2015 saw the approval of four new drugs by the FDA for the treatment of patients with multiple myeloma. However, myelomatologists remain a productive lot and 2016 provided another bumper harvest of manuscripts in multiple myeloma. It is perhaps worth inking a few lines to highlight their major contributions.
The incorporation of monoclonal antibodies in our therapeutic armamentarium was perhaps the highlight of the year. Several of the trials that formed the basis of this revolution in myeloma therapy were published in manuscript form this year.
Lonial, et al., published results on an open label randomized phase II trial of daratumumab monotherapy in patients with treatment refractory multiple myeloma (SIRIUS) (Lancet 2016;387(10027):1551-60). Findings were reported for 106 patients who received daratumumab 16 mg/kg. Patients had received a median of five previous lines of therapy. Responses were noted in 31 patients (29.2%). Median duration of response was 7.4 months and progression-free survival 3.7 months. At 12 months, 64.8 percent of patients were alive.
Comment: This trial formed the basis for the accelerated approval for daratumumab in December 2015.
Palumbo, et al., published results of the CASTOR trial, a phase III trial, randomizing patients to the three-drug regimen of daratumumab, bortezomib, and dexamethasone or bortezomib and dexamethasone alone (N Engl J Med 2016;375:754-66).
In this trial, 498 patients with relapsed and refractory multiple myeloma were randomized.
In a pre-specified interim analysis, the 12 month rate of progression-free survival was 60.7 months in the daratumumab group versus 26.9 months in the control group. After a median follow-up of 7.4 months, the median progression-free survival was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio 0.39). The overall response rate was higher in the daratumumab group than in the control group (82.9% vs. 63.2%, p<0.001). The rates of very good partial response or better (59.2% vs. 29.1%, P<0.001) and complete response or better (19.2% vs. 9%, P=0.001) were also higher in the daratumumab group. Rates of cytopenias, thrombocytopenia (45.3% vs. 32.9%), and neutropenia (12.8% vs. 4.2%) were higher in patients treated with daratumumab. Infusion-related reactions associated with daratumumab were reported in 45.3 percent of patients (grade 3 in 8.6%) with 98.2 percent of these occurring during the first infusion.
Dimopoulos, et al., subsequently published results of the POLLUX trial (N Engl J Med 2016; 375:1319-31). In this phase III trial, 569 patients with multiple myeloma who had received one or more previous lines of therapy were randomized to receive lenalidomide and dexamethasone either alone or in combination with daratumumab.
At a median follow-up of 13.5 months in a pre-specified interim analysis, progression-free survival at 12 months was 83.2 percent in the daratumumab group as compared to 60.1 percent in the control group. Overall response rates (92.9% vs. 76.4%, p<0.001) were higher in the daratumumab group. The rate of minimal residual disease negativity (threshold for detection of one tumor cell per 105 white cells) was 22.4 percent in the daratumumab group compared with 4.6 percent in the control group. Grade 3 for neutropenia was seen in 51.9 percent of patients in the daratumumab group versus 37 percent in the control group. Rates of thrombocytopenia were 12.7 percent versus 13.5 percent and anemia 12.4 percent versus 19.6 percent in the two groups, respectively. Daratumumab-associated infusion reactions occurred in 47.7 percent of patients with most reactions being grade 1 or 2 in severity.
Comment: The CASTOR and POLLUX trials formed the basis for the FDA approval in November 2016 for these three-drug regimens.
Nijhof, et al., reported that, in a cohort of 102 patients treated with daratumumab monotherapy, pretreatment levels of CD38 expression on multiple myeloma cells were significantly higher in patients who achieved at least partial response compared with patients who achieved less than partial response (Blood 2016;128(7):959-70). CD38 expression was reduced in both bone marrow localized and circulating multiple myeloma cells following the first daratumumab. CD38 expression levels on multiple myeloma cells increased following daratumumab discontinuation. Resistance to daratumumab was accompanied by increased expression of complement inhibitory proteins
Krejcik, et al., analyzed peripheral blood of bone marrow cells from patients with relapsed refractory myeloma from two daratumumab monotherapy studies before and during therapy and at relapse (Blood 2016;128(3):384-94). They identified a novel subpopulation of regulatory T-cells expressing CD38. These T-regs were more immunosuppressive in vitro than CD38 negative T-regs and were reduced in daratumumab treated patients. In parallel, daratumumab induced robust increases in helper and cytotoxic T-cell absolute counts.
Comment: The mechanisms by which daratumumab kills malignant plasma cells and development of resistance to therapy continue to be unraveled.
