Recap: Recent Advances in Multiple Myeloma: Applying Real-world Evidence to Clinical Practice

Following on the heels of the 2022 American Society of Clinical Oncology Annual Meeting, several experts in multiple myeloma sat down to discuss real-world evidence as it applies to the treatment of patients with multiple myeloma in today’s treatment landscape. Rafael Fonseca, MD, professor of medicine and director for Innovation and Transformational Relationships at Mayo Clinic in Phoenix, Arizona, led the discussion, joined by Luciano Costa, MD, PhD, professor of medicine–hematology and oncology in the Department of Medicine at University of Alabama at Birmingham O’Neal Comprehensive Cancer Center; Ajay K. Nooka, MD, MPH, director of the Myeloma Program and an associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, and medical director of the Winship Data and Technology Applications Shared Resource at Winship Cancer Institute of Emory University in Atlanta, Georgia; and Matthew James Pianko, MD, a clinical assistant professor at the University of Michigan Health in Ann Arbor.

“Randomized controlled trials [RCTs] are done specifically for a reason: regulatory approvals and to clearly identify the safety [profile] of the specific drug in evaluation. This is done in a cohort of patients that is preselected. These patients must qualify for all the inclusion criteria. Unfortunately, that patient population does not reflect those we treat daily,” Nooka said. “There are guiding principles from the RCTs in terms of the regulatory aspects, but when we treat real patients, there’s complexity and diversity.”

Nooka offered the experience of 1000 real-world patients treated at Emory University from January 2007 through August 2016 who were consecutively treated with induction lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) therapy followed by risk-adapted maintenance. At the time the data were published, the median overall survival (OS) was 78.2 months (95% CI, 62.2-94.2) for high-risk patients and had not been reached for standard-risk patients. Rates of OS at 5 years were 57% and 81%, respectively, and 10-year rates were 29% and 58%.¹

“If you look at the SEER [Surveillance, Epidemiology, and End Results] data set, the 5-year survival [rate in multiple myeloma is] 58%.² Clearly, there’s a discrepancy [in outcomes],” said Nooka. “Offering the right treatments to patients and understanding where to intensify and where to pull back is important. These could all be evaluated now that we do have long follow-up of greater than 10 years.”

Real-world Use of Systemic Therapy for Transplant-Eligible Disease

In patients with frontline transplant-eligible multiple myeloma, the panel agreed that few circumstances justify opting for a 3- vs a 4-drug regimen, with many clinicians being early and enthusiastic adopters of monoclonal antibodies plus traditional therapy backbones.

Limitations of adding that fourth drug, such as daratumumab (Darzalex) or isatuximab (Sarclisa), may relate to reimbursement issues or the potential risk of infections, but panelists agreed that the risk-benefit ratio favors quadruplets.

Digging Into Optimal Therapy Cycles

One main consideration when using any frontline regimen in this setting is the number of cycles of induction therapy necessary to induce a favorable response prior to proceeding to transplant. Nooka said the key is to balance the duration of therapy with an adequate response, as adverse effects (AEs) are liable to increase in step with the likelihood of an adequate response.

“The response flattens after a few cycles, so there should be a desired target response to go to consolidation with the transplant,” he said. “I limit these to between 4 [and] 6 cycles and if the desired response is greater than a partial response, I’m ready to move forward.”

Fonseca echoed this sentiment, stating that the use of 4 cycles is informed by real-world experience and is relatively standard unless patients experience suboptimal response. Similarly, Costa agreed that 4 cycles of induction are typical before pushing to transplant but added that the use of minimal residual disease (MRD) data following successful induction may stand to influence how clinicians approach this going forward.

Harnessing Minimal Residual Disease to Inform Treatment

Considering the use of MRD in a response-adaptive treatment approach is being tested in numerous ongoing RCTs, with positive results potentially standing to inform future drug indications. However, for some on the panel, use of MRD as a predictive tool to guide treatment selection is still far from reality.

For one thing, Pianko said MRD can serve to inform a conversation about treatment decisions with patients, but in an era with clear treatment pathways, its use as a definitive tool to guide therapy is still “murky.” Nooka said looking at MRD results is great for prognosis, but a single outcome at any given time should not be weighted too heavily into decision-making because MRD dynamics are liable to change at varying time points throughout treatment.

Costa detailed trials that are using MRD by next-generation sequencing to shape response-adapted approaches, such as the phase 2 MASTER trial (NCT03224507) examining daratumumab, carfilzomib (Kyprolis), lenalidomide, and dexamethasone (Dara-KRd) for the management of frontline multiple myeloma. In 80% of study participants treated with the regimen, MRD negativity defined as 10–5 was achieved, and nearly all patients were able to stop therapy after autologous transplant without disease progression or MRD resurgence.³

Another ongoing phase 3 trial called MIDAS (NCT04934475) will determine whether MRD data can inform the use of isatuximab plus KRd with or without transplant in patients with multiple myeloma who are younger than 66 years.

