These results with the addition of daratumumab to bortezomib/dexamethasone represent a significant prolongation of progression-free survival, associated with the highest rates and extent of response yet achieved with any therapy for relapsed multiple myeloma.— Kenneth C. Anderson, MD
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The CD38 antigen was first recognized on normal and abnormal plasma cells over 3 decades ago. Indeed, this antigen was originally classified as T10, as it was the tenth antigen described on T cells. Its distribution of expression included activated B and T cells, natural killer cells, leukocytes, hematopoietic progenitor cells, and endothelial cells. Although DNA-based CD38 vaccines and CD38 immunotoxin were evaluated in preclinical studies, clinical trials targeting CD38 were not conducted due to concerns over untoward effects on these normal cells and that there may not be a sufficient therapeutic index or window.
Early preclinical studies of the anti-CD38 monoclonal antibody daratumumab (Darzalex) revealed that it triggers complement dependent and antibody-dependent cellular cytotoxicity, as well as inhibits CD38 activity, and that crosslinking of CD38 on the multiple myeloma cell surface triggers apoptotic signaling. Moreover, in preclinical models, daratumumab triggered synergistic multiple myeloma cytotoxicity in combination with either lenalidomide (Revlimid) or bortezomib (Velcade).
Excitingly, phase I/II clinical trials defined the schedule of administration (weekly × 8, biweekly × 8, then monthly) and dose (16 mg/kg) of daratumumab that achieved 30% overall response, including complete response and very good partial response, in multiply relapsed myeloma. This dose and schedule effectively targets tumor cells, even in far-advanced disease. Therefore, single-agent daratumumab received accelerated approval from the U.S. Food and Drug Administration.
Remarkably, at the 2016 European Hematology Association meeting, Dimopoulos et al recently reported that adding daratumumab to lenalidomide/dexamethasone reduced the risk of disease progression or death by 63% in patients with relapsed multiple myeloma.1 The addition of daratumumab to this regimen also was associated with an increased extent of response, including complete response with minimal residual disease negativity.
CASTOR Trial Results
In the CASTOR trial reported by Palumbo et al,2 and summarized in this issue of The ASCO Post, a major difference in progression-free survival was found when daratumumab was added to bortezomib/dexamethasone vs bortezomib/dexamethasone alone in patients with relapsed multiple myeloma. At interim analysis with median follow-up of only 7.4 months, there were 67 events, an estimated disease-progression rate of 60.7% at 12 months, and a progression-free survival median not reached in the triplet group; compared with 122 events, an estimated progression-free survival rate of 26.9% at 12 months, and a median progression-free survival of 7.2 months in the doublet group. This finding represents a 69% reduction in the risk of disease progression or death. Therefore, the independent data and safety monitoring committee recommended this trial be unblinded and daratumumab be given to treat disease progression in the bortezomib/dexamethasone-treated group.
It is important to note that the progression-free survival prolongation was evident irrespective of prior bortezomib treatment, in multiple myeloma refractory to the last line of previous therapy, in patients aged < and ≥ 65 years, in all International Staging System stages of multiple myeloma, and regardless of the number of lines of previous therapy or prior autologous stem cell transplantation. Moreover, overall response rates were 82.9% in the daratumumab group vs 63.2% in the control group (P < .001), with ≥ very good partial response in 59.2% vs 29.1% (P < .001) and ≥ complete response in 19.2% vs 9.0% (P = .001). Due to the short follow-up, median progression-free survival during the next line of therapy and median overall survival were not reached in either treatment group.
Tolerability was good, with adverse events observed with daratumumab plus bortezomib/dexamethasone treatment similar to those attendant to bortezomib/dexamethasone, including thrombocytopenia, peripheral sensory neuropathy, and diarrhea. The major difference observed with daratumumab was infusion reactions, which occurred with the first infusion and were readily treated with corticosteroids. Treatment discontinuation rates were similar in both groups: 7.4% with daratumumab plus bortezomib/dexamethasone vs 9.3% with bortezomib/dexamethasone.
Cautious Enthusiasm
These results with the addition of daratumumab to bortezomib/dexamethasone represent a significant prolongation of progression-free survival, associated with the highest rates and extent of response yet achieved with any therapy for relapsed multiple myeloma. Moreover, responses were observed even in refractory and high-risk del17p multiple myeloma, a subgroup in which early relapses are common and durable responses rarely observed.
Although these results are exciting, this analysis was done very early, and further follow-up is needed to assess the durability of responses and progression-free survival on the one hand vs adverse events that may manifest only with prolonged treatment on the other. Clinical trials will identify biomarkers of response and determine whether therapy can be discontinued at the time of maximal response. On the other hand, clinical trials will also determine whether any adverse events are observed with prolonged treatment, such as low blood cell counts due to progenitor cell depletion or opportunistic infections in the setting of depletion of activated immune effector cells expressing CD38. Unexpectedly, it has recently been reported that those regulatory T cells that highly express CD38 are depleted by daratumumab, leading to enhanced clonal anti–multiple myeloma immune responses.3 Therefore, it may be possible with daratumumab combination therapy not only to deplete multiple myeloma to the level of minimal residual disease negativity, but also to restore host anti–multiple myeloma immunity.
The CASTOR study changes the treatment paradigm for relapsed/refractory multiple myeloma, establishing the utility of proteasome inhibitor and daratumumab combination therapy. Now we have evidence that daratumumab can augment either lenalidomide or bortezomib therapy alone, setting the stage for daratumumab, lenalidomide, and bortezomib combination therapy in relapsed disease. Importantly, initial therapy with daratumumab added to lenalidomide, bortezomib, and dexamethasone may further enhance the extent of minimal residual disease–negative complete responses in newly diagnosed multiple myeloma and markedly improve patient outcome. ■
Disclosure: Dr. Anderson has served as an advisor for Celgene, Millennium, Gilead, and Bristol-Myers Squibb and is a scientific founder of Acetylon, Oncopep, and C4 Therapeutics.
References
2. Palumbo A, Chanan-Khan A, Weisel K, et al: N Engl J Med 375:754-766, 2016.
3. Krejcik J, Casneuf T, Nijhof IS, et al: Blood 128:384-394, 2016.
