Emerging treatments for relapsed or refractory multiple myeloma include options beyond triplet regimens, including immunotherapy and mutation-driven therapy. Several exciting drugs are poised to be available in the clinic in 2020, according to speakers at the recent JADPRO Live, the annual conference of the Advanced Practitioner Society for Hematology and Oncology: Joshua Richter, MD, of Tisch Cancer Institute and Icahn School of Medicine at Mount Sinai, New York, and Amy Pierre, MSN, ANP-BC, of Memorial Sloan Kettering Cancer Center, New York.
‘Not a Single Disease Entity’
Dr. Richter reminded attendees that multiple myeloma “is not one disease,” but a “clonally heterogeneous disease” that varies not only between individuals, but also within each patient. At diagnosis, most patients already demonstrate four to six subclones of disease that become dominant or recessive as patients go through treatment.
Joshua Richter, MD
Amy Pierre, MSN, ANP-BC
“Variability in clones and in risk means we need drugs with multiple mechanisms of action to kill cells. This is why triplets and even quadruplets have become the standard, because one or two drugs may only control some of the clones,” he explained.
Ms. Pierre noted that with contemporary treatment, heavily pretreated patients with relapsed or refractory multiple myeloma now have a median overall survival after relapse of about 8 months. If they become “penta-refractory” to all three major classes of drugs (protease inhibitors, immunomodulatory drugs, and monoclonal antibodies), however, this drops to 3 months or less. “We need new treatment targets to combat this problem,” she said.
The “penta-refractory” patients represent an unmet need, as do elderly and frail patients, Ms. Pierre stated. Also needed are better access to treatment for African American patients, better symptom management (especially for pain and neuropathy), “and a cure!”
New Regimens Active
“Across the past 11 years, we’ve had 11 drugs approved for myeloma, and approvals are accelerating,” Dr. Richter said. “Four to five drugs or therapies are slated to be approved next year, including several others that might be approved along with new combinations.”
Meanwhile, newer regimens currently in use have combined the lenalidomide/dexamethasone backbone with carfilzomib, ixazomib, daratumumab, and elotuzumab, achieving high response rates (80%–90%) and deep, durable responses. “This is amazing in the relapsed or refractory setting,” Ms. Pierre noted. “We’re seeing very long progression-free survival times (20–44 months) and overall survival times, with medians that have not even been reached in some studies.”
Similarly, with protease inhibitor–based therapies (including pomalidomide), overall response rates are very high, and patients are achieving complete and very good partial responses, representing more than a 90% reduction in the monoclonal burden. Progression-free survival times are 1 year and longer, and median survival times have not been reached.
Alternative Approaches
A number of alternatives to standard treatments can serve as a bridge to a clinical trial, chimeric antigen receptor (CAR) T-cell therapy, or transplant, Dr. Richter said. One of these alternatives is the alkylator bendamustine, which he called “a good tool in your toolbox for patients who have had standard treatments.” Other options include the chemotherapy regimens DCEP (a 96-hour continuous infusion of dexamethasone, cyclophosphamide, etoposide, cisplatin), DT-PACE (dexamethasone, cisplatin, doxorubicin, cyclophosphamide, etoposide with or without thalidomide), and VDT-PACE (with bortezomib). Another good late-line option is the histone deacetylase inhibitor panobinostat, which synergizes well with many myeloma drugs, noted Dr. Richter.
The newest alternative, which is eliciting much excitement, is selinexor, a first-in-class oral selective inhibitor of nuclear export. “Selinexor has the potential to become the next checkpoint inhibitor in cancer, because it works in many different malignancies and will have far-reaching ramifications,” according to Dr. Richter.
In the pivotal STORM trial of penta-refractory patients, selinexor plus dexamethasone was effective, even in patients with prior CAR T-cell therapy.1 With selinexor as part of triplet regimens, Dr. Richter and colleagues have observed response rates exceeding 60% and median progression-free survival times of 9 months; even better outcomes have been observed with selinexor paired with daratumumab. As quadruplet regimens become more common as upfront therapy, and these patients experience disease progression, “you have to start considering drugs like selinexor,” he added. The STOMP basket trial is evaluating various combination regimens involving this exciting new drug.
Which Drugs for Which Patients?
With many beneficial agents available, clinicians are tasked with selecting the best drug or combination for an individual patient with relapsed or refractory multiple myeloma and the best sequence of treatments as that patient experiences disease progression. According to Ms. Pierre, this means taking into account the timing of therapy, response to prior therapy, aggressiveness of relapse, and performance status. Shared decision-making between the patient and health-care team is important and involves “listening to your patients’ preferences and goals, considering the agents that are approved for their situation and disease trajectory, and realizing what’s appropriate for them, given their needs and their disease,” she said. In general, within the limits of a risk-adapted model, triplets are preferred over doublets, and quadruplets sometimes have a role.
