One cannot be faulted for thinking the multitude of new drug approvals in multiple myeloma that have transformed the therapeutic landscape for this disease in the recent past was going to give way to a lull in innovation for therapeutics for patients with multiple myeloma. However the multitude of abstracts presented at the American Society of Hematology (ASH) meeting in 2016 certainly put all doubts to rest. Several abstracts were presented focused on therapies with a novel mechanism of action. My colleagues who specialize in other cancer types can barely hide their jealousy at the abundance of riches that we myelomatologists dwell upon! Let us take a short tour to review what may be coming down the pike.
The CASTOR and POLLUX trials reported impressive rates of progression-free survival for the three-drug regimens of daratumumab with bortezomib and dexamethasone and daratumumab with lenalidomide and dexamethasone, respectively.
At ASH 2016 Avet-Loiseau, et al, reported on rates of MRD negativity with these two three-drug combinations (Abstract 246). MRD was assessed by next generation sequencing of the VDJ region of the IGH locus. Three sensitivity thresholds were evaluated: 10-4, 10-5, and 10-6.
Using the 10-6 threshold, 11.9 percent of patients receiving daratumumab with lenalidomide and dexamethasone and 4.4 percent of patients receiving daratumumab with bortezomib and dexamethasone were MRD negative compared with 2.5 percent and 0.8 percent rates for the Revlimid/dexamethasone and bortezomib/dexamethasone arms.
Even high-risk patients were able to achieve MRD negativity with daratumumab, and an MRD-negative status was associated with lower risk for progression. The addition of daratumumab to lenalidomide and dexamethasone or bortezomib and dexamethasone lowered the risk for progression even among MRD-positive patients compared to those receiving the two-drug regimens alone.
Comment: All previous reports of MRD negativity have been for patients receiving front-line therapy where it has been correlated with a progression-free and overall survival. This report was the first to detail the achievement of this depth of response in patients with relapsed and refractory disease and its significance.
Usmani, et al, presented results of PAVO, an open-label multicenter dose-escalation phase Ib study to assess subcutaneous delivery of daratumumab in patients with relapsed or refractory multiple myeloma (Abstract 1149).
ENHANZE is a platform for recombinant human hyaluronidase (rHuPH20) that temporarily breaks down the hyaluronan barrier, allowing rapid absorption of subcutaneously injected drugs. Herceptin SC and MabThera SC are approved in Europe as coformulate products with rHuPH20.
In the PAVO study, Group 1 (n=8) received daratumumab at a fixed dose of 1,200 mg with 30,000 units rHuPH20 and group 2 (N=45) received daratumumab at a dose of 1,800 mg with 45,000 units of rHuPH20. Patients in Group 1 had a total of 60 mL of drug infused over 20 minutes and those in Group 2 had 90 mL infused over 30 minutes.
The pharmacokinetics for the 1,800 mg subcutaneous dose was similar to that of the 16 mg/kg IV FDA-approved dosing. Adverse events for subcutaneous daratumumab plus rHuPH20 were similar to IV daratumumab with no new safety signals. At the 1,800 mg dose level in patients who had received four prior lines of therapy, efficacy was consistent with IV daratumumab in a similar population with 38 percent overall response rate including one stringent complete response.
The next stage of the study would randomize patients to the recommended subcutaneous dose versus daratumumab IV 16 mg/kg.
Comment: Daratumumab is currently licensed for IV administration and, in clinical trials, the median duration of first, second, and subsequent IV infusions has been 7, 4.2, and 3.4 hours, respectively. IV daratumumab has been associated with infusion reactions that are manageable and occur mainly during the first infusion. A subcutaneous route of administration would greatly reduce the treatment time for patients.
Venetoclax a BCL-2 inhibitor is currently approved for treatment of patients with chronic lymphocytic leukemia who have 17p deletion and have been treated with at least one prior therapy.
Pre-clinical studies have shown BCL-2 and MCL-1 promote survival of multiple myeloma cells by allowing them to avoid apoptosis. In vitro studies have shown venetoclax induces multiple myeloma cell death in cell lines in primary patient samples. In these studies, cells positive for t(11;14) were found to be particularly susceptible. These cells have higher ratios of BCL-2/MCL-1 and BCL-2/BCL-XL mRNA.
At ASH 2016, Kumar, et al, reported on a phase I study of venetoclax monotherapy for patients with relapse/refractory multiple myeloma (Abstract 488). Sixty-six patients who had received a median of five previous lines of treatment were enrolled.
Monotherapy was safe and well-tolerated. An overall response rate of 21 percent was observed for the total population. In 30 patients who had t (11;14), an overall response rate of 40 percent was seen. A higher overall response rate of 88 percent was noted in the nine patients who had a high BCL-2/BCL-XL ratio.
Moreau, et al, reported on a phase Ib open-label dose-escalation study of venetoclax combined with bortezomib and dexamethasone in relapsed and refractory multiple myeloma (Abstract 975).
Patients had had a median of three prior lines of therapy. Sixty-six patients were enrolled. An overall response rate of 67 percent in the entire cohort of patients was noted. The overall response rate was 90 percent for patients not refractory to bortezomib and 31 percent in bortezomib-refractory patients. Once again, patients with high BCL-2 gene expression demonstrated higher clinical response.
