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Are We Ready to Treat Smoldering Myeloma? No!

By Matti McFarlane, MSc Candidate, TMED801 Student

 

On Thursday, November 3rd the TMED first year class had the pleasure of hearing from Dr. Aaron Goodman, MD, from University of California San Diego during Oncology’s guest Medical Grand Rounds. He spoke about the current limitations in treating the blood conditions of smoldering multiple myeloma (SMM) and multiple myeloma, as well as the importance of critically analyzing the current research in this field. Following his presentation, Dr. Goodman kindly met with the TMED students during a facilitated discussion, sharing his thoughts on the importance of patient-centred care, the current directions of cancer research and his experiences as a hematologist/oncologist.

 

In Canada, the 5-year net survival for multiple myeloma patients is only 50% (1) . Dr. Goodman spoke about SMM and multiple myeloma as a paradigm for understanding the design of cancer clinical trials and how to interpret current literature. He began by highlighting the vast improvements in treating multiple myeloma, such as immunomodulatory therapeutics, which have significantly impacted overall patient survival (2). He described SMM as an asymptomatic disease state. More specifically, it is a premalignant clonal plasma cell disorder with a heightened risk of progressing to multiple myeloma (3).

 

Subsequently, Dr. Goodman described the deficits in the most recent diagnostic criteria for SMM and the United States’ guidelines for treatment (4,5). He discussed the challenges associated with the various risk stratification models, which attempt to define the likelihood of disease progression (6). The heterogeneity of these stratification models has led to inconsistent results in clinical trials. Currently, it is very difficult to define which patients are at high risk for progressing to the cancerous disease state. He emphasized that although there are limitations in the current models, the future is bright. Genomic profiling is a promising avenue for identifying patients most at risk for disease progression (7). Dr. Goodman outlined his reservations towards the current treatment guidelines, which recommend treating high-risk SMM patients with the drug lenalidomide before the onset of any clinical symptoms (8). He described perceived issues with hallmark clinical trial study design that support lenalidomide’s recommendation. Specifically, lenalidomide based studies were under powered, used outdated disease classification systems, poor endpoints, ethical concerns etc. Overall, he provided evidence that well-designed clinical trials are warranted to better inform clinical guidelines, treatment, and how clinicians approach care for asymptomatic SMM patients.

 

Continually, Dr. Goodman discussed the research limitations for “active” multiple myeloma, defined as patients with clinical symptoms (i.e., end-organ damage). Specifically, he described: the perceived usefulness of surrogate endpoints frequently used in clinical trials [i.e., Progression Free Survival may not be an appropriate surrogate for Overall Survival], unethical control arms, and poor reporting of post protocol therapy. He contended that many clinical trials inadequately answer clinically relevant questions, such as the benefit of novel (toxic and expensive!) drug protocols on overall patient survival and quality of life. He critiqued the inferior treatment quality in multiple myeloma clinical trial control arms and the lack of gold-standard care for patients following study conclusion (9). Overall, Dr. Goodman raised ethical concerns about how these clinical trials are conducted. Ultimately, some studies may be doing more harm than good for multiple myeloma patients.

 

Following his presentation, Dr. Goodman sat down for an engaging facilitated discussion with TMED students. He spoke to the importance of patient-centred care in his practice, and the role he takes as his patients’ advocate. Additionally, he excitedly engaged our class in a discussion surrounding the promising role of CAR-T cell therapy in cancer therapeutics, which was his inspiration for pursing medicine. He spoke about the unethical practices of multiple myeloma clinical trials and highlighted how they often take advantage of countries where gold-standard treatments are not accessible. This discussion gave insight into the important role translational medicine research can have on patient care, globally. When studies are poorly designed, it leads to less efficacious treatments. For clinicians, the confusing literature can lead to substandard patient care. Dr. Goodman also spoke to the importance of being able to criticize research, a skill the TMED program strives to teach us. Lastly, he gave insight into one of his preferred platforms for sharing academic insights and engaging with like-minded thinkers – Twitter. Find him as @AaronGoodman33, or “Papa Heme”. 

