In my haste to get the news out about elotuzumab’s FDA approval yesterday, I mistakenly relied on a Cure Magazine article that stated Kyprolis was the drug used in combination with elo. I was surprised, but ran with it. I should have known better. The Cure Magazine article was mistaken. Elotuzumab (Empliciti), Revlimid and dexamethasone is the correct combination. I apologize and I’ve corrected the post.
Too bad. If elo worked as well with a proteasome inhibitor as it does with Revlimid (an IMiD), it would give our doctors a lot more options. But studies have relied on the Revlimid/elotuzumab combination from the start. When my first auto transplant failed back in 2011, Dr. Robert Orlowski, with M.D. Anderson in Houston, offered to try and fit me into a trial featuring Revlimid, elotuzumab and dex. The only catch: the control arm was Revlimid and dexamethasone; I was already refractory to that combination.
Making things more interesting: there was no way to know which trial arm I would be assigned to. Dr. Orlowski did graciously offer to allow me to opt out if I was assigned to the control arm. But that was a lot of work for an uncertain outcome. Even if I got into the elo arm, there were no guarantees that it would work.
As it turned out, I decided to go in a different direction. But I’ve been following the progress of elo ever since.
Why Revlimid? Did researchers try pairing elo with Velcade and find the results weren’t as good? Or were things more serendipitous than that? I’ll ask around this weekend and see if I can pin down the history. My understanding is there are ongoing studies pairing elo with several other classes of drugs. Maybe members of the Bristol-Myers Squibb research team chose to focus on the combination most likely to work and ran with it, waiting to try other combinations after elo was on its way to being FDA approved.
Want specifics? Here is Bristol-Myers Squibb’s official press release following yesterday’s approval:
Bristol-Myers Squibb and AbbVie Receive FDA Approval of Empliciti™ (elotuzumab) for the Treatment of Patients with Multiple Myeloma Who Have Received One to Three Prior Therapies
• First and only immunostimulatory antibody approved for multiple myeloma
• Approval based on ELOQUENT-2, which established the combination of Empliciti with lenalidomide and dexamethasone (Rd) delivered a significant progression-free survival benefit vs. Rd alone, demonstrated over two years (HR 0.70 [95% CI: 0.57, 0.85; p = 0.0004])
Monday, November 30, 2015 3:14 pm EST
PRINCETON, N.J.–(BUSINESS WIRE)–Bristol-Myers Squibb Company (NYSE:BMY) and AbbVie (NYSE:ABBV) today announced the U.S. Food and Drug Administration (FDA) has approved Empliciti (elotuzumab) for the treatment of multiple myeloma as combination therapy with Revlimid® (lenalidomide) and dexamethasone (ERd) in patients who have received one to three prior therapies. The approval of this first and only immunostimulatory antibody for multiple myeloma is based on data from the randomized, open-label, Phase 3, ELOQUENT-2 study, which demonstrated that the ERd regimen resulted in a 30% reduction in the risk of disease progression or death compared to Rd alone (HR 0.70 [95% CI: 0.57, 0.85; p = 0.0004]).
The co-primary endpoints were progression-free survival (PFS), as assessed by hazard ratio, and overall response rate (ORR). With a minimum of two years follow-up, ERd delivered a benefit in PFS that was maintained over time, with PFS rates of 68% versus 57% at one year and 41% versus 27% at two years in the ERd and Rd arms, respectively. The ERd regimen also demonstrated a significant improvement in ORR, achieving an ORR of 78.5% (95% CI: 73.6% to 82.9%) versus 65.5% in the Rd arm (95% CI: 60.1% to 70.7%). The most common adverse reactions in ERd and Rd, respectively (>20%) were fatigue (61.6%, 51.7%), diarrhea (46.9%, 36.0%), pyrexia (37.4%, 24.6%), constipation (35.5%, 27.1%), cough (34.3%, 18.9%), peripheral neuropathy (26.7%, 20.8%), nasopharyngitis (24.5%, 19.2%), upper respiratory tract infection (22.6%, 17.4%), decreased appetite (20.8%, 12.6%), and pneumonia (20.1%, 14.2%).
“At Bristol-Myers Squibb, we are leading a revolution in cancer treatment that is changing expectations for patients with some of the hardest-to-treat cancers. With today’s approval of Empliciti, we are pleased to now bring the promise of our Immuno-Oncology research to patients with multiple myeloma,” said Francis Cuss, MB Bchir, FRCP, chief scientific officer, Bristol-Myers Squibb. “Empliciti represents a fundamentally different approach of directly activating the immune system in patients with relapsed or refractory multiple myeloma, delivering improved outcomes for those in need.”
Empliciti is available for injection for intravenous use in 300 mg and 400 mg vials. The company expects to begin shipping Empliciti within the next 48 hours. Empliciti is also under review by the European Medicines Agency and has been granted accelerated assessment.
