The study aimed to compare the efficacy, safety, and cost per cycle of regimens in phase 3 clinical trials by using a meta-analysis featuring 14 trials spanning over 20 years and involving almost 8000 patients.

“When choosing a regimen in relapsed and refractory myeloma, efficacy is important, but at the same time the safety of the regimen is equally important. Cost associated with drugs and their toxicity are generally overlooked,” said Dr Dhakal.

The researchers used a Bayesian network meta-analysis to compare different regimens in myeloma. “A network meta-analysis allows researchers the opportunity to compare multiple interventions both within trials and across different trials,” said Dr Orlowski. “The addition of Bayesian models allows determination of confidence intervals.”


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The researchers compared grade 3 to grade 4 adverse events across trials, taking into account the heterogeneity of the patient population between trials and the variability of the effect of interventions. Cost per cycle of each regimen was then calculated to include the cost of managing adverse events experienced on the regimen. Lastly, the efficacy of each regimen was taken into account to provide a list of ranked probabilities of each trial, scoring for safety, efficacy, and cost.

“Daratumumab, lenalidomide, and dexamethasone proved best for reducing progression in the setting of early relapse, but also had highest total cost per cycle. Panobinostat, dexamethasone, and bortezomib [were] ranked as the least safe, which, given the nature of the analysis, is perhaps a strong statement, especially as tolerability and safety are related but distinct,” said Dr Richardson.

In the trial Dr Richardson mentioned, PANORAMA-1 (ClinicalTrials.gov Identifier: NCT01023308), bortezomib was administered intravenously and on a more intensive schedule, compared with the subcutaneous and less-intensive administration that occurs in the present day, resulting in less toxicity.

“We also understand better how to manage side effects associated with panobinostat use. Conversely, stating that carfilzomib-based therapy is the safest based upon this analysis — despite cardiopulmonary, vascular and renal issues now being well recognized — may also require some qualification,” said Dr Richardson.

The authors do clearly point out that a major consideration when interpreting their analysis is that the trials were conducted over 20 years, during which the landscape of multiple myeloma treatment was significantly different.

“All of the treatments that are used in the analyses may not be used that frequently and there is wide heterogeneity in the practice patterns in both within and outside [of] the US,” said Dr Dhakal, noting that thalidomide-containing regimens are not used in the US, but are common outside of the US.

“I think a key challenge is that the study evaluates multiple variables in a dynamic space over a timeframe where everything has changed quickly — thus, it may provide information on how to compare phase 3 trials in terms of cost, adverse events, and outcome at one level, but the validity of this approach may be limited, as the authors acknowledge,” said Dr Richardson.

Many of the studies and the overall analysis did not consider individual patient variation, such as molecular subtype of disease. In the present day, gene-expression profiling is often used to categorize myeloma and it stratifies patients into 11 different subtypes, some of which have different outcomes.

“Even some of the large studies included in this analysis may not have enough patients of all of the subtypes to be able to tell whether 1 therapy is best for 1 specific subgroup, or if it is equally effective for all of them. Also, in part because myeloma is not a common cancer, and many of the therapies are directed at characteristics of the biology of myeloma cells that to some extent may be present in all of the subtypes, it is rare for these trials to even screen patients for which subtype they have,” said Dr Orlowski.

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The study authors wrote that they hope the study will provide guidance to clinicians on choosing an appropriate regimen for each patient and allow patients to derive benefit from the selected treatments — but external experts warn that the data need to be interpreted very carefully due to multiple variables in the study.

“The authors state that their analysis provides information that can help with prescribing regimens for individual patient needs, and I understand the intent of the conclusion — but I’m not sure their analysis allows that conclusion to be so definitively drawn. We need to be careful not to discriminate against specific regimens unless the reasons are well understood, applicable to the current therapeutic landscape, and validated as part of real-world experience,” said Dr Richardson.

“Selection of the best treatments always needs to happen in the context of a discussion between the patient and their family and caregivers with the doctor and the health care team,” said Dr Orlowski, mentioning that important factors include the characteristics of the patient’s disease, how it responded to prior therapies, and the care goals of the patient and their family. “The current data certainly add to our knowledge base in an important and unique way, but should not be used in isolation as the sole reason to decide for or against a specific therapy,” he added.

References

  1. Dhakal B, Narra RK, Giri S, et al. Association of adverse events and associated cost with efficacy for approved relapsed and/or refractory multiple myeloma regimens: A Bayesian network meta‐analysis of phase 3 randomized controlled trials [published online March 10, 2020]. Cancer. doi: 10.1002/cncr.32831
  2. Myeloma Trialists Collaborative Group. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. J Clin Oncol. 1998;16(12):3832-3842.
  3. Costa LJ, Brill IK, Omel J, Godby K, Kumar SK, Brown EE. Recent trends in multiple myeloma incidence and survival by age, race, and ethnicity in the United States. Blood Adv. 2017;1(4):282-287.
  4. Kristinsson SY, Anderson WF, Landgren O. Improved long-term survival in multiple myeloma up to the age of 80 years. Leukemia. 2014;28(6):1346-1348.