 

I would like to thank Dr. Goodman for generously speaking to the TMED students during his short visit to Kingston. You have certainly instilled in us that we must not be afraid to remind our colleagues that, first and foremost, we must all strive to put patient well-being above all else.

 

References

 

1.         Lee S. Survival statistics for multiple myeloma [Internet]. Canadian Cancer Society. [cited 2022 Nov 9]. Available from: https://cancer.ca/en/cancer-information/cancer-types/multiple-myeloma/p…

2.         Cowan AJ, Green DJ, Kwok M, Lee S, Coffey DG, Holmberg LA, et al. Diagnosis and Management of Multiple Myeloma: A Review. JAMA. 2022 Feb 1;327(5):464–77.

3.         Rajkumar SV, Landgren O, Mateos MV. Smoldering multiple myeloma. Blood. 2015 May 14;125(20):3069–75.

4.         Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. The Lancet Oncology. 2014 Nov 1;15(12):e538–48.

5.         NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Multiple Myeloma. Multiple Myeloma. 2013;68.

6.         International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM) | Blood Cancer Journal [Internet]. [cited 2022 Nov 9]. Available from: https://www.nature.com/articles/s41408-020-00366-3

7.         Bustoros M, Sklavenitis-Pistofidis R, Park J, Redd R, Zhitomirsky B, Dunford AJ, et al. Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression. J Clin Oncol. 2020 Jul 20;38(21):2380–9.

8.         Goodman AM, Kim MS, Prasad V. Persistent challenges with treating multiple myeloma early. Blood. 2021 Jan 28;137(4):456–8.

9.         Mohyuddin GR, Koehn K, Sborov D, McClune B, Abdallah AO, Goodman AM, et al. Quality of control groups in randomised trials of multiple myeloma enrolling in the USA: a systematic review. Lancet Haematol. 2021 Apr;8(4):e299–304.

Name
Hailey Schincariol

Sun, 11/13/2022 - 11:24

Hi Matti,

Thank you for the excellent summary of Dr. Goodman’s grand rounds - You did great job facilitating the TMED discussion! Before the grand rounds, I had never heard of smouldering myeloma, despite knowing what myeloma was, so I found the rounds especially educational for me! When reading into the literature, I noticed many articles noted that myeloma is relatively rare, however, it is becoming more common with the worldwide incidence jumping 126% between 1990 and 2016 (Cowan et al., 2018). Why do you think the incidence of myeloma is increasing? I think it may be due to the advancement in diganostics in the field of cancers, but I am curiosity to see if you have any other suggestions?

Cowan, A. J., Allen, C., Barac, A., Basaleem, H., Bensenor, I., Curado, M. P., Foreman, K., Gupta, R., Harvey, J., Hosgood, H. D., Jakovljevic, M., Khader, Y., Linn, S., Lad, D., Mantovani, L., Nong, V. M., Mokdad, A., Naghavi, M., Postma, M., Roshandel, G., … Fitzmaurice, C. (2018). Global Burden of Multiple Myeloma: A Systematic Analysis for the Global Burden of Disease Study 2016. JAMA oncology, 4(9), 1221–1227. https://doi.org/10.1001/jamaoncol.2018.2128

Name
Hailey Schincariol

Hi Hailey!

Thank you for your reply. I also found the rounds extremely interesting, as I had not heard of a pre-malignant state associated with multiple myeloma either.

You ask a great question. In his talk, Dr. Goodman explained that smoldering multiple myeloma (SMM) is often an incidental finding, as it is an asymptomatic condition. It was first defined in 1980 by Kyle and Greipp (1). Overtime, the understanding of prevalence, diagnostic criteria, and risk of progression to multiple myeloma has greatly increased (2). Therefore, I think your comment is valid in suggesting that prevalence and incidence will increase as the diagnosis of SMM evolves and clinicians have a greater understanding of defining the condition. Currently, there is a lack of sufficient population-based studies/registries (2). This creates challenges in conducting epidemiological studies and identifying the true picture of patients with smoldering multiple myeloma. Notably, SMM lacks an International Classification of Diseases diagnostic code (it is grouped in with multiple myeloma). However, some etiological features have been identified. For example, the incidence of SMM increases with age (3). Global crude incidence is likely increasing due to a larger ageing population, as well as increased overall survival due to modern medicine (4). I would be interested to see if population-based registries are eventually established for SMM, and how this will affect the global incidence and prevalence of the condition.

