The flurry of new drug approvals at the end of 2015 for Darzalex® (daratumumab), Ninlaro® (ixazomib), and Empliciti® (elotuzumab) left the myeloma community wondering what could possibly be next. While there have been no new drug approvals since that 2015 windfall, clinical trials have resulted in expanded indications for previously approved drugs, including:
• November 2016 – expanded approval of Darzalex, which now includes the combination therapies Darzalex + Velcade® (bortezomib) + dexamethasone (based on the CASTOR trial) and Darzalex + Revlimid® (lenalidomide) + dexamethasone (based on the POLLUX trial) for patients who have had at least one prior therapy.
• February 2017 – the official approval of Revlimid as post-autologous transplant maintenance therapy both by the FDA in the US and by the European Medicines Agency (EMA) in Europe. The basis for these approvals was overall survival (OS) data from two large randomized trials, one of which was conducted in the US, the other in France.
Now we are focusing not only on expanded approvals for existing drugs, but on potential new approvals for agents still in clinical trials. We are eager to see if they might fill specific “unmet needs” in the myeloma treatment armamentarium. Drugs to treat patients who are “penta-refractory” to Revlimid, Pomalyst® (pomalidomide), Velcade, Kyprolis® (carfilzomib), and an anti-CD 38 monoclonal antibody (either the approved agent Darzalex or the experimental agent isatuximab, also known as SAR650984) are high on the wish list, as are drugs that can target specific high-risk genetic mutations. Trials of combination regimens designed to cure patients with high-risk smoldering multiple myeloma (SMM) are also a priority, and are in process in America and in Europe.
The IMF is proud to be the sponsor of a number of trials that are, or soon will be, taking place in the US, Europe, and Asia to meet unmet needs around the globe. Already under way in multiple centers in Spain through the Spanish clinical trials group PETHEMA is the Black Swan Research Initiative®-sponsored CESAR trial (NCT02415413), a study of Kyprolis + Revlimid + dexamethasone (KRd) followed by high-dose therapy with melphalan and autologous stem cell transplantation (ASCT), followed by consolidation with KRd, and maintenance with Revlimid + dexamethasone in patients under 65 years with high-risk SMM. CESAR is the first of two myeloma “cure trials” that will attempt to treat high-risk SMM early, intensively, and effectively. The goal is for every patient to achieve sustained MRD-negative status. The CESAR trial has been actively accruing patients for almost two years.
The second of the Black Swan-sponsored cure trials for patients with high-risk SMM, the ASCENT trial, is scheduled to open soon at the Mayo Clinic in Rochester, Minnesota. It is not yet listed on the clinicaltrials.gov database. In this two-arm trial all patients will receive four cycles of KRd + daratumumab, and then patients who are eligible for high-dose melphalan with ASCT will proceed to transplant, while those who are ineligible will receive four more cycles of KRd + daratumumab. All patients in both arms of the study will receive another four cycles of KRd + dara at reduced doses as consolidation, and then all patients will receive maintenance therapy for one year with even lower doses of Kyprolis + Revlimid + daratumumab. We will announce the official opening of the trial and the addition of sites via the IMF’s weekly e-newsletter Myeloma Minute, and via our website myeloma.org.
The IMF is also sponsoring two trials through its Asian Myeloma Network (AMN). Both trials are designed to meet the needs of patients in seven Asian countries/regions plus Australia and New Zealand, where access to treatments is quite limited outside the context of a clinical trial. Planned to launch later in 2017 are two randomized studies for patients with relapsed/refractory myeloma. The first of these is a phase II study of different Kyprolis doses in combination with cyclophosphamide + dexamethasone for patients who have had prior exposure to Velcade. This trial will enroll 50 patients in Asia and 50 patients in Australia and New Zealand. The second randomized trial, which will accrue 120 patients in Asia, is a phase III study comparing Pomalyst + cyclophosphamide + dexamethasone with Pomalyst + dexamethasone.
AbbVie and Genentech’s venetoclax (known as Venclexta® in the US and Venclyxto® in Europe) has been approved as a treatment for CLL patients with the 17p- chromosomal mutation, but is still experimental for patients with myeloma. Data presented on a monotherapy study and a combination study of venetoclax + Velcade at ASH 2016 demonstrated venetoclax’s efficacy as a single agent when targeted to myeloma patients with the t(11;14) mutation, making it the first therapy for myeloma that successfully targets a particular genetic mutation. The study of venetoclax + Velcade showed efficacy across a wider spectrum of patients, with a 68% overall response rate (ORR) and a very good partial response (VGPR) rate of 40%.
The largest currently recruiting venetoclax trial is a randomized phase III study of venetoclax + Vd versus Vd for patients with relapsed/refractory myeloma who have either not yet had a proteasome inhibitor or are still sensitive to them. This study is currently accruing patients at 89 sites around the world, including the US, Australia, Brazil, Canada, France, Germany, Hungary, Ireland, Italy, Japan, Republic of Korea, Russian Federation, Spain, Taiwan, and the UK (NCT02755597). A second randomized study of venetoclax in combination with a proteasome inhibitor is the phase II study of venetoclax + Kyprolis + dexamethasone versus Kyprolis + dexamethasone for patients with relapsed/refractory myeloma who have had 1-3 prior lines of therapy and who are proteasome inhibitor-naive or -sensitive. It is currently recruiting patients at seven US sites (NCT02899052).
Small phase I trials of venetoclax in combination with an experimental antibody-drug conjugate (ABBV-838) and as monotherapy for patients with a range of hematologic malignancies are available in Australia (NCT02951117) and Japan (NCT02265731).
