The care of multiple myeloma (MM) patients has been enhanced over the past decade by the use of immunomodulatory drugs (IMiD) (e.g., thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib), and a histone deacetylase inhibitor (panobinostat).
Within the last year, two monoclonal antibodies have been added to the list of therapies to treat MM. Elotuzumab, which targets the CD319 surface antigen (the protein encoded by the SLAMF7 gene), received approval from the FDA on November 30, 2015 for the treatment of MM patients. This approval was limited to a combination therapy with lenalidomide and dexamethasone and to those patients having had one to three prior lines of treatment. Two weeks earlier, daratumumab, which targets the CD 38 transmembrane protein, became the first monoclonal antibody approved for MM therapy in those patients having received at least three previous treatments.
Daratumumab, which is a human IgG1Κ antibody that targets the CD38 protein, is thought to kill the CD38-expressed tumor cells via a number of different mechanisms. The most prominent are complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC). Apoptosis was also observed during in vitro studies, which were performed using MM patient-derived tumor cell lines and CD38-positive cells that lacked ADCC activity. This apoptosis is thought to occur as a result of Fc receptor mediated cross-linking.
Daratumumab-specific antibody-dependent cellular phagocytosis (ADCP) was also observed in a dose-dependent manner for a MM patient-derived cell line. In addition to these activities, daratumumab has been shown to have the following immunomodulatory effects: mitigation of immunosuppression; expansion of CD8+ cytotoxic T-cells and CD4+ T-helper cells; stronger cytotoxic T-cell responses; and increased clonality for the T-cell receptor (TCR) repertoire. The correlated increase in TCR clonality and CD8+ T-cells would seem to indicate antigen-driven T-cell expansion.
The target of daratumumab, CD38, in addition to serving as an antigen, also functions as an enzyme, helping to metabolize nicotinic acid adenine dinucleotide phosphate and cyclic adenosine diphosphate-ribose, which both serve to control intracellular calcium levels. Rapid calcium level fluctuation, which has been observed for CD38-specific activating monoclonal antibodies, initiates multiple substrate phosphorylation intracellularly. Given the expression levels on normal myeloid and lymphoid cells (low) and cancerous plasma cells (high), as well as the modulatory role it plays in intracellular signaling processes, CD38 thus represents an attractive target for immunotherapy.
In 2006, the FDA approved the combination of lenalidomide and dexamethasone for the treatment of MM patients having received one prior therapy. While the antitumor mechanism(s) of IMiDs like lenalidomide or thalidomide are not fully understood, it is known that compounds of this class do bind to the cereblon, which is the protein that serves as the substrate recognition portion of an E3 ubiquitin ligase complex.
A study showed that the lenalidomide-cereblon complex targets Ikaros family zinc finger proteins 1 (Ikaros, IKZF1) and 3 (Aiolos, IKZF3) for proteasomal degradation (Science 2014;343(6168):305-9). This means that instead of deactivating cereblon, lenalidomide retargets its activity. This is especially interesting, as there is the implication that the teratogenicity from this class of drugs might be separable from their desirable anti-cancer activities. The authors of this study postulate that this specific mechanism for action (i.e., proteasomal degradation) may also be successfully applied by using drugs like lenalidomide which reassign ubiquitin ligases that target currently intractable oncologically-relevant proteins (e.g., β-catenin, c-Myc).
Phase I/II Study
Recently, the results of a small phase I/II clinical trial evaluating the daratumumab-lenalidomide-dexamethasone triplet therapy in relapsed and relapsed/refractory MM patients were published (Blood 2016;128:1821-28).
The authors speculate that the apparent synergy observed for the daratumumab/lenalidomide/dexamethasone combination might arise in part as a consequence of the CD38 up regulation observed in MM cell lines when dosing with IMiDs (including lenalidomide). Additionally, lenalidomide enables the proteasomal degradation of the interleukin-2 suppressing Ikaros and Aiolos, thus promoting immune cell activation and expansion.
The dose-escalation phase of this study evaluated four different dosages of daratumumab (2, 4, 8 and 16 mg/kg) in combination with lenalidomide (25 mg/day orally on days 1-21 of each 28-day cycle) and dexamethasone (40 mg/week). Since no dose-limiting toxicities were observed in the first part of this study (13 patients), and based on pharmacokinetic, safety, and efficacy data from daratumumab monotherapy studies, the highest dosage of daratumumab (16 mg/kg) was used with the same levels of lenalidomide and dexamethasone for the second (dose expansion) part of this study (32 patients). Evaluations were done for the efficacy, safety profile, immunogenicity, and daratumumab infusion rate of this regimen.
In part two of this study, infusion-related reactions (IRR) were observed in 56 percent of the patients (18), and of these, most occurrences were with the first infusion and were also more prominent with accelerated daratumumab infusion rates. For those patients having IRR, all experienced them during the first daratumumab infusion, none for the second infusion, and three during the third or later infusions.
Efficacy studies were performed using a computerized algorithm that relied upon International Myeloma Working Group (IMWG) uniform response criteria. Generally, overall response rates (ORR) for parts I and 2 were quite good (84.6% and 81.3%, respectively). The 18-month overall survival (OS) rate was 90.4 percent (95% CI, 73.1-96.8), while the progression-free survival (PFS) was 72.1 percent (95% CI, 51.7-85.0) for the same time period. At the time of analysis, median OS and PFS values were not obtained.