References

1. Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med. 1980 Jun 12;302(24):1347–9.

2. Blum A, Bazou D, O’Gorman P. Smoldering multiple myeloma: prevalence and current evidence guiding treatment decisions. Blood Lymphat Cancer. 2018 Apr 20;8:21–31.

3. Ravindran A, Bartley AC, Holton SJ, Gonsalves WI, Kapoor P, Siddiqui MA, et al. Prevalence, incidence and survival of smoldering multiple myeloma in the United States. Blood Cancer J. 2016 Oct 21;6(10):e486.

4. Turesson I, Bjorkholm M, Blimark CH, Kristinsson S, Velez R, Landgren O. Rapidly changing myeloma epidemiology in the general population: increased incidence, older patients, and longer survival. Eur J Haematol. 2018 Apr 20;10.1111/ejh.13083.

Name
Matti McFarlane

Name
Maria Korovina

Mon, 11/14/2022 - 13:55

Hi Matti,

Thank you for sharing a summary and your thoughts on the MGR. Throughout the talk and the facilitated discussion, Dr. Goodman mentioned the importance of being a patient advocate within the hospital setting and the research world. We listened to Dr. Goodman discuss the various ways he uses his platform to point out flaws within the research surrounding smoldering myeloma. As you mentioned, Dr. Goodman writes letters and speaks out on his Twitter platform regarding the mistakes he sees in the protocols of various studies. Do you think it would be beneficial to explain these flaws in a lay form and help the general audience understand the issues behind some of these papers? Could engaging a larger audience help individuals with family members with myeloma stay within the loop of all the current research within the scientific field? Could this be a potential method of advocating for patients outside the hospital setting?

Cheers,

Maria

Name
Maria Korovina

Hi Maria,

Thank you for your reply! Dr. Goodman certainly highlighted the importance of being an advocate for patients, especially with a condition that is not yet well-characterized.

In response to your discussion point, I think that explaining flaws with research in a lay form would be beneficial to patients and advocates outside of the medical field. I feel that a significant barrier to advancements in biomedical discovery, patient care, and trust of the healthcare system is due to the complexity of understanding scientific literature. This topic directly applies to the efforts of our program in translational medicine, as there is a defined need to translate scientific findings into clinical practice. I believe an important step to that process is ensuring patients understand advancements in research to increase support for implementation initiatives. In the case of smoldering myeloma, if patient groups were to better understand the issues with the direction of current clinical trials, perhaps they could have some influence on which trials are approved. One proposed idea to improve scientific communication is to adjust how journal articles are written. Kuehne and Olden suggest that lay summaries should be included in journal articles in order to increase the visibility, impact, and transparency of scientific research (1). This could broaden the impact of research overall, and hopefully improve patient care as well.

Reference

1. Kuehne LM, Olden JD. Opinion: Lay summaries needed to enhance science communication. Proc Natl Acad Sci U S A. 2015 Mar 24;112(12):3585–6.

Name
Matti McFarlane

Name
Jana Livingston

Mon, 11/14/2022 - 14:46

Hi Matti,

I enjoyed reading your post about Dr. Goodman’s presentation, you did a great job summarizing this topic and the ensuing facilitated discussion. This grand round has raised awareness about smoldering myeloma along with the lack of adequate clinical trials in this field. After reading into the literature, I came across recently published results of a phase 3 trial in the journal Blood1. This study looks at the efficacy of adding isatuximab (monoclonal antibody), to the initial line of treatment for newly diagnosed patients with multiple myeloma1. The treatment arm had greater MRD (minimal residual disease) negative results compared to the control – meaning no disease was identified after treatment1. However, severe adverse events were prevalent in both the control and treatment groups1. I’m curious about your thoughts on these results. Do you think this study shares some of the common study flaws highlighted by Dr. Goodman or is this a step in the right direction for treating multiple myeloma?

