This ‘embarrassment of riches’ is not embarrassing at all. It’s a consequence of collaborations between patients and academic, industry, and advocacy groups. Now, the challenge is to take the pieces and put them together in a coherent fashion.
—Sagar Lonial, MD
This is a revolutionary time in multiple myeloma. The three drugs approved in November—daratumumab, elotuzumab, and ixazomib—promise to change the landscape of treatment and improve overall survival.
—S. Vincent Rajkumar, MD
The use of newer drugs, earlier in disease, is vital…. Their approvals add profoundly to the armamentarium in taking on this challenge.
—Paul G. Richardson, MD
Few malignancies have received as much attention, in the way of newly approved drugs, as multiple myeloma did in 2015. In November alone, 3 new agents were approved, bringing the total to 4 for the year as part of a record 7 approvals and to 16 regulatory approvals over the past 12 years.
Speakers at myeloma sessions at the 2015 American Society of Hematology (ASH) Annual Meeting played to packed audiences. At a special session that was called “unprecedented” at the ASH meeting, U.S. Food and Drug Administration (FDA) reviewers described the rationale for the approvals while myeloma experts discussed how they will likely use the new drugs in clinical practice.1
Changing the Treatment Landscape
“This is a revolutionary time in multiple myeloma. The three drugs approved in November—daratumumab (Darzalex), elotuzumab (Empliciti), and ixazomib (Ninlaro)—promise to change the landscape of treatment and improve overall survival,” said S. Vincent Rajkumar, MD, Professor of Medicine at the Mayo Clinic, Rochester, Minnesota.
Because of “the plethora of new drugs,” he said, more than 80% of newly diagnosed patients are living more than 4 years.
“Elotuzumab and daratumumab are the first available monoclonal antibodies [in this setting]. It’s been a long wait…. Ixazomib is the first oral proteasome inhibitor, and it promises to make our treatments more convenient,” Dr. Rajkumar said. The fourth drug approved in 2015 was panobinostat (Farydak), the first histone deacetylase inhibitor for myeloma.
The drugs all received priority review or accelerated approval, which mobilizes drug delivery to patients who have exhausted other treatment options.
Newly diagnosed patients also gained a new treatment option in 2015: lenalidomide (Revlimid) plus dexamethasone, which was previously indicated only in patients who have received at least one treatment.
“We have to thank the FDA for approving these drugs so rapidly,” Dr. Rajkumar commented at the special session.
Sagar Lonial, MD, Professor of Medicine at Emory University School of Medicine, Atlanta, proclaimed this “a year of success,” and commented, “This ‘embarrassment of riches’ is not embarrassing at all. It’s a consequence of collaborations between patients and academic, industry, and advocacy groups. Now, the challenge is to take the pieces and put them together in a coherent fashion.”
More Drugs, More Combinations
According to Dr. Lonial, more new drugs and more drug classes make for more effective combination therapy. Myeloma is not a single-clone disease; therefore, it is best attacked via multiple agents working through different mechanisms.
“There is a very strong case in support of combinations. Benefits of combinations are there, for both high-risk and standard-risk patients,” he emphasized. Combination therapies targeting all coexisting subclones can achieve better depth and duration of response than sequential therapy, he added.
“Here at ASH, the combination of a proteasome inhibitor and immunomodulatory drug has come of age,” Dr. Lonial said, citing several studies supporting this concept. In SWOG 0777, the triplet of bortezomib (Velcade)/lenalidomide/dexamethasone significantly reduced the risk of both progression and death by 29% over lenalidomide/dexamethasone alone.2 This study confirmed, he said, that “three-drug induction is optimal, and an [immunomodulatory drug/proteasome inhibitor] combination is best.”
Positioning the New Drugs
While elotuzumab, daratumumab, ixazomib, and panobinostat are indicated for relapsed/refractory myeloma, these new agents will also be incorporated into the front-line setting, according to Dr. Rajkumar, who acknowledged this is an off-label use.
Ixazomib will be a good substitute for bortezomib (in combination with lenalidomide/dexamethasone) for standard-risk patients who are frail or elderly (≥ 75 years) and for newly diagnosed patients who need a convenient alternative to bortezomib, he suggested.
“What strikes me is that this is a very simple regimen, as you take just three drugs a month, and the side-effect profile is outstanding,” Dr. Rajkumar commented. The drug would also be useful under other circumstances where bortezomib cannot be used. “Keep in mind, you may have a situation where you can use ixazomib in newly diagnosed patients,” he said.
Phase III trials in the front-line setting are underway examining lenalidomide/dexamethasone in combination with ixazomib, elotuzumab, and daratumumab.
Paul G. Richardson, MD, the R.J. Corman Professor of Medicine at Harvard Medical School and Director of Clinical Research and Clinical Program Leader of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, Boston, discussed how he would position the new drugs in patients with relapsed and refractory disease.
“In myeloma, you can revisit classes of drugs that you previously gave, recognizing that rational combinations of the same drugs make sense as you seek to salvage patients with recurrent disease…. Tolerability and quality of life should be kept in mind in assuring our patients not only live longer, but live well,” Dr. Richardson emphasized.