Phase III POLLUX Trial
Initial results were recently published in the New England Journal of Medicine for the phase III POLLUX trial evaluating the triplet combination of the monoclonal antibody daratumumab, the IMiD lenalidomide, and the steroidal dexamethasone for the treatment of patients having relapsed or refractory multiple myeloma (DOI: 10.1056/NEJMoa1607751).
The study, led by Meletios Dimopolous, MD, of the National and Kapodistrian University of Athens, Greece, evaluated the use of daratumumab-lenalidomide-dexamethasone (daratumumab group) versus a control group dosed with lenalidomide-dexamethasone.
Relapsed or refractory MM patients included in this study were required to have undergone one or more previous lines of therapy. Patients who had disease that was refractory to lenalidomide as well as those who had to discontinue prior lenalidomide treatment because of adverse events were excluded from these studies.
A total of 569 patients were enrolled in this multicenter, open-label study, of which, 286 were randomly assigned to the daratumumab group and 283 to the control group. Patients ranged in age from 34 to 89 with a median age 65. In terms of prior therapies, patients had had between 1-11 previous lines of therapy (median value-1 prior line), with 19.2 percent having three or more. Among these previous therapies were autologous stem-cell transplant (63.3% of patients), proteasome inhibitors (85.6% of patients), IMiDs (55.2%, also including lenalidomide (17.6% of patients)), with 43.9 percent of patients having undergone prior proteasome and IMiD therapy. In this patient population, 27.4 percent had MM disease that was refractory to their last line of treatment.
Methodology of POLLUX
Both the control and daratumumab groups were orally dosed on days 1-21 of each 28-day cycle at 25 mg lenalidomide if their creatinine clearance was >60 mL/minute or alternatively at 10 mg if their creatinine clearance was between 30-60 mL/minute. Both patient groups also received 40 mg dexamethasone per week, however, there was a difference in the dosing for each group.
While the control group received a single weekly dose of dexamethasone, the daratumumab group received slightly different dosing. Dimopolous explained, “Twenty milligrams of dexamethasone is given intravenously before the daratumumab injection and 20 mg is given orally the next day after completion of the injection.” This was done to minimize IRR which were seen in previous studies involving daratumumab. Dimopolous also noted that “whenever moderate to severe IRR is observed, additional steroid dosing may be necessary.” Patients from both groups who were over 75 or whose BMI was less than 18.5 were dosed with 20 mg dexamethasone per week at the discretion of their physician.
The primary endpoint for this study was PFS, as determined by a computerized algorithm that relied on the aforementioned IMWG criteria. Secondary endpoints included the following: ORR; time to disease progression (time-to-event analysis); OS; rate of very good partial response or better (including very good partial, complete or stringent complete responses); time to and duration of response; percentage of patients beneath the threshold for minimal residual disease.
Disease monitoring was complicated by the therapeutic use of monoclonal antibodies. As Dimopolous explained, “the monoclonal antibody may interfere in patients having a small residual peak of IgGΚ. In that case, a specific immunofixation must be performed.”
At the 13.5 month median follow-up period, there were a total of 169 cases of disease progression or death (116 (41.0%) in the control group and 53 (18.5%) in the daratumumab group). The disease progression or death hazard ratio for the daratumumab group versus the control group was 0.37 (95% CI, 0.27-0.52; P<0.001 via stratified log-rank test). The PFS at 12 months (using Kaplan-Meier methodology) was 83.2 percent in the daratumumab group (95% CI, 78.3-87.2) and 60.1 percent in the control group (95% CI, 54.0-65.7). The median PFS was not reached for the daratumumab group, however, a value of 18.4 months was obtained for the control group (95% CI, 13.9- could not be determined). The ORR in the patient population that had an evaluable response was 92.9 percent in the daratumumab group vs. 76.4 percent in the control group (P<0.001).
There was a significant difference between the rates of very good partial response or better for both groups, with the daratumumab group having a value of 75.8 percent compared to the control group's 44.2 percent (P<0.001). This trend also held at the complete response or better level (daratumumab-43.1%; control-19.2%; P<0.001). It is worth noting that several months of continuous therapy was necessary to attain complete response. For the daratumumab group, the median duration of response had not been reached, while for the control group, a value of 17.4 months was obtained (95% CI, 17.4 – could not be estimated).
The most common adverse event (AE) of grade 3 or 4 was neutropenia, which was observed in 51.9 percent of the daratumumab group versus 37.0 percent in the control group. Other grade 3 or 4 AEs observed were: anemia (12.4%-daratumumab; 19.6%-control); thrombocytopenia (12.7%-daratumumab; 13.5%-control); and pneumonia (7.8%-daratumumab; 8.2%-control).
Given the significant PFS obtained in this study, when asked if there plans to evaluate the daratumumab-lenalidomide-dexamethasone combination in newly-diagnosed MM patients, Dimopolous said “there are ongoing studies.”
Currently, a phase III trial (NCT02252172) is underway to compare the daratumumab-lenalidomide-dexamethasone regimen to the lenalidomide-dexamethasone therapy in newly-diagnosed MM patients who are not candidates for high-dose chemotherapy and autologous stem cell therapy.
Richard Simoneaux is a contributing writer.