Last month's 57th American Society of Hematology Annual Meeting and Exposition (Dec. 5-8) was quite the meeting for physicians looking after patients with multiple myeloma. With numerous presentations spanning the gamut from randomized Phase III trials to advances in immuno-oncology and new data on stem cell transplantation in addition to other notable presentations in the clinical and basic sciences, researchers in multiple myeloma ensured they were a force to contend with. It is worth reviewing some of the notable presentations from the meeting.
Randomized Phase III Trials: Three-Drug Induction Wins
Durie et al presented results of the randomized Phase III S0777 trial comparing the three-drug combination of bortezomib, lenalidomide, and dexamethasone (VRd) with lenalidomide and dexamethasone (Ld) in patients with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (Abstract 25). Induction consisted of six 28-day cycles of Ld and eight 21-day cycles of VRd followed by Rd maintenance for all patients. 232 patients were randomized to Rd and 242 to VRd.
After a median follow-up of 55 months, the overall response rate was 81.5 percent for VRd versus 71.5 percent for Ld, with complete remission (CR) rates of 15.7 and 8.4 percent, respectively. The median progression-free survival (PFS) was 43 months for VRd and 13 months for Rd (p= 0.0018). The overall survival (OS) also favored the VRd arm—75 months versus 64 months for Rd (p= 0.0025). There was significantly greater grade 3 neuropathic and GI adverse events in the three-drug arm.
Moreau et al presented the results of the Phase III TOURMALINE-MM1 study (Abstract 727). Patients on this study were randomized to treatment with ixazomib, the first oral proteasome inhibitor recently approved by the FDA in combination with lenalidomide and dexamethasone (IRd), with ixazomib being dosed at 4 mg on days 1, 8, and 15 of a 28-day cycle. Lenalidomide was given at a dose of 25 mg on days 1 through 21 with dexamethasone 40 mg on days 1, 8, 15, and 22 in both arms. Cycles were continued until progression or unacceptable toxicity.
A total of 722 patients were randomized. Patients could have received one to three prior treatments. Patients refractory to previous proteasome inhibitor-based or lenalidomide-based treatment were excluded from the study. The primary endpoint of median PFS was superior in the IRd arm compared with the Ld arm (20.6 months vs. 14.7 months, p=0.012).
The overall response rate (ORR) (78.3% versus 71.5%, p=0.035) and CR rates (11.7% vs. 6.6%, p=0.019) favored the three-drug arm. The median OS was not reached in either arm. A higher frequency of grade 3 or higher adverse events was seen in the three-drug arm, primarily due to thrombocytopenia. However, the rates of adverse events resulting in discontinuation or on study death were similar between the two arms.
Monoclonal Antibodies: Dawn of a New Era
Usmani et al presented results on the clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma (Abstract 29). Daratumumab, a novel CD38-targeting monoclonal antibody was recently approved by the FDA.
This presentation pooled results from two daratumumab monotherapy studies GEN501, an open-label multicenter Phase I/II dose-escalation and dose-expansion study in patients relapsed from or refractory to at least two prior lines of therapy including proteasome inhibitors and immunomodulatory drugs; and SIRIUS, an open-label multicenter Phase II study in patients who had received three or more prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug or who were double refractory to a proteasome inhibitor and an immunomodulatory drug.
The presentation reported on a total of 148 patients who had received a median of five prior lines of therapy. In the combined population, 39 percent were refractory to carfilzomib and 55 percent, to pomalidomide. The overall RR was 31 percent after a median follow-up of 14.8 months.
The median duration of response was 7.6 months, and the median overall survival was 19.9 months. A total of 48 percent of patients had infusion-related reactions, mostly Grade 1-2 occurring with the first dose of the drug.
Plesner et al reported on a Phase I/II study (GEN503) of daratumumab of combination of lenalidomide and dexamethasone in patients who had relapsed and relapsed and refractory multiple myeloma (Abstract 507). Thirty-two patients were enrolled on the study. 72 percent of patients had prior exposure to an immunomodulatory drug (lenalidomide in 34% and thalidomide in 44%) and 91 percent had prior exposure to a proteasome inhibitor.
