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Daratumumab combination improves PFS, ORR in relapsed, refractory multiple myeloma
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CHICAGO — The addition of daratumumab to bortezomib and dexamethasone significantly prolonged PFS and time to progression in patients with relapsed or refractory multiple myeloma, according to early results of the CASTOR study presented during the plenary session of the ASCO Annual Meeting.
The combination with daratumumab also doubled the rates of very good partial and complete response and demonstrated a safety profile consistent with the known toxicity profiles of the agents.
Daratumumab (Darzalex, Janssen) became the first human anti–CD38 monoclonal antibody approved for the treatment of multiple myeloma by the FDA in November 2015. It has been shown to induce deep and durable responses in patients with relapsed or refractory disease.
“In the era of immuno-oncology, we hope to have our own R-CHOP, which has been shown to be a major treatment for lymphoma and which is available with different antibodies for multiple myeloma,” Antonio Palumbo, MD, chief of the myeloma unit in the department of oncology at University of Turin, in Italy, said during a press conference. “With daratumumab we have a monoclonal antibody that is eating the most relevant tumor antigen for plasma cells, a very specific target.”
Palumbo and colleagues evaluated the safety and efficacy of the addition of daratumumab to bortezomib (Velcade; Millennium, Takeda) and dexamethasone in 488 patients who had received at least one prior therapy (median, n = 1; range, 1-10).
The researchers randomly assigned patients to eight cycles every 3 weeks of bortezomib (1.3 mg/m2 on days 1, 4, 8 and 11) and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12), with (n = 251) or without (n = 247) IV daratumumab (16 mg/kg per week cycles 1-3; on day 1 of cycles 4-8; then every 4 weeks until progression).
Sixty-six percent of patients had previously received bortezomib, and 32% were refractory to their last prior therapy.
PFS served as the study’s primary endpoint. Secondary endpoints included time to response, overall response rate, OS and safety.
Researchers planned to conduct an interim analysis after approximately 177 PFS events had occurred. Median follow-up was 7.4 months.
Median PFS in the daratumumab arm had not been reached at the time of reporting, and was 7.1 months for the bortezomib and dexamethasone arm. This data equated to a 61% reduction in the risk for progression or death with the addition of daratumumab, thus meeting the study’s primary endpoint at the interim analysis (HR = 0.39; 95% CI, 0.28-0.53).
“This is unprecedented in randomized studies that compare novel treatment for relapsed and refractory multiple myeloma,” Palumbo said.
Patients assigned daratumumab also experienced a significantly longer time to progression (median, not reached vs. 7.2 months; HR = 0.3; 95% CI, 0.21-0.43).
The ORR was significantly higher in the daratumumab arm (83% vs. 63%; P < .0001). Daratumumab doubled rates of complete response or better (19% vs. 9%; P = .0012) and very good partial response or better (59% vs. 29%; P < .0001).
Median duration of response has not been reached in patients assigned daratumumab and was 7.9 months among patients assigned bortezomib and dexamethasone alone.
The most common any-grade adverse events included thrombocytopenia (59% vs. 44%), peripheral sensory neuropathy (47% vs. 38%), diarrhea (32% vs. 22%) and anemia (26% vs. 31%). Grade 3 or worse adverse events observed in more than 10% of patients included thrombocytopenia (45% vs. 33%), anemia (14% vs. 16%) and neutropenia (13% vs. 4%).
Forty-five percent of patients in the daratumumab arm experienced infusion-related reactions, the majority of which were low grade (grade 3, 9%; grade 4, 0).
Seven percent of patients assigned the daratumumab combination and 9% assigned bortezomib and dexamethasone alone discontinued treatment due to adverse events.
“The benefit of daratumumab with bortezomib and dexamethasone was maintained across different subgroups: younger patients, older patients, good prognoses, bad prognoses,” Palumbo said. “The final conclusion is that daratumumab in this combination might be considered a new standard of care for relapsed and refractory multiple myeloma.”– by Cameron Kelsall
Reference:
Palumbo A, et al. Abstract LBA4. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.