Emerging Therapies in Clinical Trials
Enrollment in a clinical trial is always the preferred option, especially in earlier-stage disease, where many novel agents are being tested. There is much diversity in the clinical trials enrolling at Mount Sinai, Dr. Richter’s institution. “The field is extremely crowded, with many drugs in the pipeline, so we’re really hopeful about the future and therapies we will have,” Dr. Richter said, who elaborated on some of the agents in these trials.
Similar to CAR T-cell products but easier to produce are the “off-the-shelf” BiTE (bispecific) antibodies, ie, “bifunctionals.” One such agent generating much interest is the CD38/CD3-targeting drug GBR 1342, which in preclinical models appears to be more active than daratumumab. The next-generation immunomodulatory drug iberdomide (CC-220), which “is probably the most active immunomodulatory drug out there,” noted Dr. Richter. “It will be a backbone therapy and a mainstay of treatment in the future.”
A novel therapeutic likely to be approved within a year is venetoclax (which is already approved in acute myeloid leukemia and lymphoma). Venetoclax inhibits BCL-2, an antiapoptotic protein. It synergizes well with carfilzomib, which indirectly inhibits another antiapoptotic protein, MCL-1, “together producing amazing responses.” Venetoclax works in two types of patients with myeloma: those with (11;14) translocations and those who are high expressers of BCL-2. In these subsets, responses appear to be rapid and durable, and remissions are durable. “When the dominant clone is 11;14, we should bring venetoclax in,” recommended Dr. Richter.
Dr. Richter also is excited to see the emergence of antibody-drug conjugates. One targeting B-cell maturation antigen (BCMA), an antigen expressed on all myeloma cells, is belantamab. Belantamab is likely to be approved in 2020 and will “usher in a new realm of treatment,” because it is an off-the-shelf product “that really works” and often produces “amazing responses,” according to Dr. Richter. “We can’t wait to get this drug in the clinic.”
Another new approach in relapsed or refractory multiple myeloma is mutation-driven therapy, which is being tested in the MyDRUG study. This trial is enrolling high-risk patients, who undergo gene sequencing and then are treated with ixazomib/pomalidomide/dexamethasone plus a drug that addresses the identified driver of their disease (for example, BRAF mutation). “Here, we are really giving personalized therapy. When we have this type of evaluation, we can start thinking outside the box,” Dr. Richter continued.
Trials are also evaluating next-generation CD38 drugs—TAK-079 and SAR442085—and drugs hitting novel targets, including Onc201, AMG 397, and BETi. Additionally, the lipophilic peptide-conjugated alkylator melflufen, which is essentially a monthly infusion of a version of melphalan, may prove useful in penta-refractory patients.
Focus on CAR T-Cell Therapy
CAR T-cell therapy is expected to be approved for myeloma in 2020, mostly likely bb2121, which targets BCMA. BCMA-directed CAR T-cell products such as bb2121 can elicit responses, even in patients with low expression of BCMA. After treatment with bb2121, the median progression-free survival is almost 1 year for all-comers but increases to almost 18 months in patients achieving minimal residual disease–negative status.2 These outcomes are impressive among patients with a median of seven prior lines of therapy, whose expected overall survival would cap around 3 months, he said. There are currently more than 19 trials underway in the CAR T-cell space, noted Dr. Richter.■
DISCLOSURE: The symposium was sponsored by an educational grant from Celgene, Janssen, and Oncopeptides. Dr. Richter has served on the speakers bureaus of Celgene and Janssen and served as a consultant or advisor for Amgen, BMS/Pfizer, Celgene, Janssen, Karyopharm, Oncopeptides, Sanofi, and Takeda. Ms. Pierre has consulted for Celgene and served on the advisory boards of Amgen and Karyopharm.
REFERENCES
1. Chari A, Vogl DT, Dimopoulos MA, et al: Results of the pivotal STORM study (part 2) in penta-refractory multiple myeloma: Deep and durable responses with oral selinexor plus low dose dexamethasone in patients with penta-refractory MM. 2018 ASH Annual Meeting & Exposition. Abstract 598. Presented December 3, 2018.
2. Raje NS, Berdeja JG, Lin Y, et al: bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: Updated results from a multicenter phase I study. 2018 ASCO Annual Meeting. Abstract 8007. Presented June 1, 2018.
