Expert Reviews Results of Carfilzomib Combination in R/R Multiple Myeloma

The combination of carfilzomib (Kyprolis), immunomodulatory drugs, and dexamethasone has proved effective for the treatment of relapsed/refractory (R/R) multiple myeloma. However, for many jurisdictions, the combination can be costly. New research suggests that the combination of carfilzomib thalidomide (Thalomid), and dexamethasone could be a safe and cost-effective alternative.

The study enrolled patients with R/R multiple myeloma who had between 1-3 prior lines of treatment. The 83 patients had a median age of 66 years old. Patients were given 12 cycles, each lasting 28 days, of the three-drug combination. The primary endpoint was progression free survival (PFS). Secondary endpoints were overall response rate (ORR), overall survival (OS), adverse events (AE), and quality of life.

The median PFS was 20 months. The PFS rate at 6.5 months was 76.2%. Median overall survival has not been reached in the study. The combination achieved an ORR of 86.4%.

Most of the AEs observed in the study population were grade 2 or lower. The most common AEs were peripheral neuropathy, with 16% of patients reporting, followed by upper respiratory tract infections in 12% of patients. Those most recent data show that 41% of patients have completed 18 cycles of treatment.

In an interview with Targeted Oncology, Hang Quach, MD, a consultant clinical and laboratory hematologist at St. Vincent’s Hospital, discussed the phase 2 Australasian Leukaemia and Lymphoma Group MM 018/ Asian Myeloma Network 002 study and how it can impact the treatment of R/R/ multiple myeloma in the future.

TARGETED ONCOLOGY: What was historically seen with carfilzomib and immunomodulatory drugs in the upfront setting that inspired the idea to test this in the relapsed or refractory setting.

QUACH: The rationale behind this study was the fact that we know that a combination of immunomodulatory drugs and proteasome inhibitors are effective for multiple myeloma, and we know that indeed carfilzomib and lenalidomide (Revlimid) is more effective than lenalidomide and dexamethasone, according to the ASPIRE study. But, not all jurisdictions can afford an expensive drug combination of carfilzomib and lenalidomide, and therefore, the idea here was that thalidomide was a less costly drug compared to lenalidomide, and therefore carfilzomib, thalidomide, and dexamethasone ought to be a more affordable combination for some jurisdictions. This study was a collaboration between the Asian Myeloma Network as well as the Australia Leukemia Lymphoma Group. The focus for the combination was that it has jurisdiction or relevance in that it would be a more affordable combination for our jurisdiction in the Asia-Pacific region.

TARGETED ONCOLOGY: Can you briefly discuss the study design and the methods used for the study?

QUACH: The ALG MMA18 and the AMNO 2 study was a phase 2 single arm study of combination carfilzomib, thalidomide, and dexamethasone for the treatment of relapsed and refractory multiple myeloma. It took place across 16 centers in 5 countries in the Asia-Pacific region. In this study, patients with 1-3 prior lines of treatment were given 12 cycles of induction of carfilzomib, thalidomide, and dexamethasone followed by 6 cycles of consolidation of carfilzomib and dexamethasone and a total of 83 patients with a median age of 66 were recruited. In terms of the results, overall, the KTD combination was very well tolerated. The most common adverse events being upper respiratory tract infection and fatigue. However, most of these were grade 1 and grade 2. And grade 3 or more cardiac adverse events only occurred in approximately 2.4% of patients. The important thing about this study was that health-related quality of life was measured throughout treatment and was shown to be good and was maintained throughout the duration of treatment. In terms of further results, after a median follow up of 14 months, overall response rate was 76% with a VGPR of or better off 62%, and the median progression free survival was at 23.4 months, with a median overall survival that was not reached, and the 12 months progression free survival and overall survival was similar to 74% and 84%, respectively. So overall, what we found was that it was safe, well tolerated and efficacious, and certainly represents an important option for patients with relapsed refractory myeloma.

TARGETED ONCOLOGY: Can you explain what the implications are of these results in the treatment landscape?

QUACH: Granted the limitation of comparing across clinical trials, the efficacy that we see here with KTD is quite comparable with what we see with carfilzomib, thalidomide, and dexamethasone in other studies, including the ASPIRE study. The important thing here is that given that thalidomide is less costly than lenalidomide, KTD could be a more affordable combination for certain jurisdictions, particularly within the Asia-Pacific region, and hence a wide accessibility for patients with relapsed/ refractory myeloma. So, this particular study has importance and relevance within the Asia-Pacific region.

TARGETED ONCOLOGY: Based on this study and what we're seeing in other studies in this space, what do you see with this regimen in the future?

QUACH: I think in the future, KTD will represent a very viable treatment option for relapsed/refractory multiple myeloma. It would have relevance, even in the current era, whereby a number of patients, the majority of patients, even within the Asia-Pacific region would have had seen bortezomib upfront, or even lenalidomide upfront. This is a bortezomib-free combination.

Unfortunately, in the population that was accrued into the study, the majority of patients have seen immunomodulatory agent, but for the majority, the agent was thalidomide rather than lenalidomide. So, we don't know how this combination will fare in patients who have been refractory to lenalidomide, but that notwithstanding, a carfilzomib-based regimen is shown to be effective for patients post lenalidomide in other studies.

TARGETED ONCOLOGY: What research is ongoing to answer some of those unanswered questions that hematologists have?

QUACH: Pertaining to this particular study, we don't know the difference between the toxicity profile between Asian and Caucasian patients. This is one of the questions we would like to answer in this study. Currently, 50 patients ofthe 83 patients in the study are Caucasian. Within the Australia Leukemia Lymphoma Group, and 30 patients are Asian. We've yet to have long enough follow-up to compare the toxicity profile between the Asian and Caucasian cohorts and whether or not there is any difference in response with respect to carfilzomib. But that would be an interesting question we'd like to answer.

TARGETED ONCOLOGY: Are there any abstracts that are coming up that you're excited to see?

QUACH: I think it's from a global perspective for the abstract, regarding the new immunotherapies very tantalizing and exciting, particularly updated data on novel T cell engages, such as blinatumomab (Blincyto) and the Bristol Myers Squibb compound, the CC 489 compound. I think the particularly exciting is the data on CAR T-cells, particularly allogeneic CAR T-cells that would offer a possibility for an off the shelf product for CAR T-cells. I think that this would be very widely applicable more so than the traditional CAR T- cells, autologous CAR T-cells. It's exciting and I look forward to these abstracts very much.

TARGETED ONCOLOGY: What does the future of multiple myeloma research look like, in your opinion?

QUACH: I think the future of myeloma looks very bright and exciting. As evidenced by the number of exciting abstracts presented during at ASH 2020, I think we're about to enter a new era, which will certainly guarantee improvement in PFS and OS for patients with multiple myeloma.

^REFERENCE:

^{Quach, H., Harrison, S., Lee, J. et all. Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 75 Blood https://doi.org/10.1182/blood-2020-139174}