Daratumumab Triplet for First-Line Myeloma, but Questions Remain

Alexander M. Castellino, PhD

May 29, 2019

The triplet combination of daratumumab (Darzalex, Janssen), lenalidomide (Revlimid, Celgene), and dexamethasone (multiple brands) is a new chemotherapy-free option for first-line therapy for patients with multiple myeloma who are ineligible for autologous stem cell transplant, say researchers. The triplet reduced the risk for disease progression or death by 44% compared with a standard regimen of lenalidomide and dexamethasone.

In addition, nearly twice as many patients who received the triplet showed a complete response or better (47.6% vs 24.9% for the control group), and minimal residual disease was seen in more than three times as many patients who received the triplet (24.2% vs 7.3% for the control group; P < .001).

These results, from a prespecified interim analysis of the MAIA study, were published online May 30 in the New England Journal of Medicine. Thierry Facon, MD, professor in the Department of Haematology, Lille University Hospital, France, is the lead and corresponding author.

Daratumumab is a human monoclonal antibody that targets CD38. It is already approved as frontline therapy in combination with bortezomib (Velcade, Takeda), melphalan (multiple brands), and prednisone (multiple brands) for patients who are ineligible for stem-cell transplant. The approval was based on results from the ALCYONE trial.

These latest results establish a new treatment option. "The findings of the trial highlight the superior efficacy of a three-drug induction regimen incorporating daratumumab in combination with lenalidomide and dexamethasone," writes Jacob Laubach, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, in an invited editorial.

Laubach notes that the findings from the study underscore the safety of the combination in older, frail patients. However, he also points out that questions remain as to the feasibility of rechallenging after resistance to daratumumab-based therapy develops.

Implications for Clinical Practice

Medscape Medical News asked multiple myeloma expert S. Vincent Rajkumar, MD, from the Mayo Clinic, Rochester, Minnesota, for comments about the new article.

The current standard of care in the United States is the triplet regimen of bortezomib, lenalidomide, and dexamethasone. It has been the standard of care for many years for patients with newly diagnosed multiple myeloma, with or without the intent for initial autologous stem cell transplant, Rajkumar told Medscape Medical News. It became the standard of care on the basis of results from the SWOG trial S0777, which demonstrated the superiority of the triplet combination over a doublet regimen with respect to overall survival (OS) and progression-free survival (PFS).

Further, the bortezomib-based triplet has the advantage of a longer safety follow-up and additional safety data from the IFM 2009 randomized controlled trial.

Currently, the results of MAIA are unlikely to change the standard of care in the United States, Rajkumar said.

"MAIA results are important, and with additional data on OS from this trial and other trials testing daratumumab-based triplets, I think daratumumab will be incorporated in the frontline setting in some form," Rajkumar told Medscape Medical News.

In his editorial, Laubach notes that as highly active induction regimens become assimilated into clinical practice, the assessment of minimal residual disease status may guide management decisions for patients.

Laubach told Medscape Medical News that the daratumumab triplet used in MAIA and the bortezomib triplet will be used most widely in the United States, where regimens that incorporate melphalan are less often utilized as induction therapy. "Both regimens are supported by data from phase 3 clinical trials and can be administered safely in older patients," he said. The daratumumab triplet will be preferred for patients with preexisting peripheral neuropathy, he added. Both regimens can be safely administered to patients with renal impairment with appropriate dose and schedule modifications of lenalidomide, Laubach noted.

Laubach suggested that the combination of daratumumab, melphalan, bortezomib, and prednisone will be utilized in parts of the world where melphalan continues to be a mainstay of induction therapy.

He also sees a role for doublet regimens in frontline treatment. "It's also important to note that two-drug regimens such as lenalidomide and dexamethasone or bortezomib and dexamethasone will continue to be used as induction therapy for frail patients who are not felt to be candidates for a three-drug regimen," he said.

