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Division of Cancer Medicine
Department of Lymphoma/Myeloma
The University of Texas MD Anderson Cancer Center
This is an exciting time for those of us who treat patients with multiple myeloma (MM) as new treatment options and therapeutic approaches continue to emerge and provide opportunities for improved outcomes. In August 2019, I discussed how I treat patients with newly diagnosed MM. In this commentary, I discuss my current strategies for treating patients with relapsed/refractory MM, as well as emerging approaches which I have begun to or plan to use in our clinic.
For my patients with relapsed or refractory MM, I tend to divide them into 2 groups: those with relapse after 1‑3 previous lines of therapy and those with more than 3 previous lines of therapy. Whether previous therapy was stopped due to intolerance/toxicity or disease progression, the general regimens I recommend for each of these 2 groups can differ. In addition, I also consider the type of relapse: A patient with new symptoms or organ dysfunction (eg, kidney failure, very high calcium) related to their disease relapse may need different treatment than a patient who is doing well with only a biochemical relapse due to a slightly increased M-protein level in the blood or urine.
Regardless of the type of relapse, it is important to realize that triplet therapy is generally more effective than doublet therapy for patients with MM. Moreover, now that clinicians have a wide variety of approved medications to combine in various ways, each line of therapy should ideally include new agents and regimens to which the patient’s disease may still be sensitive.
Treating Patients With 1-3 Previous Lines of Therapy
When considering how to treat patients with MM in their first relapse, the key factors are the type of initial therapy they received and the duration of response to first-line therapy. Patients who receive effective initial treatment with triplet therapy including a proteasome inhibitor and an immunomodulatory drug (IMiD) (usually either bortezomib or carfilzomib with lenalidomide and dexamethasone) followed by high‑dose melphalan and autologous stem cell transplantation (ASCT) and maintenance therapy (eg, lenalidomide) will typically achieve a prolonged response before eventually relapsing.
For patients with 1-3 previous lines of therapy, the best approach is a triplet regimen including at least 1 new class of therapy. The most commonly used regimens include an IMiD, either lenalidomide or pomalidomide, combined with either a monoclonal antibody like elotuzumab (targeting SLAMF7) or daratumumab (targeting CD38) or a proteasome inhibitor (PI) (carfilzomib, ixazomib, or bortezomib) and dexamethasone.
For patients with a prolonged response to initial therapy (approximately 2 or more years on lenalidomide maintenance after IMiD/PI/dexamethasone induction), I consider reusing lenalidomide/dexamethasone at first relapse with the addition of a different PI than the one used in induction. Alternatively, I will often combine either lenalidomide or pomalidomide with elotuzumab or daratumumab and dexamethasone at first or second relapse. Selecting the optimal regimen for individual patients depends on first-line therapy, disease and patient characteristics, and patient preference. For example, if a patient prefers an all-oral regimen, ixazomib/lenalidomide/dexamethasone may be a good option. For patients who have baseline heart failure, I usually avoid carfilzomib-based combinations and may consider a daratumumab/IMiD/dexamethasone combination. For patients with a slow biochemical relapse, elotuzumab combinations can afford a sustained response and may be worth pursuing. In patients who do not tolerate IMiDs well, combinations such as bortezomib/daratumumab/dexamethasone or carfilzomib/daratumumab/dexamethasone are good options.
However, for patients who relapse early on adequate initial therapy (eg, IMiD/PI/dexamethasone with or without daratumumab followed by lenalidomide maintenance) and worsen quickly, I often consider other approaches. For these patients, I might suggest referring them to one of the ongoing clinical trials of cellular therapy such as CAR T-cells. For example, the phase II KarMMa-2 trial assessing treatment with CAR T-cell therapy in patients who have experienced a relapse within 18 months of initial therapy is now accruing. If a trial is not an option for patients who are relapsing early on lenalidomide, we typically switch to pomalidomide, a third-generation IMiD, in combination with various other agents, including elotuzumab, daratumumab, or carfilzomib. Trials with each of these combinations have shown high response rates and good durations of response. Additional combinations also include a monoclonal antibody with a PI and dexamethasone.
