to de­ter­mine a patient’s re­sponse to treat­ment.

These warnings were to be ex­pected from pre­vi­ous pre­sen­ta­tions and pub­li­ca­tions re­lated to Empliciti and the ELOQUENT-2 trial. There are, how­ever, two warnings in the pre­scrib­ing in­for­ma­tion that are somewhat unexpected.

First, the pre­scrib­ing in­for­ma­tion notes that patients in the ELOQUENT-2 trial who were treated with Empliciti were more likely to de­vel­op sec­ond cancers than patients who were not treated with Empliciti. The rate of “invasive sec­ond pri­mary malig­nan­cies” is cur­rently 9.1 per­cent in the Empliciti-treated patients versus 5.7 per­cent in the trial par­tic­i­pants who were not treated with Empliciti.

(The re­­sults of the ELOQUENT-2 trial that were pub­lished earlier this year did note a disparity in sec­ond­ary cancer rates be­tween the two groups of patients in the trial. However, the disparity was described in a foot­note to one of the tables in the pub­li­ca­tion, and the reported dif­fer­ence in sec­ond­ary cancer rates was not as sub­stan­tial as pub­lished in the Empliciti pre­scrib­ing in­for­ma­tion.)

Second, patients in the ELOQUENT-2 trial who were treated with Empliciti were also more likely to de­vel­op signs of noticeable liver damage. Among patients in the trial who were treated with Empliciti, 2.6 per­cent showed signs of treat­ment-induced liver damage, com­pared to 0.6 per­cent of the patients who were not treated with Empliciti.

Recommended Empliciti Dosing And Duration Of Therapy

The FDA rec­om­mends that the com­bi­na­tion of Empliciti, Revlimid, and dexa­meth­a­sone be admin­istered in 28-day cycles. There is no fixed num­ber of cycles that patients are advised to be treated with the com­bi­na­tion. Instead, it is rec­om­mended that treat­ment with the three-drug regi­men con­tinue “until dis­ease pro­gression or unacceptable toxicity.”

Empliciti is admin­istered as an in­tra­venous in­fusion. For the first two 28-day cycles, it should be given once a week to patients at a dose equal to 10 mg per kilo­gram of a patient’s body weight.

After the first two 28-day cycles, Empliciti should be given once every two weeks at the same 10 mg / kg dose.

The rec­om­mended Revlimid dosing is 25 mg on days 1 to 21 of each 28-day treat­ment cycle.

The rec­om­mended dexa­meth­a­sone dose is 36 mg per week during the weeks when patients are treated with Empliciti. These 36 mg should be split be­tween a 28 mg dose taken by mouth, and an 8 mg dose given by in­fusion 45-90 min­utes prior to the patient’s Empliciti in­fusion.

In weeks when Empliciti is not given to patients, the dexa­meth­a­sone dose should be 40 mg per week.

Patients being treated with Empliciti also should re­ceive sev­er­al addi­tional med­i­ca­tions 45 to 90 min­utes prior to each Empliciti in­fusion to reduce the chances of in­fusion-related reac­tions. These med­i­ca­tions in­clude:

• Benadryl (diphenhydramine) (25-50 mg orally or intravenously) or an equivalent H1 blocker.
• Zantac (ranitidine) (50 mg intravenously or 150 mg orally) or an equivalent H2 blocker.
• Tylenol (acetaminophen, paracetamol) (650-1000 mg orally).

Empliciti’s Cost

Empliciti will be sold in the U.S. in two vials sizes: A smaller vial that con­tains 300 mg of the drug, and a larger vial that con­tains 400 mg.

Bristol-Myers Squibb has in­formed The Beacon that the wholesale price per vial of Empliciti will be $1,776 for the 300 mg vial and $2,368 for the 400 mg vial.

Using these prices and an assumed patient weight of be­tween 154 and 176 pounds, Empliciti will cost $18,944 per four-week cycle for each of the first two cycles of treat­ment, and $9,472 per cycle there­after. This means, in turn, that Empliciti's cost per year will be $142,080 in the first year and $123,136 in sub­se­quent years.

In comparison, Velcade costs be­tween $4,800 and $8,500 per four-week cycle, de­pending on how often it is dosed. Ninlaro costs $8,670 per four-week cycle. And Kyprolis costs $10,500 per four-week cycle at the standard (20 – 27 mg/m²) dose.

Additional details about the FDA ap­prov­al of Empliciti can be found in this press re­lease from the FDA, a re­lated press re­lease from Bristol-Myers Squibb and AbbVie, and the full Empliciti pre­scrib­ing in­for­ma­tion.

The re­­sults of the ELOQUENT-2 trial were pub­lished in Lonial, S. et al., “Elotuzumab Therapy for Re­lapsed or Re­frac­tory Multiple Myeloma,” The New England Journal of Medicine, June 2, 2015 (abstract). Slides from the ASCO pre­sen­ta­tion summarizing the ELOQUENT-2 re­­sults can be viewed here (PDF, courtesy of Dr. Lonial). This Beacon news article provides an in-depth look at the trial re­­sults.

Update (Dec 2, 2015; 11:05 am) – The Empliciti cost in­for­ma­tion in this article has been up­dated to take into account the drug's official wholesale pricing, which Bristol-Myers Squibb has provided to The Beacon.