When resistance to a daratumumab-containing regimen emerges, it may be overcome with another regimen that pairs daratumumab with a new agent, according to preliminary evidence from smaller studies, Laubach said. For example, a patient who experiences progression on an induction regimen of daratumumab plus lenalidomide and dexamethasone may respond to daratumumab plus bortezomib and dexamethasone, he said.

However, patients who experience disease progression can also be offered a new line of treatment that employs one or two agents to which the patient has not previously been exposed, in the expectation that such therapy will again control growth of the tumor clone, Laubach told Medscape Medical News. For example, a patient who receives daratumumab plus lenalidomide and dexamethasone as induction and maintenance therapy would presumably receive second-line therapy that incorporates bortezomib, carfilzomib (Kyprolis, Amgen), or ixazomib (Ninlaro, Takeda).

Rajkumar told Medscape Medical News that they are exploring frontline regimens with carfilzomib as well as the other investigational anti-CD38 monoclonal antibody, isatuximab (Sanofi). "We need to then determine subsets of patients who can best benefit from the three major induction strategies available: monoclonal antibody–based triplets, proteasome-based triplets, and quadruplets that combine both a monoclonal antibody and a proteasome inhibitor along with lenalidomide and dexamethasone," Rajkumar said.

MAIA Study Design Raises Questions

Rajkumar and Prashant Kapoor, MD, also of Mayo Clinic, coauthored an opinion piece that was published March 8 in Nature Reviews Clinical Oncology. Rajkumar said that his opinions about these data had not changed since they were first presented at the annual meeting of the American Society for Hematology in 2018 in San Diego, California.

In their article, Kapoor and Rajkumar say that the primary endpoint of MAIA, PFS, is suboptimal for changing the standard of care in the United States. This triplet combination had already shown superiority in comparison with the control therapy for patients with multiple myeloma who had experienced relapse on therapy, they note.

"The most pertinent clinical question is, therefore, whether the use of daratumumab in the frontline setting is a better approach than reserving this agent for the treatment of relapsed disease," Kapoor and Rajkumar comment.

The endpoint should have been OS, not PFS. This would have accounted for effects of subsequent treatment, including daratumumab-based therapy, in the control group, they contend.

"This bar is the same one that rituximab had to overcome in order to be incorporated into the standard-of-care initial therapy of diffuse large B cell lymphoma," they write.

"In MAIA, the daratumumab-based triplet was compared with a doublet, rather than the standard of care, which is the triplet regimen of bortezomib, lenalidomide, and dexamethasone," Rajkumar told Medscape Medical News. He also noted that the bortezomib-based triplet is easier to administer and is far less expensive.

Kapoor and Rajkumar also note that because the daratumumab-based triplet was used as induction and maintenance, it had a "hardwired bias" that probably ensured its success. In designs of the daratumumab studies (ALCYONE and CASTOR), because daratumumab was used in the induction and maintenance settings, it is not possible to determine where its maximum benefit resides — in induction or maintenance.

"Ideally, a new treatment should initially be tested separately in either the induction or the maintenance setting," Kapoor and Rajkumar write. "More importantly, these designs bias the results, such that the observed findings might be artificially superior to other comparator regimens for which such a strategy to maximize improvements in surrogate end points was not used," they add.

In oncology, the critical question is whether positive studies are practice changing and alter the current standard of care, Kapoor and Rajkumar contend. They point out that they have put MAIA under the microscope and used it as a case in point to illustrate that for any clinical study, meeting the primary endpoint is only a starting point. "To change practice and standards of care, we need much more: more evidence and more reasoned consideration of the trial findings vis-à-vis the current clinical landscape," they write.

"Our goal is to deliver the best care to our patients and crucially, therefore, the results must be analysed in the context of what is known at the time when an RCT [randomized clinical trial] has been completed, rather than being interpreted in a 'vacuum,' " they write. In that context, several questions need to be addressed, they comment. They list some of them: Does the trial design address the question that is pertinent today, not what was pertinent at the time when the trial was designed? Was the design appropriate? Has the optimal control intervention changed since the trial was designed? Does the new regimen have clear advantages over the existing standard of care, not only in terms of efficacy but also cost, convenience, and safety?