Treating Patients Following 3 or More Lines of Therapy: Chemotherapy and Second ASCT
For patients who have relapsed after multiple lines of therapy, chemotherapy (alkylating agents and others) continues to be a cornerstone of treatment. I frequently use bendamustine, cyclophosphamide, or doxorubicin for patients who have limited options or whose MM is very difficult to control. Chemotherapy regimens such as high-dose cyclophosphamide, bortezomib, doxorubicin and dexamethasone (modified CBAD) or etoposide, cisplatin, doxorubicin, high-dose cyclophosphamide, and dexamethasone (D-PACE)–like regimens can be used in patients who require rapid disease control as a bridge to more permanent therapy. More permanent therapy may include ASCT or clinical trials with cellular therapy. These regimens are characterized by short PFS, so a plan for continued treatment after a few cycles of mCBAD or D-PACE–like regimens is imperative. These regimens are associated with increased risk of infection and requires concomitant use of medications to increase white blood cell count.
Cyclophosphamide is an alkylating agent that can be combined with a wide variety of other agents such as carfilzomib, bortezomib, lenalidomide, and pomalidomide. The addition of cyclophosphamide may increase the response to a treatment regimen and is usually used if treatment options are limited. Cyclophosphamide is also very useful in situations where patients cannot tolerate, are refractory to, or don’t have access to IMiDs. In our clinic, we use the modified CBAD regimen, which is similar to but less toxic than the hyper‑CVAD regimen used in leukemia. In our experience, this modified CBAD regimen is very effective with a response rate close to 100% in relapsed/refractory MM. However, this response is short lived, with treatment of 1-2 months providing a response for only approximately 3 months, so we generally use this regimen as a bridge to something else. That said, it is particularly suitable for a patient with very aggressive MM that needs to be controlled quickly with a plan to proceed to more definitive therapy afterwards.
For select younger patients with aggressive relapsed MM who do not have many alternatives, we also consider high-dose chemotherapy regimens such as VDT‑PACE or PACE‑like regimens, which include cisplatin, doxorubicin, cyclophosphamide, etoposide, and other agents. However, this type of approach is associated with a high degree of toxicity, including gastrointestinal toxicity and myelosuppression, which can take a longer time to recover from.
The use of a second ASCT for relapsed/refractory MM remains controversial. Generally, I may consider a second ASCT for certain patients who received ASCT as a part of first-line therapy but who did not relapse for at least a few years. For example, a patient who received ASCT 10 years ago and has been off and on maintenance therapy and now has a recurrence may be a candidate for a second ASCT resulting in a very good response likely to last for years. By contrast, a patient with very high‑risk MM who received an initial ASCT followed by triplet maintenance therapy (IMiD/PI/dexamethasone) but his or her MM progressed within 1 year of ASCT or continues to recur would not be a good candidate for a second ASCT. For some of these relapsed patients; however, high-dose melphalan can be considered so that it can produce enough response to bridge to another approach, often a clinical trial.
Treating Patients Following 3 or More Lines of Therapy: Emerging Treatment Approaches
BCL-2 Inhibition: Venetoclax
One of the most interesting new medications for MM is the BCL-2 inhibitor venetoclax, which is currently approved for the treatment of some leukemias. BCL-2 is a regulatory protein that is required for MM cell survival. Venetoclax is particularly effective for patients with MM and a t(11;14) translocation, which occurs in approximately 30% to 40% (or more) of patients.
There has been some question about the safety of this agent in patients with MM after reports from the phase III BELLINI study with venetoclax/bortezomib/dexamethasone vs bortezomib/dexamethasone, which initially reported a high rate of infections and early deaths with venetoclax. However, in a subgroup analysis of BELLINI at ASH 2019, the addition of venetoclax significantly improves PFS and showed similar OS in patients with t(11;14), but in non-t(11;14) populations, PFS was similar with or without venetoclax and OS favored placebo. In a recent phase I/II study presented at ASH 2019, the response rate for venetoclax plus dexamethasone in patients with t(11;14) MM was approximately 50% with a median duration of response of 12 months. In this study, some infections were observed (grade ≥ 3 sepsis in 5% to 10% of patients and grade ≥ 3 pneumonia in 3% to 5% of patients depending on phase of study), but only 1 patient died due to infection. Taken together, these data suggest that venetoclax therapy may be beneficial for patients with a t(11;14) translocation.
