The current treatment landscape for relapsed and refractory multiple myeloma is so promising, oncologists should not hesitate to consider integrating novel therapies into multiple myeloma management, Kenneth C. Anderson, MD, said.
Kenneth C. Anderson, MD
The current treatment landscape for relapsed and refractory multiple myeloma is so promising, oncologists should not hesitate to consider integrating novel therapies into multiple myeloma management, Kenneth C. Anderson, MD, told colleagues during a "How I Treat" session at the 2016 Annual ASH Meeting on Hematologic Malignancies, a meeting he also co-chaired.
“We have 16 FDA approvalsincluding 7 in 2015 alone—for multiple myeloma and our median patient survival has been prolonged 3-4fold,” said Anderson, a 2014 Giant of Cancer Care in Myeloma. “Novel agents target multiple myeloma in the bone marrow microenvironment to overcome conventional drug resistance in vitro and in vivo. They are effective in relapsed/refractory, relapsed, induction, consolidation, and maintenance therapy, but we also need new approaches to treat and ultimately prevent relapse.”
Anderson, the program director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at the Dana-Farber Cancer Institute, noted that a key aspect of managing relapsed and refractory multiple myeloma is determining when to consider retreatment. “Patients with [an] asymptomatic rise in M-protein are experiencing biochemical relapse, but can safely be observed to determine the rate of rise and nature of the relapse,” he said.
However, Anderson said that the presence of CRAB (calcium elevation >11.5 mg/L or the upper limits of normal, renal dysfunction with serum creatinine >2 mg/dL, anemia, and bone disease) criteria is an indication to treat in the relapsed setting. In patients with asymptomatic progression, treatment can prevent CRAB, Anderson noted. “At my center, we don’t wait for CRAB to treat.”
Currently, there are various therapies for relapsed multiple myeloma. For patients who relapse following 1 to 3 prior therapies, the doublet regimens of oral pomalidomide (Pomalyst)/dexamethasone (oral) or carfilzomib (Kyprolis)/dexamethasone are available options, Anderson said. Triplet therapy choices include pomalidomide with bortezomib (Velcade)/dexamethasone, carfilzomib plus lenalidomide (Revlimid)/dexamethasone, and carfilzomib with pomalidomide/dexamethasone. Newer options are elotuzumab (Empliciti)/lenalidomide/dexamethasone and ixazomib (Ninlaro)/lenalidomide/dexamethasone.
“It’s a positive that these triplets are all oral, but their activity in lenalidomide-refractory multiple myeloma is unknown,” Anderson said. “But overall, the triplets are preferred to the doublets, just as in the initial setting.”
For patients who have relapsed multiple times, both doublet and triplet regimens are available. These include single-agent daratumumab (Darzalex) for high-risk patients, daratumumab with bortezomib/dexamethasone, and daratumumab with lenalidomide/dexamethasone, all in order to increase response and duration. Panobinostat (Farydak)/bortezomib is a possibility, although this regimen can be limited by adverse events. Additionally, Anderson prefers triplet regimens in the multiple relapsed setting, as well.
Daratumumab, a human CD38 IgG kappa monoclonal antibody that directly and indirectly kills myeloma cells is considered a major advance in the field, Anderson said, adding that it depletes CD38 immunosuppressive regulatory cells and promotes T-cell expansion and activation.
Selective histone deacetylase 6 (HDAC6) inhibitors appear to be an intriguing possibility, too, he added. These include ricolinostat (ACY-1215) and ACY-241. Referring to them as well-tolerated daily oral medications, Anderson said they achieve durable responses when combined with bortezomib, lenalidomide, or pomalidomide in relapsed/refractory myeloma. An ongoing phase Ia/Ib open-label trial is exploring ACY-241 alone or in combination with pomalidomide or dexamethasone (NCT02400242).
ACY-241 augments autologous multiple myeloma-cell cytotoxicity, which is enhanced by a CD38 antibody, pomalidomide, and/or PD-1/PD-L1 inhibitors. It also increases costimulatory molecules, proliferation, Th-1 cytokine production, and cytotoxic T lymphocytes. ACY-241 also decreases regulatory T cells and augments natural killer (NK) cell function, alone and with PD-L1 antibodies.
“I think HDAC inhibitors are going to be a member of the immunotherapy team for us,” Anderson said.
Anderson is also investigating B-cell maturation antigen (BCMA), a selective plasma cell antigen. “I think this is a very good molecular target for us to pursue,” he said, adding that a BCMA auristatin immunotoxin induces strong anti-myeloma effects. “The immunotoxin strategy may prove to be very effective since it directly induces apoptosis.” Additionally, BCMA-BiTE (bispecific T-cell engagers)based immunotherapies are now in preclinical development, soon to move to the clinical realm, Anderson said.
There is also promise in using immunotherapy to create an immune-suppressive microenvironment in multiple myeloma. “If you can block PD-L1, you block interaction between cells. That will take the brakes off,” he said. “There are T cells and NK cells that want to do the right thing, if only they could. A checkpoint inhibitor might help.”
Finally, Anderson described the possibilities of chimeric antigen receptor (CAR) T-cell therapy for myeloma. “CAR-T cells and NK cells have in vitro and in vivo activity against multiple myeloma, and multiple promising targets exist,” he said. These include CD19, CD138, CD38, CD56, Kappa, Lewis Y, CD44v6, CS 1 and BMCA. Of these, he believes CD38, CS 1 and BCMA are the best options.
“Clinical trials are underway with anecdotal reports of prolonged responses, but no robust efficacy data are available yet,” he said. “Many questions remain about CAR design, including optimal vectors, co-stimulatory domains, dose, and schedule. Perhaps cocktails of multiple CARs or CARs plus chemotherapy will be required to achieve the best outcomes.”
Anderson concluded by reiterating that therapy for relapsed multiple myeloma depends on each patient’s prior treatment and clinical features. “Targeting protein degradation, restoring antimultiple myeloma immunity, and targeting the consequencesnot the causes—of genomic heterogeneity and instability offers great promise to further improve patient outcomes.”
Anderson KC. Updates on treatment of relapsed/refractory multiple myeloma. Presented at: 2016 Annual ASH Meeting on Hematologic Malignancies; September 16-17, 2016; Chicago, IL.