The monoclonal antibody daratumumab has been widely embraced for the treatment of multiple myeloma, but for newly diagnosed patients, its benefit has been proved only in some patients, according to Craig Hofmeister, MD, MPH, Associate Professor of Medicine at the Winship Cancer Institute of Emory University.
Craig Hofmeister, MD, MPH
At the 2019 Debates and Didactics Conference in Sea Island, Georgia, sponsored by Emory, Dr. Hofmeister made the case for limited use of the drug in newly diagnosed patients.1 “On average, I don’t think daratumumab is going to provide a ton of value. However, in certain patients—the ‘perfect’ patients who have low-risk myeloma—it will likely provide longer survival and will ideally allow them to go into deep remission, where ongoing maintenance lenalidomide can be curtailed. That’s where this drug can be valuable,” he said.
Clinical Data and Costs
In the two phase III trials of most relevance to U.S. physicians—MAIA2 and CASSIOPEIA3—an overall survival benefit was unproven, but the period of disease control was mostly doubled. The wholesale cost, however, of adding daratumumab (for the average time on study) was $274,950 for 36 months in MAIA (daratumumab + lenalidomide/dexamethasone [Rd]) and $345,150 for approximately 48 months in CASSIOPEIA (daratumumab + bortezomib/thalidomide/dexamethasone [VTd]).
The MAIA trial evaluated daratumumab plus Rd in transplant-ineligible patients, continued until disease progression or death. In CASSIOPEIA, newly diagnosed patients were randomly assigned to receive four pretransplant induction and two posttransplant consolidation cycles of VTd alone or in combination with daratumumab. In a second randomization, patients received maintenance daratumumab or observation.
“In general, based on data across the trials, you’re going to double your period of disease control with the addition of daratumumab, and that’s good. However, there are going to be some problems: more infections, frequent intravenous infusions, and additional costs.”
Putting that cost into a day-to-day value equation, Dr. Hofmeister commented: “In my family, we’ve debated buying a Tesla vs a Prius, and it’s a difference of $40,000. Here, there’s a difference of $350,000—not a small difference.”
Who Benefits From Upfront Daratumumab?
Some, but not all, subsets of patients benefit from the upfront use of daratumumab, as Dr. Hofmeister explained by looking at the MAIA and CASSIOPEIA trials. In MAIA, at a median follow-up of 28 months, disease progression or death occurred in 26.4% of the daratumumab plus Rd arm and 38.8% of the control (Rd) group.
“However, if you look at patients who are higher risk—those with t(4;14), del(17p), or t(14;16) abnormalities, or those with ISS [International Staging System] stage 3 disease—there was no progression-free survival benefit,” Dr. Hofmeister pointed out.
In CASSIOPEIA, at day 100 after transplantation, 29% of the daratumumab plus VTd group and 20% of the VTd group had achieved a stringent complete response (P = .0010), and 39% and 26%, respectively, achieved a complete response or better (P < .0001). Median progression-free survival from first randomization was not reached in either group.
“But again, for patients at highest genetic risk and for those with ISS stage 3 disease, daratumumab has not yet proved to be beneficial,” noted Dr. Hofmeister. “In these high-risk groups, you’re not getting a lot of value for adding daratumumab to your induction therapy.”
Consequences of ‘Following the Hype’
“You’ve got to think about infections,” Dr. Hofmeister added, showing data from the three key clinical trials. “With daratumumab, 65% to 85% of patients had infections, vs 57% to 73% without daratumumab. There’s somewhere between 15% to 50% more infections, and about double the number of pneumonia,” Dr. Hofmeister pointed out.
“And these patients are ‘perfect’ clinical trial patients without many comorbidities,” he added. “You can expect that in the clinic, with your ‘non-Olympian’–type patients, things are worse than this…. If we follow the hype, that adding a new antibody is cool, let’s not forget we’re likely to have more infections than reported in the registration trials to date.”
Emory’s Treatment Algorithm for Newly Diagnosed Myeloma
Dr. Hofmeister shared an algorithm for the general treatment of newly diagnosed multiple myeloma. In his treatment plan, the use of upfront daratumumab is limited.
He explained that the preferred management of monoclonal gammopathy of unknown significance (MGUS) at Emory is to consider a clinical trial led by Madhav Dhodapkar, MBBS, involving the antibiotic rifaximin (with no placebo arm). Rifaximin is believed to alter the microbiome, and this could potentially prevent the transformation to myeloma. “Please consider sending your patients with MGUS for evaluation for this innovative trial,” he told attendees.
Patients with smoldering myeloma deemed to be at low risk for disease progression are managed by observation. Intermediate-risk patients with smoldering myeloma and those with monoclonal gammopathy of clinical significance receive lenalidomide with or without dexamethasone.
Patients with smoldering myeloma at highest risk and those diagnosed with myeloma receive some type of induction therapy, followed by stem cell transplantation and maintenance therapy. Patients with low-risk myeloma—ISS stage 1 to
2 disease and no high-risk genetic features—receive daratumumab as part of induction therapy and maintenance therapy. Frail patients, based on other medical illnesses or poor performance status, also receive daratumumab plus an immunomodulatory drug–based induction regimen at lower doses.
“In this algorithm, based on phase III trial data, there are really just two situations where you can think of using upfront daratumumab,” he emphasized. They are for low-risk and unfit patients with newly diagnosed disease. ■
DISCLOSURE: Dr. Hofmeister has received grants from Janssen, grants and personal fees for serving on a marketing advisory board from Celgene, personal fees for research advisory board service from Karyopharm and Imbrium Therapeutics, personal fees for research advisory board service from Oncopeptides, and personal fees for regulatory advisory board from Adaptive Biotechnologies.
REFERENCES
1. Hofmeister C: Should monoclonal antibodies be added to front-line myeloma treatment? 2019 Debates and Didactics Conference. Debate 3. Presented July 26, 2019.
2. Facon T, Kumar S, Plesner T, et al: Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med 380:2104-2115, 2019.
3. Moreau P, Attal M, Hulin C, et al: Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): A randomised, open-label, phase III study. Lancet 394:29-38, 2019.