Discontinuation rates due to adverse reactions were similar across the ERd and Rd control arms (6.0% vs. 6.3%). ERd is associated with the following Warnings and Precautions: Infusion Reactions, Infections, Second Primary Malignancies, Hepatotoxicity, Interference with Determination of Complete Response, Pregnancy/Females and Males of Reproductive Potential, and Adverse Reactions. Please see the detailed Important Safety Information and a link to the Prescribing Information below.
“Multiple myeloma remains largely incurable, with only half of patients surviving five years after diagnosis,” said Sagar Lonial, M.D., chief medical officer of the Winship Cancer Institute of Emory University. “The approval of elotuzumab (Empliciti) provides renewed hope for the multiple myeloma community who urgently need a treatment option that extends the time patients live without their disease progressing.”
“Empliciti in combination with lenalidomide and dexamethasone is an important new option for patients with multiple myeloma and healthcare providers who are treating this cancer,” said Michael Severino, M.D., executive vice president of research and development and chief scientific officer, AbbVie. “AbbVie is pleased to have partnered with Bristol-Myers Squibb in making this new treatment available for patients with relapsed or refractory multiple myeloma.”
ELOQUENT-2 (CA204-004) is a randomized, open-label, Phase 3 study evaluating Empliciti in combination with lenalidomide and dexamethasone (ERd) versus lenalidomide and dexamethasone (Rd) alone in patients with relapsed or refractory multiple myeloma. The trial enrolled 646 patients who had received one to three prior therapies. Patients were randomized 1:1 to receive either Empliciti 10 mg/kg in combination with Rd or Rd alone in 4-week cycles until disease progression or unacceptable toxicity. Baseline patient demographics and disease characteristics were well balanced between treatment arms and included a meaningful portion of patients who were ≥ 65 years old, had high-risk cytogenetics, and/or were refractory to the most recent line of therapy. The minimum follow-up for all study subjects was 24 months. The co-primary endpoints were PFS, as assessed by hazard ratio, and ORR as determined by a blinded Independent Review Committee using the European Group for Blood and Marrow Transplantation response criteria. Results of the ELOQUENT-2 study were published in The New England Journal of Medicine on June 2, 2015.
The study demonstrated that the ERd regimen resulted in a 30% reduction in the risk of disease progression or death compared to Rd alone (HR 0.70 [95% CI: 0.57, 0.85; p = 0.0004]). Additionally, the PFS rates in the ERd arm versus the Rd arm were 68% versus 57% at one year and 41% versus 27% at two years, respectively. The ERd regimen demonstrated a significant improvement in ORR, achieving an ORR of 78.5% (95% CI, 73.6% to 82.9%; p = 0.0002) in the ERd arm versus 65.5% in the Rd arm (95% CI, 60.1% to 70.7%). The median PFS in the ERd group was 19.4 months (95% CI, 16.6 to 22.2) versus 14.9 months (95% CI, 12.1 to 17.2) in the Rd group. At the time of the interim analysis, there were fewer deaths in the ERd versus Rd study arm (94 [29%] versus 116 [36%], respectively).
Serious adverse reactions were reported in 65.4% of patients treated on the ERd arm and 56.5% for patients treated on the Rd arm. The most frequent serious adverse reactions in the ERd arm compared to the Rd arm were: pneumonia (15.4%, 11%), pyrexia (6.9%, 4.7%), respiratory tract infection (3.1%, 1.3%), anemia (2.8%, 1.9%), pulmonary embolism (3.1%, 2.5%), and acute renal failure (2.5%, 1.9%). The most common adverse reactions in ERd and Rd, respectively (>20%) are fatigue (61.6%, 51.7%), diarrhea (46.9%, 36.0%), pyrexia (37.4%, 24.6%), constipation (35.5%, 27.1%), cough (34.3%, 18.9%), peripheral neuropathy (26.7%, 20.8%), nasopharyngitis (24.5%, 19.2%), upper respiratory tract infection (22.6%, 17.4%), decreased appetite (20.8%, 12.6%), and pneumonia (20.1%, 14.2%). Infusion reactions occurred in 10% of patients treated with ERd; these adverse events were Grade 3 or lower (Grade 3, 1%; Grade 4, 0%) and were manageable. In the trial, 1% of patients discontinued due to infusion reactions and 5% of patients required interruption of the administration of Empliciti for a median of 25 minutes. Grade 3/4 laboratory abnormalities that worsened from baseline and had a 10% or higher incidence for ERd patients and a 5% higher incidence than Rd patients were: lymphopenia (76.7%, 48.7%), leukopenia (32.4%, 25.6%), hyperglycemia (17.0%, 10.2%), and hypocalcemia (11.3% and 4.7%).Overall, the proportion of patients who discontinued treatment due to adverse reactions was similar for the ERd and Rd arms (6.0% vs. 6.3%, respectively).
