Oral presentation by Dr. Pieter Sonneveld
Currently, patients who relapse after bortezomib, lenalidomide, and high-dose therapy represent a therapeutic challenge. Depending on the depth and duration of previous response, revisiting previous therapies may be an option. For patients who have had an inadequate response or quick relapse after standard induction or high-dose therapy, newer-generation proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) have become standard of care. Daratumumab is not yet widely available in Canada, but increasing access is anticipated in the coming months and years. Where possible, enrolment in a clinical trial is recommended for patients with relapsed or refractory multiple myeloma (RRMM). However, RRMM continues to be a therapeutic challenge and the incremental benefit of each succeeding line of therapy tends to be modest in many patients. Most patients tend to get their best response to highly potent therapies when they are used earlier in the disease course and in triplet or quadruplet regimens. We try to use effective agents as early as possible, but our utilization may be limited by funding, access, experience, or patient factors. There is limited data to guide the use of one regimen over another in the setting of RRMM at any given time.
This phase II study was designed to look at carfilzomib, pomalidomide, and dexamethasone (KPd) as salvage therapy at first relapse (or for primary refractory disease) in the patients previously enrolled in the EMN02 trial. Carfilzomib and pomalidomide were administered for 4 monthly re-induction cycles as per the accepted dosing schedule (Days 1, 2, 8, 9, 15, and 16 for carfilzomib and days 1–21 for pomalidomide) with weekly dexamethasone. Patients who had not previously received high-dose melphalan and autologous stem cell transplant went on to receive this therapy. Patients then received a further 4 cycles of KPd as consolidation therapy and those achieving stable disease or better went on to single-agent pomalidomide maintenance. In this regard, the salvage therapy was administered similarly to first-line therapy, in contrast to the indefinite administration of many second-line and beyond regimens currently in use.
In the interim analysis, performed on a small population of 60 patients, about a third achieved complete response or stringent complete response, over two thirds achieved very good partial response, and 87% achieved at least a partial response. Responses were fairly rapid, with a median response time of 2 months, and the median progression-free survival was 18 months. As expected, high-risk cytogenetics were associated with inferior responses. About two thirds of patients were able to complete the protocol as planned. Almost all of these patients had progressed on lenalidomide maintenance. The number and depth of responses with KPd is encouraging considering that all of these patients had seen PIs and IMiDs previously and had progressed on lenalidomide maintenance. This is a common scenario that we are now seeing routinely in clinical practice in transplant-eligible patients.
Grade 3 and 4 hematology toxicity was reported in 30% of patients, which is comparable to other triplet regimens. There were small but notable numbers of non-hematologic grade 3 and 4 adverse events (AEs), including cardiovascular and respiratory events (5% each), infections (20%), and neuropathy (3%). The cardiorespiratory events are of particular concern considering that many of our patients already present with comorbidities such as ischemic heart disease or chronic obstructive pulmonary disease, and these patients may tolerate such AEs poorly. The grade 3/4 infection rate is also quite high at 20% and there were 2 fatalities from pneumonia, highlighting the degree of immunosuppression in these patients.
Acyclovir prophylaxis is a necessity in these patients, as is close monitoring and rapid treatment of infectious complications (often pneumonia). Granulocyte-colony stimulating factor support, if available, may help to support the neutrophil count enough to allow fewer dose reductions. Cardiac and respiratory complications can be a challenge, so at-risk patients need to be monitored closely for any evidence of cardiorespiratory distress and undergo appropriate investigations, such as echocardiogram, electrocardiography, or chest x-ray/computed tomography scan, as indicated. Referral to other specialists to maximize cardiac and respiratory status prior to or early in the course of therapy is helpful. We also try to limit the amount of intravenous fluids and the number of transfusions administered around the time of carfilzomib to decrease the risk of a cardiac complication.
KPd represents an attractive option for an effective triplet therapy in patients who have relapsed following previous bortezomib induction with or without consolidation therapy, as well as lenalidomide maintenance. However, the high cost of this regimen will be a barrier to incorporating it as early as second line. Also, the cardiorespiratory and infection risks will make this a challenging regimen for more frail patients. Although I will continue to seek access to this regimen in a selected patient population, more data is needed before this is considered a standard of care for patients in second-line therapy.
I think we will see combinations of highly potent next-generation PIs and IMiDs being recommended earlier in therapy, in the second-line or even first-line setting. However, I also believe that as newer agents with novel mechanism of actions are investigated, they will also move earlier in the treatment course. Sequencing of therapies, and the ever-present issue of the increasing cost of these regimens, will continue to represent significant challenges.