After a median follow-up of 15.6 months, the ORR was 81 percent, including 28 percent very good partial responses and 34 percent CR/stringent CR (sCR). The PFS was 72 percent at 18 months, and overall survival was 90 percent at 18 months. The type and rate of infusion related reactions were similar to those reported in studies of daratumumab monotherapy.
Chari et al reported on an open label multicenter Phase IB study of daratumumab in combination with pomalidomide and dexamethasone in patients with at least two lines of prior therapy with relapsed or relapsed and refractory multiple myeloma (Abstract 508). Ninety-eight patients who had a median of four prior lines of therapy were enrolled; 66 percent of patients were refractory to bortezomib, 30 percent were refractory to carfilzomib, and 69 percent were refractory to lenalidomide; and 67 percent were dual refractory.
The ORR was 71 percent, including a 67 percent response rate in double-refractory patients. After a median follow-up of 4.2 months, the six-month estimated PFS was 66 percent. No additional safety signals were observed.
Martin et al reported a dose-finding Phase II trial of isatuximab (SAR65984), another anti-CD38 monoclonal antibody, as a single agent in relapsed/refractory multiple myeloma (Abstract 509). In this Phase II dose-finding study, a total of 97 patients who had received a median of five prior lines of therapy were enrolled. Sixty-eight percent were refractory to an immunomodulatory drug and a proteasome inhibitor, with 41 percent refractory to lenalidomide, pomalidomide, bortezomib, and carfilzomib.
The preliminary ORR was 24 to 29 percent in the two highest dose-intensity cohorts consistent with earlier Phase I results. The drug was well tolerated, with predominantly grade 1/2 infusion reactions.
Dimopoulos et al reported updated results of ELOQUENT-2, a Phase III randomized open-label study of elotuzumab in combination with lenalidomide and dexamethasone (ERd) in patients with relapsed/refractory multiple myeloma (Abstract 28). Elotuzumab, a monoclonal antibody to SLAMF7, was recently approved by the FDA, and the results of the ELOQUENT-2 were first presented at the ASCO 2015 meeting (OT 6/10/15 issue).
This update provided longer follow-up results. Previously, one-year PFS figures were 68 percent versus 57 percent and two-year PFS figures were 41 percent versus 27 percent in favor of the three-drug combination of ERd compared with Rd alone. In this update, the three-year PFS was 26 percent and 18 percent in the two arms, respectively. A time to next treatment analysis favored the elotuzumab arm (33 vs. 23 months). Interim overall survival analysis demonstrated a trend in favor of ERd (43.7 vs. 39.6 months, P=0.0257).
Palumbo et al reported on two-year follow-up of the Phase II randomized elotuzumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone trial (Abstract 510).
This trial enrolled a total of 152 patients. The median PFS in the elotuzumab, bortezomib, and dexamethasone arm was 9.9 months versus 6.8 months in the bortezomib and dexamethasone arm. The two-year follow-up showed a 24 percent reduction in the risk of disease progression, and OS analysis showed a 25 percent reduction in the risk of death.
An interesting observation was that patients with FC-gammaR3a high affinity (VV) had better outcomes than those with low affinity (FF receptor subgroup).
Checkpoint Inhibitors and Chimeric Antigen Receptor (CAR) T Cells: The Future is Here
San Miguel et al presented results of KEYNOTE-023, a Phase I/II study of pembrolizumab in combination with lenalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma (Abstract 505).
Pembrolizumab at 200 mg given every two weeks along with lenalidomide at 25 mg on days 1 through 21 and dexamethasone at 40 mg weekly was found to be the maximally tolerated dose. Of 17 patients evaluated, nine (53%) had a partial response (PR) and four patients had a very good partial response (VGPR). Among the nine patients with lenalidomide-refractory disease, three (33%) had a PR and two (22%) had a VGPR. The median duration of response was 9.7 months.
Badros et al presented results of a Phase II study of pembrolizumab with pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (Abstract 506).
In this single-arm Phase II study, patients received 28-day cycles of pembrolizumab at a dose of 200 mg IV every two weeks plus pomalidomide at 4 mg on 21 of 28 days and dexamethasone at 40 mg weekly.
