Management of Relapsed and Refractory Multiple Myeloma
Can agents to which the MM was previously refractory be reused?
With the understanding that MM is not a disease defined by a single molecular mutation, but rather clones and subclones, it is reasonable to think that even treatments that have previously failed may be beneficial to patients if they have been off those treatments for some length of time and sensitive subclones reemerge. Additionally, combining the “failed” agent with a new drug may overcome the previously seen refractoriness, as in the case of panobinostat + bortezomib [48]. That said, given the multitude of new treatment options for RRMM and data from such trials as ENDEAVOR as mentioned, revisiting previously used drugs is probably best reserved for second or greater relapses.
What should be the duration of therapy for RRMM?
There is no evidence to guide duration of therapy in RRMM. Most patients with relapsed disease will be considered for continuous treatment until disease progression, which usually means treatment for 6 to 12 months with full-dose induction, often to maximal response, followed by transition to some form of lower-dose maintenance in which parts of a multi-drug regimen may be eliminated and/or the doses for the remaining drugs may be reduced. Patients with a slow-velocity relapse and no markers of high-risk disease may be suitable candidates for a defined course of treatment without maintenance therapy [11], but most patients nowadays remain on some form of maintenance for RRMM after achieving remission.
What supportive care is needed in RRMM?
Bone Health
Skeletal-related events, namely fractures, can be devastating in MM. Bisphosphonates have been shown to decrease such events in MM and zoledronic acid has shown a trend toward improved survival, perhaps related to its impact on the bone marrow microenvironment or direct toxicity to myeloma cells [60,61]. It is unclear whether bisphosphonates improve overall survival in the relapsed setting, although zoledronic acid has shown decreased skeletal-related events in the setting of biochemical-only disease progression [13,62]. In active RRMM, our general practice is to resume parenteral bisphosphonate therapy (either zoledronic acid or pamidronate in our U.S. practices) usually every 3 to 4 weeks, depending on the length of the chemotherapy cycle.
Supportive Care
RRMM is a complex disease in which patients often experience a multitude of symptoms and other complications as a result of the disease itself as well as therapy. Aggressive supportive care is of paramount importance. As examples, zoster prophylaxis is required for virtually all patients on proteasome inhibitors, anticoagulation/antiplatelet therapies should be considered for venous thrombotic event prophylaxis, and proton pump inhibitors may be appropriate for these patients who often have a real risk of peptic ulcer disease due to the use of corticosteroids, nonsteroidal anti-inflammatory drugs, and/or aspirin prophylaxis. Attention to dental health is important for patients on bisphosphonates to minimize the risk of osteonecrosis of the jaw. Nutritional problems should be monitored and can arise due to anorexia, dysgeusia, diarrhea, or constipation. Peripheral neuropathy is extremely common and support should be offered in the form of adjusting therapy to minimize risk of worsening it, analgesics if needed, assistive devices to aid in ambulation, and/or physical therapy. Depression and anxiety are understandably prevalent in patients with RRMM, who face an incurable disease that provides constant reminders of its presence due to symptoms, the need for daily pills, or frequent clinic visits for treatment and/or blood product transfusions [63]. Supporting a patient’s emotional health is a vital component of enhancing quality of life in RRMM.
Case Studies Continued
Patient A was noted to have biochemical progression initially, with relapse detectable only in serum free light chains. Treatment commenced at the time of worsening anemia. Notably, his disease originally secreted IgG-kappa and at relapse secreted kappa free light chain only; that is, he developed “light chain escape,” which signifies a high-risk disease and likely heralds clonal evolution [64]. He had excellent caregiver support and lived within 20 minutes of a treatment center. His performance status remained good at the time of relapse and he had normal organ function. He was treated with carfilzomib + pomalidomide + dexamethasone for 4 cycles, achieving a very good partial response. He then received a second ASCT with melphalan conditioning and again achieved stringent complete response. Indefinite maintenance therapy commenced with pomalidomide, and at 16 months post-ASCT he was doing well and still in remission.
Patient B was symptomatic at the time of disease progression. As her primary complaint was that of a painful humeral lytic lesion, she first underwent a course of palliative radiation, which alleviated her pain. She did not wish to restart systemic treatment and instead elected to watch her MM closely with her oncologist on a monthly basis. By 3 months, her M-spike had reached 0.6 g/dL and her serum creatinine had increased slightly, resulting in a creatinine clearance of 34 mL/min. She lived approximately 90 minutes from the closest treatment facility and found it difficult to come for visits more than once monthly. Her Eastern College Oncology Group (ECOG) performance status was 2. With her advanced age and frailty, she was not considered to be a good candidate for ASCT. She requested to go back on lenalidomide and decided with her oncologist to try ixazomib + lenalidomide + dexamethasone, with which she achieved a very good partial response. She had difficulty with myelosuppression with lenalidomide, which was dropped after 4 cycles, and she is planned for ixazomib maintenance until disease progression or drug intolerance. She receives monthly zoledronic acid to reduce the risk of fractures.
Patient C has high-risk disease as indicated by R-ISS III stage disease at diagnosis and progression only 8 months after ASCT and while on bortezomib maintenance therapy. Although he currently only has evidence of biochemical relapse, prompt initiation of treatment was warranted to prevent further renal compromise such as during his initial presentation [65]. Further, PET-CT showed the presence of extramedullary soft tissue disease, another high-risk feature. He was a robust patient with good social support and received carfilzomib + pomalidomide + dexamethasone re-induction. He was not considered for a second ASCT given his short duration of response. With his high-risk features of early relapse after ASCT, R-ISS III, and extramedullary disease, it was recommended that he continue triplet drug therapy until disease relapse or drug intolerance.
Ongoing and Future Trials
The management of RRMM will continue to evolve as paradigms for treating MM change and new treatment options become available. In particular, immunotherapies (ie, approaches that harness the immune system’s ability to fight cancer) are under exploration and some such drugs that are already FDA-approved in other diseases are being tested in MM. Chimeric antigen receptor-T cells (CAR-T), a form of cell-based immunotherapy, have generated tremendous excitement in acute lymphocytic leukemia [66] and are being tested in MM [67]. New analogs of old drugs may offer more effective, less toxic ways to control MM. The role of ASCT is being explored in randomized trials investigating whether ASCT should be pursued early or late in a patient’s MM course. These studies will no doubt further augment the armamentarium of anti-myeloma drugs that have already resulted in the increasingly longer survival we see today in this disease [3,68]. That said, MM remains incurable, and almost all patients who live long enough eventually relapse and die of MM. Hence, further research and progress are critical.
Summary
A well-designed clinical trial should be considered for all patients with RRMM, and in lieu of an available trial, regimen selection should be tailored upon disease and patient characteristics. Carfilzomib-based regimens are among the most popular at the time of first relapse currently based upon their efficacy in bortezomib-refractory cases and tolerability. Pomalidomide shows activity in lenalidomide-refractory patients. Due to intra-clonal heterogeneity, triplet regimens are preferred for fit patients, reserving doublet or monotherapy for those patients who are frail or who have an indolent disease relapse. Ongoing research will undoubtedly improve outcomes for RRMM, a disease for which the prognosis is far better than it formerly was, but which still has quite a bit of room for improvement.
Corresponding author: Brandi Reeves, MD, University of North Carolina – Chapel Hill, 170 Manning Dr., Physicians’ Office Building, CB 7305, Chapel Hill, NC 27599, brandi_reeves@med.unc.edu.
Financial disclosures: Dr. Tuchman reports the following: speakers’ bureau: Celgene, Takeda; consulting: Celgene, Takeda; research support: Celgene, Takeda, Novartis, Onyx.