In our clinic, we consider venetoclax as an off‑label use for patients with MM and t(11;14) with few treatment options remaining and use it mostly in combination regimens with carfilzomib or bortezomib and dexamethasone. We only consider this approach in patients who have already received many other therapies and who have no other options likely to provide such a strong response. However, safety is still a concern and patients should be closely monitored for signs and symptoms of infection and treat promptly. In addition, complete blood counts should be monitored throughout the treatment course, and any cytopenias should be managed promptly. Use of broad-spectrum prophylactic antibiotics, such as levofloxacin, may be considered.
XPO-1 Inhibition: Selinexor
Another newer medication that has been approved for relapsed/refractory MM is the selective inhibitor of nuclear export selinexor in combination with dexamethasone. The initial FDA approval was based on data from the phase II STORM trial, which reported a response rate of approximately 30%. The median PFS was almost 4 months and the median OS was almost 9 months in a heavily pretreated population of patients with MM. Additional investigations of selinexor include the phase I/II STOMP trial of selinexor, pomalidomide, and dexamethasone in patients with relapsed/refractory MM (n = 51). In this trial, approximately 50% of patients achieved a response and 74% of patients had stable disease or better. As has been seen previously, patients treated with selinexor do experience adverse events, including fatigue, neutropenia, thrombocytopenia, and asthenia, but certainly these data suggest that selinexor-based therapy is a reasonable treatment approach for heavily pretreated patients.
In our clinic, we use selinexor according to the label: in patients who have received at least 4 previous lines of therapy and whose disease is refractory to at least 2 PIs, at least 2 IMiDs, and an anti-CD38 monoclonal antibody. In our experience, we have seen some good responses with this agent. However, caution is required with selinexor due to potential adverse events, including hyponatremia, requiring monitoring of sodium levels, and gastrointestinal toxicities.
Anti-BCMA–Targeted Therapy: BiTEs and CAR T-Cell Therapy
BCMA—a member of the TNF receptor family of proteins—has been identified as a therapeutically relevant target in MM as it is highly expressed preferentially in malignant plasma cells but can also be found on mature B-cells and plasma cells.
A bispecific T-cell engager (BiTE) comprises 2 single-chain antibody fragments that link to both an antigen on tumor cells and a cell-surface receptor on T-cells, thereby activating T-cells and engaging them with tumor cells. Currently, most BiTEs for MM are targeted to BCMA on the MMM cells and CD3 on T-cells, with other targets also being developed.
The most mature data using this approach in MM are from studies of AMG 420, a BiTE with a short half-life that targets BCMA on MM cells and CD3 on T-cells. In a phase I trial that enrolled patients with relapsed/refractory MM, AMG 420 demonstrated an ORR of 70% with a median duration of response of 9 months for patients who received the maximum tolerated dose of 400 μg/day. The first clinical phase I study of CC-93269, another BCMA-targeted BiTE, in 30 patients with relapsed/refractory MM was presented at ASH 2019. The initial ORR was 88.9% with 44.4% CRs among patients treated with the 10-mg dose. If these results are validated in larger studies, these medicines could become important in treatment of MM in the near future.
CAR T-cells are an autologous, patient-specific therapy. In MM, numerous clinical trials are looking at the use of BCMA-targeted CAR T-cells for relapsed/refractory disease. For example, the phase Ib/II CARTITUDE 1 trial, conducted in the United States, examined the CAR T-cell construct JNJ-4528 in 29 patients with heavily pretreated relapsed/refractory MM and reported that 69% of patients achieved CR or better, and all 17 patients analyzed achieved measurable residual disease (MRD) negativity. In a longer follow-up of the LEGEND-2 trial that was conducted in China with a similar CAR construct to JNJ-4528, the ORR was 87.7%, with 74.0% of patients achieving CR and 68.0% of patients achieving MRD negativity. In this longer follow-up of LEGEND-2, the median overall PFS was 19.9 months and the median OS was 36.1 months.
Of note, new clinical trials of CAR T-cell therapy are exploring this treatment paradigm earlier in treatment (eg, after first relapse). There are also clinical trials in newly diagnosed MM comparing standard ASCT with CAR T-cell therapy.
How are you treating your patients with relapsed/refractory MM? I encourage you to answer the polling question and join the conversation in the discussion box below.
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