Disclosure: Janssen Research & Development provided funding for this study. Palumbo reports institutional research funding from, as well as consultant roles with, Genmab, Janssen–Cilag and Takeda. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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Julie M. Vose, MD, MBA, FASCO
This is an important study looking at the addition of immunotherapy to standard therapy, which is a theme we are seeing in a lot of our diseases. It has now come to multiple myeloma, with improvements seen in PFS, and likely to be seen in OS later on.
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Ravi Vij, MD
The CASTOR Trial data presented by Antonio Palumbo, MD, in the plenary session evaluating the addition of daratumumab (Darzalex, Janssen) to bortezomib (Velcade, Millennium/Takeda) and dexamethasone is unparalleled so far in data for relapsed/refractory multiple myeloma. These patients had received an average of one other prior therapy, and anywhere from one to three prior therapies was permitted.
The rate of 1-year PFS in the three-drug regimen arm was 60.7%, compared with 26.9% for bortezomib and dexamethasone alone (HR = 0.39; 95% CI, 0.28-0.53), which represents an approximately 61% reduction in time to progression. The data on time to progression was even more impressive.
Data from the POLLUX trial presented at the European Hematology Association Congress on the addition of daratumumab to lenalidomide and dexamethasone showed an even more impressive improvement in PFS (HR = 0.37; 95% CI, 0.27-0.52). The median PFS in the daratumumab arm has not been reached, compared with a median of 18.4 months for patients who received lenalidomide and dexamethasone alone.
There have been a number of drug approvals in the last year for patients who have failed one or more lines of therapy. This has included approvals for carfilzomib (Kyprolis, Onyx Pharmaceutics), lenalidomide (Revlimid, Celgene) and dexamethasone; ixazomib (Ninlaro, Millennium/Takeda), lenalidomide and dexamethasone; and elotuzumab (Empliciti, Bristol-Myers Squibb), lenalidomide and dexamethasone, all of which had approximately 30% reduction in risk for progression. This daratumumab data are nearly double in terms of its impact on PFS.
Certainly, these two phase 3 trials of daratumumab combination therapies have the potential to change our treatment algorithm. Once the drug gets approved in the earlier line of treatment based on these studies, it will move from the relapsed/refractory third-line setting, where it is currently being used, to the second-line setting.
There is great excitement around the immune-based therapy approach for cancer, and myeloma has had drugs in the immunomodulatory drug class like pomalidomide (Pomalyst, Celgene), lenalidomide and thalidomide for a long time, but only recently have we had monoclonal antibodies. In the future will have additional classes immunotherapy drugs, such as checkpoint inhibitors and CAR T cells, move into the therapeutic armamentarium of multiple myeloma
Reference:
Palumbo A, et al. Abstract LB2236. Presented at: European Hematology Association Congress; June 9-12, 2016; Copenhagen.
Perspective
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Ruben Niesvizky, MD
Daratumumab (Darzalex, Janssen) is a human IgG1k monoclonal antibody directed against the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death — or apoptosis — and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.
The U.S. approval of daratumumab for patients with multiple myeloma who have received at least three prior lines of therapy — including a proteasome inhibitor and an immunomodulatory agent — or who are double refractory to a proteasome inhibitor and an immunomodulatory agent came about after the results of phase 2 single-agent data were reported. Indeed, the study using daratumumab at 16 mg/kg showed in this very ill population a 29.2% response rate and a median duration of response of 7.4 months.
The recent report at ASCO determined the PFS of the combination of the three-drug regimen of daratumumab plus bortezomib and dexamethasone compared with the control regimen, which consisted of bortezomib and dexamethasone alone. As expected, the three-drug combination performed much better, and the fact the results showed a 61% decreased risk for progression or death is staggering. We are very eager to see follow-up of long-term, more mature results that might inform us if this signal is sustained. Nevertheless, this is enough argument to move the drug earlier in the course of patients, and hopefully it will be incorporated earlier in first line. We still have to learn to discern which patients will benefit from this drug, the effect on stem cell viability and collection, and long-term benefit.
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