A phase III study comparing venetoclax with bortezomib and dexamethasone to bortezomib and dexamethasone alone is currently ongoing.
Comment: Venetoclax has impressive single agent activity in patients with t (11,14) and patients with higher BCL-2 gene expression. These may become biomarkers for selection of patients likely to benefit from this agent.
XPO1 is a nuclear exporter for the majority of tumor suppressors, the glucocorticoid receptor, and several oncoprotein mRNAs. Selinexor is a first-in-class XPO1 inhibitor that induces a nuclear retention and activation of the tumor suppressors and glucocorticoid receptor in the presence of steroids and suppresses oncoprotein expression.
Vogl, et al, reported on a phase II trial of selinexor and dexamethasone (STORM) in patients with heavily pretreated refractory multiple myeloma (Abstract 491). Forty-eight patients were quad refractory (refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide) and 31 patients were penta refractory (quad refractory and also refractory to anti-CD38 antibodies, daratumumab, or isatuximab). In this heavily pretreated group of patients, an overall response rate of 21 percent was noted. Overall response rates seemed to be similar in the quads and penta refractory cohorts. The median duration of response was 5 months and the median overall survival was 9.3 months.
Bahlis, et al, reported on a phase I study of selinexor in combination with bortezomib and dexamethasone in patients with refractory myeloma (STOMP trial) (Abstract 977). Thirty-three patients who had received a median of four (1-11) prior regimens were enrolled. An overall response rate of 77 percent was noted, and 67 percent of patients with proteasome inhibitor refractory disease and 100 percent of patients who were not refractory to proteasome inhibitor therapy was noted.
Jakubowiak, et al, reported results of a phase I trial of selinexor, carfilzomib, and dexamethasone in patients with relapsed/refractory multiple myeloma (Abstract 973). Twenty-one patients who had received a median of four (2-10) prior lines of therapy were enrolled. An overall response rate of 63 percent was noted. The response rate was 67 percent for patients refractory to carfilzomib in their last prior line of therapy.
Comment: These trials all attest to the efficacy of selinexor in patients with multiple myeloma. In all these trials, the major adverse events have been nausea, anorexia, fatigue, thrombocytopenia, and anemia. These have been noted even with other studies with selinexor, but it appears that with proactive intervention and supportive care these adverse events have become more manageable with time.
Driessen, et al, reported on a phase II study of the HIV protease inhibitor nelfinavir in combination with bortezomib and dexamethasone in patients with advanced proteasome inhibitor refractory multiple myeloma.
The biology of proteasome inhibitor resistance is driven by adoptive down-regulation of unfolded protein response that regulates plasma cell maturation and sensitivity to proteasome inhibitor treatment. The oral HIV protease protease inhibitor nelfinavir has antimyeloma activity in vivo, triggers UPR activation and sensitizes multiple myeloma to proteasome inhibitors, and overcomes proteasome inhibitor resistance in vitro.
In this phase II study, 34 patients were treated with oral nelfinavir 2500 mg b.i.d. days 1 through 14 in combination with bortezomib and dexamethasone. Patients had had a median of five prior lines of therapy. All patients had proteasome inhibitor refractory multiple myeloma. An overall response rate of 65 percent was seen (VGPR 5, PR 17, MR 3). In patients double refractory to proteasome inhibitors and lenalidomide, an overall response rate of 69 percent was noted.
Comment: This is a remarkable study showing that a generic drug nelfinavir can possibly be employed to salvage patients failing therapy with a proteasome inhibitor.
Stem Cell Transplantation
Stadtmauer, et al, reported on results of the phase III StaMINA trial (Abstract LBA-1). This trial enrolled autologous stem cell transplant eligible patients less than 70 years of age with symptomatic myeloma who had received two or more cycles of systemic therapy. Patients all underwent autologous stem cell transplantation with melphalan 200 mg/m2. They were subsequently randomized to one of three treatment arms—lenalidomide maintenance; bortezomib, lenalidomide, and dexamethasone for four 28-day cycles, followed by lenalidomide maintenance; or tandem autologous stem cell transplantation followed by lenalidomide maintenance.
Seven hundred and fifty eight patients were enrolled. The primary endpoint (progression-free survival at 38 months) did not differ between the three treatment arms of tandem ASCT (56.5%), RVD consolidation (56.7%), and single autologous stem cell transplantation (52.2%). Survival was also similar for patients with high-risk disease in all three arms of the study.
Results of this trial were somewhat contradicted by that reported by the European Myeloma Network (EMN02/HO95MM trial) by Sonneveld, et al (Abstract 242). This trial was designed to compare four cycles of bortezomib, melphalan, and prednisone to high-dose melphalan and autologous stem cell transplantation either as single or double intensification after induction with bortezomib, cyclophosphamide, and dexamethasone. A second randomization to consolidation therapy with two cycles of Velcade, lenalidomide, and dexamethasone was performed after intensification to be followed by lenalidomide maintenance until progression or toxicity in both arms.