Best,
Jana

Reference:

1. Goldschmidt H, Mai EK, Nievergall E, Fenk R, Bertsch U, Tichy D, et al. Addition of Isatuximab to Lenalidomide, Bortezomib and Dexamethasone As Induction Therapy for Newly-Diagnosed, Transplant-Eligible Multiple Myeloma Patients: The Phase III GMMG-HD7 Trial. Blood. 2021;138(Supplement 1):463–463.

Name
Jana Livingston

Hi Jana,

Thank you for your interesting reply! Dr. Goodman certainly stressed the importance of strengthening our critical appraisal skills and being able to assess clinical trial designs. When looking at the trial you found, I believe that it does demonstrate some of the issues Dr. Goodman pointed out in his lecture. Primarily, the study used a surrogate endpoint for overall survival, minimal residual disease, and did not consider quality of life. Importantly, the number of adverse events is concerning, as well as the proportion of patients that discontinued treatment. At least one adverse event (equal to or above grade 3) occurred in 63.6% of patients in the treatment arm, and four patients died in this arm as well (1). I believe that this is somewhat concerning. Additionally, quality of life should be an important outcome in this trial. I believe that we will all be looking at scientific studies through a different lens after Dr. Goodman’s informative talk!

Reference

1. Goldschmidt H, Mai EK, Nievergall E, Fenk R, Bertsch U, Tichy D, et al. Addition of Isatuximab to Lenalidomide, Bortezomib and Dexamethasone As Induction Therapy for Newly-Diagnosed, Transplant-Eligible Multiple Myeloma Patients: The Phase III GMMG-HD7 Trial. Blood. 2021 Nov 5;138(Supplement 1):463.

Name
Matti McFarlane

Name
Abby Mocherniak

Tue, 11/15/2022 - 11:49

Hi Matti!

I really enjoyed reading your post on Dr. Goodman's presentation surrounding smouldering multiple myeloma (SMM) and existing research in this area. I think you did an excellent job of summarizing all of the key points Dr. Goodman covered in his lecture, and throughout our facilitated discussion. I first heard of SMM though my work with the Princess Margaret Cancer Foundation, but didn't have a solid understanding of what this was until Dr. Goodman's talk, so I found it a really interesting topic to learn more about!

As you mentioned, Dr. Goodman critiqued the inferior treatment quality in multiple myeloma clinical trial control arms and the lack of adequate care for patients following study conclusion. This is something I found quite alarming to hear, especially that this is still happening in clinical studies today. Clinical oncology research with human subjects requiries ultimate trust on the part of patients and ultimate respect for persons on the part of clinical researchers. I think in the situations Dr. Goodman discussed, it is important to consider the harm-benefit ratios for clinical trial participants, and that unfavourable prognosis in patients with multiple myeloma is not justification for experimental protocols that would put participating patients at greater risk, or have further detrimental impacts on their health/treatment outcome. I am wondering how you think we can change our current approach to ethics in these clinical trials to ensure patients are protected and respected, with researchers abiding by existing ethical frameworks?

I look forward to hearing your thoughts!

Abby

Name
Abby Mocherniak

Hi Abby,

I appreciate your thought-provoking comments, and I share similar thoughts concerning the harm-benefit ratio for clinical trials. It seems there should be no excuse for the lack of gold-standard treatment of patients within clinical trials. Additionally, it is now my perception that there is not a strong enough rationale to justify treating smoldering multiple myeloma patients. The adverse effects of investigational drugs on asymptomatic patients are concerning. In response to your point of discussion, I believe that there may need to be adjustments to the structure of ethics review boards. From my understanding of ethics review boards, the members composing the board are not experts in the field for the study of interest (1). Hence, they may not be able to fairly evaluate the ethical implications of the study on patients. Potentially, experts in the field, (with a strong understanding of the disease and critical appraisal of scientific research, such as Dr. Goodman!), should be consulted before ethics approval is granted. Additionally, there might be a need for surveillance and quality improvement studies for ethics review boards, or a systematic approach to ensuring ethics review boards are conducting best-practice principles. Thank you for the interesting point, and hopefully ethical considerations will change for these trials with further critical appraisal.

1. Page SA, Nyeboer J. Improving the process of research ethics review. Research Integrity and Peer Review. 2017 Aug 18;2(1):14.