Protesome Inhibitors & Immunomodulatory Drugs
Moreau, et al., published results of the double-blind placebo controlled phase III TOURMALINE-MM1 phase III trial (N Engl J Med 2016;374(17):1621-34). In this study, 722 patients who had relapsed refractory or relapsed and refractory multiple myeloma were randomized to receive ixazomib with lenalidomide and dexamethasone or placebo with lenalidomide and dexamethasone.
Progression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (20.6 months vs. 14.7 months, p=0.001). The overall rates of response were 78 percent in the ixazomib group and 72 percent in the placebo group with very good partial response or better seen in 48 percent and 39 percent, respectively.
The rates of serious adverse events were similar in the two groups (47% in the ixazomib group and 49% in the placebo group). Thrombocytopenia of grade 3 and 4 severity occurred more frequently in the ixazomib group (19% vs. 9%). Rashes occurred more frequently in the ixazomib group (36% vs. 23%) as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27 percent in the ixazomib group and 22 percent in the placebo group. The patient reported quality of life was similar in the two study groups.
Comment: This trial led to the FDA approval of ixazomib lenalidomide and dexamethasone regimen for patients who have failed one line of therapy in November 2015.
Berenson published results of CHAMPION-1, a phase I-II study of once weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma (Blood 2016;127(26):3360-8.). This study evaluated once weekly carfilzomib with dexamethasone with the carfilzomib given as a 30-minute IV infusion on days 1, 8, and 15 of 28 day cycles. The phase I portion used a 3+3 dose escalation scheme to determine the maximum tolerated dose of carfilzomib. During phase II, patients received carfilzomib on the same schedule with dexamethasone 40 mg on days 1, 8, 15, and 22 for the first 8 cycles and thereafter, dexamethasone was omitted on day 22 for cycles 9+. A total 116 patients were enrolled.
The maximally tolerated dose was 70 mg/m2. One hundred four patients received carfilzomib at 70 mg/m2. With a median of one prior regimen, 52 percent of patients were bortezomib refractory. The overall response rate was 77 percent. The most common > grade 3 adverse events were fatigue (11%) and hypertension (7%). However, there were a number of deaths on this study that were felt to be possibly related to the treatment regimen.
Comment: We need more data on the safety of the 70mg/m2 once weekly dosing regimen for carfilzomib before adopting this in clinical practice.
Baz, et al., reported on a randomized multicenter phase II study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma (Blood 2016;127(21):2561-8). Patients were randomized 1:1 to receive pomalidomide 4 mg on days 1 through 21 of a 28-day cycle in combination with pre dexamethasone or pomalidomide, dexamethasone, and cyclophosphamide 400 mg orally on days 1, 8, and 15. Eighty patients were enrolled.
The overall response rate was 38.9 percent and 64.7 percent, respectively (p=0.035). The median progression-free survival was 4.4 months and 9.45 months, respectively (p=0.106). The toxicity was predominantly hematologic but was not statistically higher in the three-drug treatment arm.
Nijhof, et al., reported on a phase I-II study of lenalidomide combined with low-dose cyclophosphamide and prednisone and lenalidomide refractory multiple myeloma (Blood 2016;128:2297-2306). In this study, the maximally tolerated dose was defined as 25 mg of lenalidomide (day 1 through 21 of a 28-day cycle) combined with continuous cyclophosphamide 50 mg daily, and prednisone 20 mg daily. At the maximally tolerated dose (n=67), the overall response rate was 67 percent with median progression-free survival and overall survival figures of 12.1 months and 29 months, respectively. Neutropenia (22%) and thrombocytopenia (22%) were the most common grade 3/4 hematological adverse events.
Comment: These two studies demonstrate the effectiveness of cyclophosphamide when combined with immune-modulating drugs and steroids in a three-drug regimen for relapsed and refractory multiple myeloma.
Moreau, et al., reported results of the perspective IFM 2013-04 trial (Blood 2016;127:2569-74).The InterGroupe Francophone du Myelome conducted a randomized trial to compare bortezomib, thalidomide, and dexamethasone (VTD) with bortezomib, cyclophosphamide, and dexamethasone (VCD) as induction before high-dose therapy and autologous stem cell transplantation in patients with newly diagnosed myeloma. Three hundred forty patients were randomized.
After 4 cycles on an intent to treat basis, 66.3 percent of patients in the VTD arm achieved at least a very good partial response versus 56.2 percent in the VCD arm (p=0.05). Toxicity was higher in the VCD arm with significantly increased rates of grade 3 for anemia, thrombocytopenia, and neutropenia. Rates of peripheral neuropathy were significantly higher in the VTD arm. The authors concluded that their data supported the preferential use of VTD rather than VCD in preparation for ASCT.