A total of 33 patients were enrolled, of whom 23 (70%) were refractory to an immunomodulatory drug and a proteasome inhibitor. An ORR of 60 percent in 27 evaluable patients was observed.
The response rate was 55 percent in 20 patients double refractory to an immunomodulatory drug and a proteasome inhibitor.
Ali et al in a late breaking abstract (LBA-1) reported on remissions of multiple myeloma in a first-in-human clinical trial of T cells expressing an anti-B cell maturation antigen (BCMA) chimeric antigen receptor. BCMA is a protein expressed by normal and malignant plasma cells. The researchers conducted a Phase I trial of anti-BCMA chimeric antigen receptor (CAR) that incorporates an anti-BCMA single chain variable fragment, a CD28 domain, and a CD3-zeta T cell activation domain.
Autologous T cells were genetically modified to express the CAR. Patients received a chemotherapy regimen of cyclophosphamide at 300 mg/m2 and fludarabine at 30 mg/m2 for three days before a single infusion of the CAR-BCMA T cells. A total of 12 patients were treated. The authors reported upon two PRs, one VGPR, and one sCR. It appears that responses were more robust at the highest dose level at the MT BCMA CAR T cells.
Autologous Stem Cell Transplantation: The Evidence Still Supports It
Attal et al reported on results of a Phase III study of the Intergroupe Francophone du Myeloma (IFM)/DFCI 2009 trial (Abstract 391). Patients were assigned to one of two treatment arms.
On the conventional-dose arm, patients received eight cycles of treatment with VRd. Patients on this arm underwent stem cell mobilization with high-dose cyclophosphamide and GCSF after three cycles of VRd. On the transplant arm, patients received three cycles of VRd followed by stem cell collection and then autologous stem cell transplantation with melphalan at 200 mg/m2 used for conditioning. This was followed by two cycles of VRd as consolidation. Maintenance treatment consisted of lenalidomide at 10 to 15 mg/day and was given to patients in both arms for one year.
A total of 764 patients were enrolled and 700 were randomized. After a median follow up of 39 months, the independent data monitoring committee recommended the trial be stopped on account of the superior results noted for patients on the transplant arm. The CR rates, VGPR rates, and PR rates on the transplant and VRd arms were 59 percent, 29 percent, 11 percent and 49 percent, 29 percent, and 20 percent, respectively (p=0.02).
Eighty-eight percent of the patients on the transplant arm achieved at least a VGPR compared with 78 percent on the VRd arm (p=0.001). Eighty percent of patients on the transplant arm achieved minimal residual disease (MRD) negativity by flow cytometry compared with 65 percent on the VRd arm (p=0.001). The median PFS was 43 months for the transplant arm and 34 months for the VRd arm (P < 0.001).
No data was presented on the rates of salvage transplantation in the conventional chemotherapy arm. The authors concluded that in an era of new drugs, transplantation should remain a standard of care.
Sonneveld et al presented long-term follow-up results of the HOVON-65/GMMG-HD4 trial (Abstract 27). In this trial 827 patients were randomized to induction therapy with vincristine, doxorubicin, and dexamethasone (VAD) or bortezomib, doxorubicin, and dexamethasone (PAD), followed by either one or two autologous stem cell transplants using high-dose melphalan for conditioning. Maintenance consisted of thalidomide 50 mg daily in the VAD arm and every-two-week bortezomib in the PAD induction arm, both given for two years.
The PFS at 96 months favored the bortezomib arm (17% vs. 10%, p=0.001). The OS at 96 months was 48 percent versus 45 percent in the two arms (p=0.04). PFS from the start of maintenance favored bortezomib over thalidomide (p< 0.01), but there was no difference in overall survival from start of maintenance by treatment arm.
The use of bortezomib during induction and maintenance seemed to overcome the effects of renal impairment, with survival rates at 96 months of 47 percent and 48 percent in patients with or without renal impairment (p=0.6) compared with 12 percent and 42 percent (p< 0.001) in the control arm.
Bortezomib also seemed to overcome the adverse impact of deletion 17p. However, limited benefit was observed for patients with t(4;14) and 1q+ by treatment with bortezomib.
Links to Studies
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