Anti-BCMA CAR-T cell therapy
Interest remains high in chimeric antigen-receptor T-cells (CAR-T cell), particularly in those designed to target the B-cell maturation antigen (BCMA), which is heavily expressed on the surface of myeloma cells. While this approach is known to be very effective, it can also trigger an immune system response called cytokine release syndrome (CRS), which, when severe, can be fatal. Six phase I anti-BCMA CAR-T cell trials are currently recruiting patients at sites in the US, Canada, Europe, and China. Sponsors of these trials range from GlaxoSmithKline (GSK2857916; trial identifier NCT02064387) to bluebird bio (bb2121; NCT02658929), to Memorial Sloan-Kettering Cancer Center (EGFR+/BCMA-41BBz CAR T-cell; NCT03070327), to the NCI (cyclophosphamide, fludarabine, and anti-BCMA CAR T-cells; NCT02215967), to the University of Pennsylvania (CART-BCMA, NCT02546167), to Southwest Hospital in Chongqing, China (anti-BCMA-CAR-transduced T-cells; NCT02954445). All but the GSK2857916 and bb2121 trials are single-center studies. GSK2857916 is enrolling patients at five US sites, one site in Canada, and one site in the UK, while the bb2121 study is recruiting patients at nine US sites.
Because of their striking efficacy in other formerly intractable cancers, hopes have been high that check-point inhibitors, which unleash powerful immune responses, would be equally effective in myeloma. Trials for relapsed and refractory myeloma patients pairing immunomodulatory agents Revlimid or Pomalyst with pembrolizumab were promising, but the results were not comparable to those in advanced melanoma, non-small cell lung cancer, or squamous cell cancer of the head and neck, indications for which pembrolizumab is now approved (with the brand name Keytruda®). Now the University of Michigan and University of Wisconsin are collaborating on a phase II trial using pembrolizumab for six months following ASCT along with ongoing Revlimid maintenance therapy in an attempt to increase response depth and duration (NCT02331368). The trial is open to patients with any stage of myeloma who are ASCT-eligible. The study is currently enrolling patients only at the University of Michigan Comprehensive Cancer Center and the Medical College of Wisconsin.
The other check-point inhibitor trial now being conducted for patients with myeloma is a phase III randomized, but non-blinded, study of combinations of nivolumab (brand name Opdivo®, approved for metastatic melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, Hodgkin lymphoma, and squamous cell carcinoma of the head and neck) + Empliciti (elotuzumab®) + Pomalyst + dexamethasone compared to Pomalyst + dexamethasone (Pd) alone. The trial, called “CheckMate 602” (NCT02726581), is for patients with relapsed/refractory myeloma. Subjects in the control arm (Pd) are allowed to cross over to the exploratory arm (nivolumab + Empliciti + Pd) if their disease progresses. 126 study locations will enroll participants in the US, Austria, Canada, the Czech Republic, Denmark, Germany, Israel, Italy, Mexico, Norway, Poland, Portugal, Puerto Rico, Spain, Sweden, and Switzerland.
Karyopharm Pharmaceuticals’ experimental agent, selinexor, is the first in a new drug class that prevents the export of tumor suppressor genes from the nuclei of cancer cells. Approximately 2,000 myeloma patients have been studied thus far in clinical trials with selinexor. Recently, the FDA placed a hold on all trials with selinexor so that all trial-related documents, including the patient informed consent form, can be updated with a more complete list of serious side effects that have occurred during selinexor clinical trials. Side effects, which can be serious, include diarrhea, vomiting, and low blood counts. The trials will re-open if the FDA approves the updated information, which has already been submitted.
Two selinexor trials will be actively recruiting myeloma patients in 2017. The first of these trials is an expansion of the phase II STORM trial, which tested selinexor + dexamethasone in patients who were either quad-refractory (to Velcade, Revlimid, Kyprolis, and Pomalyst) or penta-refractory (to the preceding drugs plus an anti-CD38 monoclonal antibody). The expansion “phase IIb” part of this trial is accruing an additional 122 penta-refractory subjects (those who have exhausted all the most effective approved therapies). STORM is already recruiting at 23 sites in the US. In the coming months, additional trial sites will be opened in the US, as well as in Austria, Belgium, France, Germany, and Greece. For updates, keep checking matrix.myeloma.org and enter the clinicaltrials.gov identifier number NCT02336815 in the search box.
Pending FDA trial design approval, the BOSTON trial will soon be accruing myeloma patients in early relapse. BOSTON is a sequel to the 33-patient, three-arm, phase I STOMP trial, in which selinexor was evaluated in combination with Velcade, Revlimid, or Pomalyst in patients who had heavily pretreated relapsed and/or refractory myeloma. Data from STOMP demonstrated that the combination of selinexor + Velcade + dexamethasone (SVd) is both highly effective and well tolerated: for the 16 heavily pretreated patients in the Velcade + dexamethasone arm of the trial, the overall response rate was 77%; the patients who were not refractory to prior therapy with a proteasome inhibitor had a 100% response rate. The BOSTON trial, in which the plan is to accrue 362 patients who have had at least one prior therapy and randomize them to receive either Velcade + dexamethasone (Vd) or SVd. Both oral selinexor and subcutaneous Velcade will be given once a week, with dexamethasone given at 20mg the day of, and the day after, Velcade. Patients who progress on Vd will be allowed to cross over into the SVd arm of the study. If approved for accrual, trial sites are expected to open in the US and Canada in April; 17 countries in Europe are expected to begin accruing patients in June or July.
For more information, visit Myeloma Matrix 2.0: Smart Search at matrix.myeloma.org, a tool that makes it possible to search for clinical trials by drug name, drug type, trial phase, and disease status.