Interpretation of the implications for clinical practice demands consideration of many more factors beyond a strongly positive result, which is solely intended for regulatory approval of the experimental regimen, they conclude.

In discussing these data with Medscape Medical News, Rajkumar said that the design problems are not unique to MAIA and that many factors influence the design of a trial, including regulatory considerations in Europe. "I am currently leading clinical trials with similar design issues," he said.

MAIA Study Details

MAIA is an ongoing, randomized, open-label, phase 3 trial that enrolled patients with newly diagnosed multiple myeloma. The patients' ECOG (Eastern Cooperative Oncology Group) performance standard was 0–2. They were ineligible for high-dose induction chemotherapy followed by stem cell transplant either because of age (≥65 years) or coexisting conditions that precluded their receiving induction chemotherapy.

Patients were randomly assigned to receive either the triplet therapy, which included daratumumab (n = 368), or standard therapy of lenalidomide and dexamethasone (n = 369).

For each 28-day cycle, daratumumab was given at a dose of 16 mg/kg of body weight once weekly during cycles 1 and 2; every 2 weeks during cycle 3 through 6; and every 4 weeks for subsequent cycles. Lenalidomide and dexamethasone were provided at the approved doses.

Patients received therapy until disease progression or unacceptable toxicity occurred.

Demographic and disease characteristics were well balanced across the two groups. In the daratumumab group, the median age of the patients was 73 years; only 1.1% of the patients were younger than 65 years. For 85% of the patients, the cytogenetic profile indicated standard-risk multiple myeloma.

In the trial, 32.4% of the patients in the daratumumab group and 56.7% of the patients in the control group had discontinued treatment at the time of data cutoff for the primary analysis. The most common reasons for discontinuing were the occurrence of progressive disease (32.4% for the daratumumab group vs 56.7% for the control group) and adverse events (7.4% vs 16.2%).

The median duration of treatment for the daratumumab group was 25.3 months, vs 21.3 months for the control group. The median number of treatment cycles was 27 for the daratumumab and 22 for the control group.

For the primary endpoint of PFS, median PFS was not reached for patients in the daratumumab group; it was 31.9 months for those in the control group. The hazard ratio for patients in the daratumumab group (vs the control group) was 0.56 (95% confidence interval, 0.43 – 0.73; P < .001).

After a median follow-up of 28 months, 30-month OS was 70.6% for the patients who received the daratumumab regimen and 55.6% for those in the control group. Median OS was not reached for either group, and a longer follow-up is required.

The superiority of the daratumumab regimen was noted for all subgroups except for patients who had hepatic impairment at baseline.

Rates of complete response or better and very good partial response or better were also significantly higher for patients receiving the daratumumab triplet regimen (79.3% vs 53.1%; P < .001) .

Minimal residual disease, defined at a threshold of 1 tumor cell per 105 white blood cells, was seen in more than three times as many patients who received daratumumab. Minimal residual disease increased over time at a higher rate in the daratumumab group than in the control group, the MAIA investigators note.

The most common adverse events of grade 3 or 4 were neutropenia (50% for the daratumumab group vs 35.3% for the control group), anemia (11.8% vs 19.7%), lymphopenia (15.1% vs 10.7%), and pneumonia (13.2% vs 7.4%).

Infusion-related adverse events occurred in the daratumumab group (40.9%) mainly during the administration of the first dose; 2.7% were of grade 3 or 4, and one patient experienced grade 4 hypertension.

The study was funded by Janssen Research and Development. Many of the authors report relationships with industry, as detailed in the original article. Laubach has disdclosed no relevant financial relationships.

N Engl J Med. Published online May 30, 2019. Abstract, Editorial

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