Name
Matti McFarlane

Name
Martha Ortega Santos

Tue, 11/15/2022 - 14:45

Hi Matti!
Great job summarizing Dr. Goodman’s MGR lecture in your blog post and facilitating our class discussion. I found both the lecture and our class conversation surrounding smoldering myeloma informative, as it highlighted the limited treatments and research currently available. One of my takeaways from this class was that there is a clear need for better diagnostic criteria and treatment for SMM and as you said genomic profiling might be a potential direction for identifying patients at risk for disease progression. Although I feel far removed from the world of myelomas I was intrigued to hear about this promising avenue. This seems to me to be a beneficial tool for improving diagnosis and treatment to better identify high-risk SMM patients and tumor vulnerabilities in order to target with precision medicine efforts. Do you have any thoughts on how this approach will potentially be implemented on a larger scale in the clinical setting? Or do you have any comments on the fact that most of this research is coming from what I can discern is one research group/collaborating effort?
Thank you!
Martha
Anand S., Bustoros M., Sklavenitis-Pistofidis R., et al. (2021). Genomic Profiling of Smoldering Multiple Myeloma Classifies Molecular Groups with Distinct Pathogenic Phenotypes and Clinical Outcomes. Blood 138(1): 723.
Bustoros M., Sklavenitis-Pistofidis R., Park J., et al. (2020). Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression. J Clin Oncol 38(21): 2380-2389.

Name
Martha Ortega Santos

Name
Matti McFarlane

Thu, 11/17/2022 - 11:52

In reply to by Martha Ortega … (not verified)

Hi Martha,

Thank you for your interesting point! Although I don’t know too much about the world of genomic profiling, I feel that wide-scale implementation of any new diagnostic technique requires sufficient resources to do so. Genomic profiling can be considered as a form of “precision medicine”, and due to this it can be quite costly (1). For example, Basharat et al. quoted costs ranging from ~$1 300 - $4 700 for some genomic profiling tests in Canada (1). I think it is a promising future direction for cancer diagnosis and a potentially important tool for informing individualized treatment, but I believe there needs to be further evidence for its widespread use. Additionally, there would need to be sufficient resources available to support the costs. However, I am excited to see how this technology advances in the coming years, and how experts plan to disseminate this important innovation. I did find in an article by Hultcrantz et al. that there are a couple of other research groups investigating the genomic profile of multiple myeloma (2). However, it certainly seems that there is a need for further groups to conduct research in this area in order to improve the validity and reproducibility of landmark studies.

References

1. Basharat S, Farah K. An Overview of Comprehensive Genomic Profiling Technologies to Inform Cancer Care. Canadian Journal of Health Technologies [Internet]. 2022 Aug 10 [cited 2022 Nov 15];2(8). Available from: https://canjhealthtechnol.ca/index.php/cjht/article/view/EH0106

2. Hultcrantz M, Yellapantula V, Rustad EH. Genomic profiling of multiple myeloma: New insights and modern technologies. Best Practice & Research Clinical Haematology. 2020 Mar 1;33(1):101153.

Name
Matti McFarlane

Name
Samantha Delios

Thu, 11/17/2022 - 07:54

Hello Matti!

Great job at summarizing Dr. Goodman’s talk. I think we all learned a great deal from what he shared with us about smoldering myeloma.
Dr. Goodman said in his talk it is difficult to define patients who are at high risk for developing a cancerous disease and seeing its progression. He also shared how many clinical trials surrounding smoldering myeloma are not 100% safe for patients (they can be toxic and expensive) and how we need to try and focus on the overall survival of these patients (as one of his publications shared many trials are based only on improvements of progression-free survival and not overall survival) [1].
One question I therefore had is what do you think would be a step in the right direction on making these trials safer? Also, how do you believe we can make the current trials that are being passed go through a harder screening process with IRB’s?
Thanks for your post!

Sam

Reference:

Mohyuddin, G. R., Ouchveridze, E., Goodman, A., & Prasad, V. (2021). The landscape of trials for smoldering multiple myeloma: endpoints, trial design, and lessons learnt. Leukemia & Lymphoma, 62(11), 2793-2795.