Comment: With the publication of these results, the utility of VCD as an induction regimen for patients prior to stem cell transplant in the U.S. has declined. However, it may still be an appropriate regimen for patients presenting with renal insufficiency and requiring prompt initiation of therapy.
Zweegman, et al., reported on a multicenter randomized phase III trial comparing melphalan, prednisone, and lenalidomide to melphalan, prednisone, and thalidomide in patients with untreated multiple myeloma (Blood 2016;127:1109-16). In this trial, undertaken by the Dutch Belgian Cooperative Trial Group for Hematology/Oncology and the Nordic Myeloma Study Group (HOVON87/NMSG18 trial), 318 patients were randomly assigned to receive melphalan, prednisone, thalidomide followed by maintenance thalidomide, and 319 patients received melphalan, prednisone, and Revlimid followed by maintenance Revlimid.
After a median follow-up of 36 months, progression-free survival was 20 months and 23 months, respectively (hazard ratio 0.87, p=0.12). Response rates and very good partial response rates were similar. Hematological toxicity was more pronounced with MPR-R, especially grade 3 and 4 neutropenia—64 percent versus 27 percent. Neuropathy of at least grade 3 was significantly higher in the MPT-T arm (16% vs. 2%) resulting in significantly shorter duration of maintenance in the MPT-T arm (5 months) compared to MPR-R (17 months). The authors concluded that MPR-R had no advantage over MPT-T irrespective of age.
Magarotto, et al., randomly assigned 662 patients > 65 years of age or transplant ineligible to receive induction with melphalan, prednisone, lenalidomide (MPR) or cyclophosphamide, prednisone, lenalidomide (CPR) or lenalidomide plus low-dose dexamethasone (Rd) (Blood 2016;127(9):1102-8). After a median follow-up of 39 months, the progression-free survival was 22 months for the triplet combinations and 21 months for the doublet (p=0.284). The 4-year overall survival was 67 percent for the triplet and 58 percent for the doublet arms (p= 0.709). Grade 3 to 4 neutropenia was 64 percent in MPR, 29 percent in CPR, and 25 percent in Rd patients (p<0.0001). It was concluded by the author that alkylator containing triplets were not superior to the alkylator free doublet and were associated with higher toxicity.
Comment: These studies suggest that the era of melphalan containing regimen for elderly and transplant ineligible patients may be drawing to a close.
Ali, et al., reported on a first in human clinical trial of chimeric antigen receptor (CAR) T-cells targeting the B-cell maturation antigen (BCMA) (Blood 2016;128(13):1688-700). Twelve patients received CAR T-cells in this does escalation trial.
Among the six patients treated at the lowest two dose levels, limited anti-myeloma activity and mild toxicity occurred. On the third dose level, one patient obtained a very good partial response. Two patients were treated on the fourth dose level of 9/10 to the power of 8 CAR T-cells per kg of body weight. The first patient at this dose level achieved a stringent complete remission that lasted for 17 weeks before relapse. The second patient achieved a very good partial remission which was ongoing at 28 weeks post T-cell infusion. Both patients on the fourth dose level had toxicity consistent with cytokine release syndrome and prolonged cytopenias.
Comment: This trial demonstrates the potential for CAR T-cell therapy in multiple myeloma.
Minimal Residual Disease
Munshi, et al., published a meta-analysis to evaluate the utility of minimal residual disease (MRD) detection in patients with newly diagnosed myeloma (JAMA Oncol 2016; DOI:10.1001/jamaoncol.2016.3160). The authors identified 21 studies that reported on MRD status and progression-free or overall survival in 20 or more patients following treatment. Fourteen studies (n=1273) provided data on the impact of MRD on PFS and 12 studies (n=1,100) on overall survival. MRD negative status was associated with significantly better PFS (hazard ratio 0.41, p<0.001). The overall survival was also favorable in MRD negative patients overall (hazard ratio 0.57, p<0.001).
Comment: This publication adds to a growing list of studies that support the integration of MRD assessment as an endpoint in clinical trials of multiple myeloma.
This is but a sampling of the number of high-impact publications on multiple myeloma published in the scientific literature in 2016. If this is any indication of what lies ahead, I look forward to 2017 with great enthusiasm!
RAVI VIJ, MD, MBA, is Professor of Medicine at the Washington University School of Medicine, St. Louis, Mo.
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