The authors reported that progression-free survival was prolonged in patients randomized to receive Velcade, lenalidomide, and dexamethasone as consolidation therapy with benefits of consolidation observed in patients with low-risk cytogenetics but not in patients with high-risk cytogenetics.
Cavo, et al, in a separate presentation from this study reported that the 3-year estimates of progression-free survival were 60 percent for those receiving a single and 73 percent for those receiving tandem autologous stem cell transplantation (hazard ratio 0.66; P=0.030)(Abstract 731).
Comment: The StaMINA trial and EMN02/HO95MM trial reached contradictory conclusions on the value of tandem transplantation and consolidation therapy post-transplant. Further in-depth analysis is required to determine why this is so.
Zimmerman, et al, reported final results of a phase II trial of extended treatment with carfilzomib, lenalidomide, and dexamethasone with autologous stem cell transplantation in patients with newly diagnosed multiple myeloma. In this trial, patients received four cycles of induction therapy with carfilzomib, lenalidomide, and dexamethasone (KRD) followed by autologous stem cell transplantation. Post-transplant, they received another four cycles of KRD consolidation and then maintenance therapy with a less-intensive schedule of KRD for a total of 18 cycles of treatment. Seventy-one percent of patients achieved MRD-negative disease with an overall 3-year progression-free survival of 86 percent.
In contrast, Roussel, et al, reported somewhat contrary results in their own experience looking at the regimen of KRD in context of stem cell transplantation (Abstract 1142). In their study, patients received four cycles of induction chemotherapy followed by stem cell transplantation. Post-transplant, patients received another four cycles of KRD consolidation followed by maintenance lenalidomide for 13 cycles.
At the end of consolidation, 68 percent of patients achieved MRD negativity. However, in their experience, several cases of thromboembolic events and cardiovascular events were noted with two deaths, one during ASCT and one during the follow-up phase, were reported.
Comment: Both the studies employing KRD pre- and post-transplant showed very impressive rates of MRD negativity at end of treatment. However, the tolerability profile of KRD differed in the two studies. Once again, only an in-depth analysis is required to determine why.
Researchers from the NCI recently published their experience utilizing BCMA-specific CAR T cells using a murine retroviral construct with CD3/CD28 domains. More recently, Berdeja, et al ,at the EORTC-NCI-AACR Molecular Targets and Cancer Therapy Symposium held just before the ASH meeting reported on results of another BCMA CAR T-cell trial using a lentivirus vector with 4-1BB as the co-signaling motif. Eleven patients were treated with 100 percent overall response rate (6/6) with doses above 5 x 107 CAR T cells. Grade 1/2 cytokine release syndrome was seen in 8/11 (73%) of patients with no serious neurological toxicities reported.
At ASH 2016, Cohen, et al, reported on a phase I study of B-cell maturation antigen (BCMA), specific chimeric antigen receptor T cells (CART-BCMA) for multiple myeloma (Abstract 1147). The present study also used a lentiviral vector with CD3/4-1BB domains.
A total of 14 patients were treated in a dose-escalation design. Patients in the first cohort received no lympho-depleting chemotherapy. Grade 3/4 cytokine release syndrome was seen in 3/9 patients with severe neurotoxicity observed and 2/9 patients. However, encouraging evidence of clinical activity was seen (2 MR, 1 PR, 2 VGPR, 1 stringent CR). Enrollment in cohorts with cyclophosphamide conditioning is ongoing.
Also at ASH 2016, Cohen, et al, presented results of a first-in-human phase I study with GSK2857916, an antibody drug conjugate to BCMA in patients with relapsed and refractory multiple myeloma (Abstract 1148). Thirty patients were treated in dose escalation, with no DLT up to 4.6 mg/kg. Major toxicities were ocular (dry eye, blurred vision, keratitis) in 53 percent (grade 3 in 7%), nausea (50%), thrombocytopenia (50%, 43% gr 3-4), and fatigue (47%). ORR was 27 percent (4PR, 3 VGPR, 1sCR), CBR 37 percent (including MR). At doses of 3.4 mg/kg or higher, 6/9 (67%) responded. The recommended phase II dose was 3.4 mg/kg, and a 40 patient expansion is ongoing.
Comment: These multiple presentations seem to fortify BCMA as an exciting new therapeutic target in multiple myeloma.
Badros, et al, reported an update of single-center phase II study of pembrolizumab in combination with pomalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma (Abstract 490). Forty-eight patients were treated. Patients had received a median of three prior lines of therapy. An overall response rate of 65 percent was observed with a median progression-free survival of 17.4 months. Eleven percent of patients had to discontinue treatment due to regimen related toxicity.
Comment: This trial has now formed the basis of a phase III study wherein pembrolizumab in combination with pomalidomide and dexamethasone is being compared to pomalidomide and dexamethasone alone.
Certainly this is just but a sampling of the clinical research presented at the ASH 2016 meeting. In addition to these and other clinical presentations, there were several sessions devoted to genomics and other preclinical research, which I am sure will translate into clinical benefit for our patients in the years to come. Watch this space in 2017!
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RAVI VIJ, MD, MBA, is Professor of Medicine at the Washington University School of Medicine in St. Louis, Mo.