Name
Samantha Delios

Hi Samantha!

Thank you for your great reply! In response to your questions, I feel that Dr. Goodman highlighted some important points that should be addressed when clinical trials are developed for smoldering myeloma. Importantly, I feel that there must be thorough consideration of the treatment-risk paradox. In the case of smoldering myeloma, it is currently defined as an asymptomatic disease state where the patient is not experiencing any clinical symptoms (1). However, the recommended treatment for high-risk smoldering myeloma patients is lenalidomide. Lenalidomide has various toxicities and potential for serious adverse effects, such as a higher incidence of secondary primary malignancies (i.e., Hodgkin lymphoma), neutropenia and thrombocytopenia, and serious dermatologic reactions (2). I feel that in clinical trial design and IRBs, this treatment-risk paradox should be heavily considered. Additionally, Dr. Goodman pointed out many issues with the current risk stratification models. Potentially, these must be further studied before clinical trials can be considered to treat this pre-malignant state. In terms of the screening process for current trials by IRBs, I feel that there is definitely a place for more rigorous criteria for approval and increased consultation with experts in the field of the proposed study.

References

1. Visram A, Cook J, Warsame R. Smoldering multiple myeloma: evolving diagnostic criteria and treatment strategies. Hematology. 2021 Dec 10;2021(1):673–81.

2. PubChem. Lenalidomide [Internet]. [cited 2022 Nov 17]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/216326

Name
Matti McFarlane

Name
Tarrah

Thu, 11/17/2022 - 10:42

Hi Matti,

You have put together a great summary of both the lecture and the small facilitated group session! As I am sure a lot of other students felt, I am wildly unfamiliar with myeloma, but at the same time wildly fascinated by it. When I think of myeloma it seems like it would be incredibly daunting trying to treat this as a physician, and equally as daunting trying to investigate it as a scientist. I think the most daunting aspect is that there are still a lot of unknowns regarding this disease, and Dr. Goodman highlighted this in his lecture. Specifically, the mechanisms that cause myeloma are very unclear. I am curious as to what you think the best practice for approaching patient questions, regarding their disease, when we are dealing with significant unknowns? Additionally, do you think there are different ways in which clinical scientists can approach understanding this disease?

Looking forward to your response,
Tarrah

Name
Tarrah

Name
Matti McFarlane

Thu, 11/17/2022 - 13:21

In reply to by Tarrah Ethier (not verified)

Hi Tarrah,

I agree that smoldering multiple myeloma is certainly a dauting disease, for patients, physicians, and researchers. I feel that the best approach in conditions where there are various unknowns is to be candid and compassionate with patients. As Dr. Goodman said, the role of the clinician is to be the patient’s advocate. This would mean taking the time to explain their condition in a way they can comprehend and to tell the patient the current research landscape in lay terms. As well, it would be important for the clinician to be informed about the most up-to-date guidelines and best practice approaches for the condition. In the case of smoldering multiple myeloma, it would be in good practice to explain to the patient their plan for monitoring disease progression and beginning treatment if the patient starts to experience symptoms. Additionally, to your point about clinical scientists understanding this disease in a different way, I feel that with the increased availability of genomic profiling of diseases there may be a clearer understanding of smoldering multiple myeloma in the near future. Potentially this is a promising field to inform clinical guidelines and treatment plans in the clinical setting. Thank you for your interesting reply!

Name
Matti McFarlane

Name
Jill Greenlaw

Mon, 11/21/2022 - 20:14

Hi Matti,

I really enjoyed reading your blog post! Both your post, and his presentation brought up some thought-provoking points about the importance of critically assessing studies and research findings to ensure that the results are meaningful and beneficial to patients. He specifically highlighted how studies with poor experimental design, meaningless endpoints and inappropriately treated control groups has hindered the progression and development of valuable treatment advances for multiple myeloma. As you mentioned in your post, it is possible that this poor-quality research is doing more harm than good! Although his presentation focused specifically on multiple myeloma research, how do you think the lessons learned from his presentation can be applicable to other areas of clinical and basic science research?

Name
Jill Greenlaw

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