“The approval of Empliciti is an innovative advancement in the treatment of multiple myeloma,” said Walter M. Capone, chief executive officer and president, The Multiple Myeloma Research Foundation. “This is an exciting opportunity for patients who experience relapse and may benefit from this new immunotherapy treatment.”
Empliciti is an immunostimulatory antibody that specifically targets Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7), a cell-surface glycoprotein. SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities. SLAMF7 is also expressed on Natural Killer cells, plasma cells, and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage.
Empliciti has a dual mechanism-of-action. It directly activates the immune system through Natural Killer cells via the SLAMF7 pathway. Empliciti also targets SLAMF7 on myeloma cells, tagging these malignant cells for Natural Killer cell-mediated destruction via antibody-dependent cellular toxicity.
Bristol-Myers Squibb and AbbVie are co-developing Empliciti, with Bristol-Myers Squibb solely responsible for commercial activities. Prior to approval, Empliciti was granted Breakthrough Therapy Designation by the FDA for use in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in patients who have received one to three prior therapies. According to the FDA, Breakthrough Therapy Designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for Breakthrough Therapy Designation requires preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy.
About Bristol-Myers Squib’s Patient Support Programs
Bristol-Myers Squibb is committed to helping patients through treatment with Empliciti. For support and assistance, patients and physicians may call 1-844-EMPLICITI. This number offers one-stop access to a range of support services for patients and healthcare professionals alike.
About Bristol-Myers Squibb’s Access Support
Bristol-Myers Squibb is committed to helping patients access Empliciti and offers numerous programs to support patients and providers in gaining access. BMS Access Support®, the Bristol-Myers Squibb Reimbursement Services program, is designed to support access to BMS medicines and expedite time to therapy through reimbursement support including Benefit Investigations, Prior Authorization Facilitation, Appeals Assistance, and assistance for patient out-of-pocket costs. BMS Access Support assists patients and providers throughout the treatment journey―whether it is at initial diagnosis or in support of transition from a clinical trial. More information about our reimbursement support services can be obtained by calling 1-800-861-0048 FREE or by visiting www.bmsaccesssupport.com. For healthcare providers seeking Empliciti specific reimbursement information, please visit the BMS Access Support Product section by visiting www.bmsaccesssupportoncology.com.
A 30% reduction in the risk to disease possession is significant. I’ll let you decide if an extra five months PFS is worth the cost and risk.
I’ll be frank. If this wasn’t the first of an exciting new class of drug, these numbers would be underwhelming. But I think researchers, specialists and the FDA think it’s important to make this first generation immunotherapy available to patients. The hope is that elo will be the first building block–the gateway drug–to a game changing biologic approach to treating multiple myeloma.
I’ve been hard on elo over the years. One reason is personal bias. I know a half dozen late stage patients–several close personal friends–that worked hard to try and gain access to elotuzumab. In the end, adding the drug to their therapy mix failed to make a measurable difference.
Contrast that with reports of near miraculous turn around among late stage patients that are trying daratumumab:
Posted on November 03 2015 by Pat Killingsworth | 2,384 views
To be fair, these are anecdotal examples, good and bad. But they help form my impressions.
My take on Empliciti? The revolutionary drug works best early on. Note patients in the ELOQUENT-2 Study were very lightly pretreated. We’re not talking patients that were relapsed/refractory to five or six prior therapies. Instead, it’s one to three prior therapies. And correct me if I’m wrong, but I thought I read that although some of the patients had used Revlimid, none of the patients were refractory to the IMiD.
As time goes on, myeloma specialists will learn which drug works best and when. My guess is elo will be a helpful addition to combination therapies up front or after first relapse. Maybe as a safe addition to ongoing maintenance post stem cell transplant.
There’s a place and time for the quickly expanding stable of anti-myeloma therapies. I chose to use “therapies” instead of “drugs.” Don’t forget about advances being made to improve auto and allo stem cell transplants. Or CAR T cell and modified T cell therapies. Or biologics using viruses to help deliver death blows to myeloma cells.
It’s a revolutionary and exciting time for the hem/oncs that treat us. Things are moving fast; at a record pace. By oncology standards change is off the charts fast and moving at a record pace. The billion dollar question: How long will it take myeloma researchers and specialists to make sense of it all and apply it effectively and selectively. Five years? A decade?
If I were a newly smoldering or newly diagnosed, standard risk multiple myeloma patient I would be off-the-charts-hopeful. But what about high risk patients? Or patients like me that have relapsed a number of times.
Record gains or not, some of us don’t have five or ten years to wait. We need a major breakthrough. Someway, somehow, researchers need to learn how to overcome drug resistance. Here’s hoping that immunotherapies, T cell therapy and/or biologics hold the key.
Feel good and keep smiling! Pat