To this end, physicians should consider age, frailty, and preexisting conditions, such as peripheral neuropathy and cardiovascular as well as thromboembolic risk. Genetic profiles, which are “highly dynamic,” and the phenomenon of clonal heterogeneity are “very real” considerations in relapse, explaining why combination approaches are consistently more effective in randomized trials.
“The ability to throw a wide net around the disease is a key way forward,” he commented. “The use of newer drugs, first in relapse and then, earlier in disease, is also vital…. Their recent approvals add profoundly to our armamentarium in taking on this challenge.”
Focusing on the monoclonal antibodies, Dr. Richardson emphasized that their novel mechanism of action should be especially effective in treating high-risk disease. “Daratumumab and elotuzumab are paradigm-changing agents. They appear to override the impact of mutations and provide entirely non–cross-resistant strategies, which we can also add to existing drugs,” he said.
All of the new agents should boost the results already being achieved with triplets that include immunomodulatory drugs, a proteasome inhibitor, and dexamethasone. To this end, regimens containing lenalidomide/dexamethasone plus bortezomib, carfilzomib (Kyprolis), panobinostat plus bortezomib or carfilzomib, ixazomib, elotuzumab, daratumumab, and the still-investigational monoclonal antibody isatuximab (SAR650984) have shown promising efficacy in clinical trials.
The newer immunomodulatory drug pomalidomide (Pomalyst) is also proving to be a very promising partner with the monoclonal antibodies, he indicated, as well as being highly effective in various other combinations, including bortezomib and carfilzomib. Specifically daratumumab given with pomalidomide/dexamethasone yielded a response rate of 71% in heavily pretreated patients.3 “This suggests that combining daratumumab with an immunomodulatory drug could be very beneficial,” he said.
Dr. Rajkumar agreed. “Clearly, the 31% response rate of single-agent daratumumab—in patients who had [experienced treatment failure on] almost everything—was very impressive from a regulatory standpoint,” he said. “But when you have a triple-refractory patient in front of you who hasn’t seen daratumumab before, most of us are probably not going to use it as a single agent, because we know that 70% will not respond.” He added, “For second and third relapse, based on data we heard at this meeting, daratumumab plus [pomalidomide/dexamethasone] will be one of our choices.”
Elaborating on the use of ixazomib, Dr. Richardson said this drug “fits very well” in the relapsed/refractory space because of its tolerability, oral route, and convenient once-weekly dosing. He sees it as especially useful in combination with lenalidomide/dexamethasone in patients with high-risk features. Ixazomib may also be a good partner for panobinostat, as well as the monoclonal antibodies, including daratumumab. Moreover, daratumumab is an anti-CD38 agent, and panobinostat upregulates CD38, he noted, making studies incorporating histone deacetylase inhibitors and monoclonal antibodies targeting CD38 of great interest.
Elotuzumab is approved in combination with lenalidomide/dexamethasone; however, Dr. Richardson pointed out that many patients will be on lenalidomide/dexamethasone maintenance when relapse occurs. In this situation, he may use elotuzumab in combination with a proteasome inhibitor, with recent data supporting the activity of this combination. In relapsed patients heavily exposed to lenalidomide, he would also consider pomalidomide in combination with one of the new drugs, “recognizing that participation in a clinical trial is ideal in that setting.”
Drs. Richardson, Rajkumar, and Lonial all emphasized that it is not a question of which new drug to use, but how to sequence the drugs, and this will be further complicated (and enhanced) when next-generation agents and drugs from new classes become available. “Our patients are likely to need all these drugs,” Dr. Richardson commented.
Dr. Rajkumar ended with a plea to the pharmaceutical industry. “It’s no longer a question of doublet vs triplet. It’s which triplet is best, and which endpoint is meaningful? Those are the trials I implore pharma to support,” he said. ■
Disclosure: Dr. Rajkumar reported no potential conflicts of interest. Dr. Lonial is a consultant for Millennium, Celgene, Novartis, Bristol-Myers Squibb, Onyx, and Janssen. Dr. Richardson has served on advisory committees for Celgene, Johnson & Johnson, Millennium, Takeda, Bristol Myers Squibb, and Novartis.
1. ASH/FDA Joint Symposium on Late-Breaking Drug Approvals: Late Breaking Approvals for Myeloma Drug Products. 2015 ASH Annual Meeting. Special-Interest Session. Presented December 7, 2015.
2. Durie B, Hoering A, Rajkumar SV, et al: Bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant. 2015 ASH Annual Meeting. Abstract 25. Presented December 5, 2015.
3. Chari A, Lonial S, Suvannasankha A, et al: Open-label multicenter phase 1b study of daratumumab in combination with pomalidomide and dexamethasone in patients with at least 2 lines of prior therapy and relapsed or relapsed and refractory multiple myeloma. 2015 ASH Annual Meeting. Abstract 508. Presented December 7, 2015.