Key Considerations in Transplant-Ineligible Disease

To kick off the discussion of treating transplant-ineligible multiple myeloma, Fonseca reviewed trials that led to approved therapies in the space (FIGURE), namely SWOG S0777 (NCT00644228), ALCYONE (NCT02195479), MAIA (NCT02252172), and TOURMALINE-MM2 (NCT01850524).^4-7

Pivotal Data in Newly Diagnosed Transplant-Ineligible Multiple Myeloma

He then pivoted to real-world data on attrition rates between lines of therapy for patients who are not eligible for transplant showing that of 22,062 patients, fewer than half (43%) went on to receive subsequent therapy after their first treatment. Those receiving only 1 line of therapy were significantly older, with higher mean Charlson Comorbidity Index (CCI) scores and incidences of comorbidities.⁸

Compounding this effect, the ability of patients to achieve a deep response drops off from first to later lines of therapy, with evidence from a study in 2016 showing that complete responses and very good partial responses occur in up to three-fourths of patients (74%), but tail off in the second (58%), third (43%), fourth (32%), and fifth line and beyond (11%).⁹

Top Considerations for Choosing First-line Therapy

These data combined with therapy effects of each approved regimen beg the question of whether the most effective regimen should be used up front or saved for later lines of therapy.

To answer this question, Fonseca reviewed data presented by his team at the 2021 American Society of Hematology Annual Meeting and Exposition showing that first-line use of daratumumab, lenalidomide, and dexamethasone (DRd) led to better OS vs waiting for second-line treatment. This correlation was seen using attrition rate scenarios of 58.8% and 27.2%. The most optimal sequence examined was DRd, then a regimen containing pomalidomide (Pomalyst) or carfilzomib in the second line, followed by frontline RVd and a second-line daratumumab-containing regimen, and then frontline Rd and a second-line daratumumab regimen.¹⁰

“The first treatment is so important because a significant number of these patients may not be receiving the second treatment. What your modeling had shown was if you’re able to give them the best treatment, [you may induce up to 9 years of survival or more], similar to what you can get with transplant-eligible patients,” said Nooka. “The best treatment is so important because the same treatment given at 2 different times in myeloma may yield 2 different responses or 2 different outcomes. Why not use it at the right time in the first place?”

With these data taken together, Pianko said his number 1 priority in the absence of transplant is finding out what his patients prefer, as quality of life in this setting is the most significant factor to many. “Patients want to have good quality of life for as long as possible. That’s our goal of therapy in transplant-ineligible multiple myeloma. There’s a balance between toxicities of therapy and goals you’re trying to achieve in this population, particularly when patients are frail, elderly, and unfit. You can run into the issue where you’re interfering with your own goal of therapy if there are adverse effects of the treatments,” he said.

For those patients whose frailty needs to be considered, Nooka said he is still giving a 3-drug regimen but with significantly dose-reduced schedules of each agent. For example, he will still administer DRd to a patient in their 90s but takes the dose of lenalidomide down to 5 mg because the progression-free survival (PFS) results from the MAIA trial are so compelling. Additionally, he tapers off the dexamethasone after the first year and continues maintenance with daratumumab, lenalidomide, or both.

Pianko’s strategy for choosing maintenance at this point comes back to considering what is best for the patient’s quality of life. “If everything is going well, the relative benefit is to simplify treatment and go to an all-oral maintenance program where possible. For some patients, there may be value to continue 2-drug maintenance. But I’m also weaning off all steroids for my transplant-eligible patients at somewhere between 8 and 12 cycles to avoid all the consequences of that.”

On the other side of that coin, Fonseca said some of his patients prefer coming in for monthly infusions rather than relying on a daily pill for their maintenance strategy. Regardless, he said, most patients make it to 2 years of maintenance and then tail off rather than receiving continuous therapy.

Comparing Doublet and Triplet Therapy

Nooka said when he is delivering treatment in the transplant-ineligible setting, he almost always opts for use of 3 drugs over 2 unless there are true contraindications for one of the agents in the regimen.

To back that up, Fonseca revisited previously reported data from the MAIA trial showing that DRd was superior to Rd alone in terms of PFS for both nonfrail (HR, 0.48; 95% CI, 0.34-0.68; P < .0001) and frail individuals (HR, 0.62; 95% CI, 0.45-0.85; P = .0003).

To back this up, Pianko went as far as to question the reason for patients’ frailty and whether withholding more efficacious treatment for the sake of avoiding AEs offers an advantage or a disadvantage to patients. “You can really salvage those patients who are frail from myeloma. Of course, there are situations where it’s impossible, but these data lend toward pushing for a third drug.”

Considering Patient-Specific Factors in a Real-world Setting

Frailty

To determine frailty in a patient who is ineligible for transplant but may be able to receive systemic therapy for their disease, Pianko considered current approaches to establishing a patient’s status.

International Myeloma Working Group (IMWG) frailty score, age, CCI score, and ECOG performance status can all factor in, but the challenge in the clinic is finding time to use these tools. Pianko went on to say he used more of a “functional approach,” such as observing how the patient gets around the office or performs a 6-minute walk test. Although it’s a subjective measure, it may offer a more practical approach to treatment “given the pressures on time” that are limiting factors in some environments.

“In the transplant-ineligible setting, refining our frailty assessments are key, and there are clear arguments for optimizing your myeloma therapy and trying to get your patients on the best therapy possible,” said Pianko.

Nooka confirmed this, expressing frustration in quantifying frailty that is aggravated by the 7 or so scales that are commonly used. Additionally, he pointed out limitations of frequently used measures, such as the automatic classification of patients over 75 years of age as frail by the IMWG frailty score, which may not properly characterize patients in the real-world setting.

“We can’t just group them into buckets and start making dose reductions when they don’t need them or giving them doublets when they would benefit from triplets,” said Nooka.

Infectious Outcomes

According to Pianko—who attested to his primary interests in infections, immunity, and the potential impacts of the microbiome on outcomes in myeloma—results of RCTs underestimate the potential risks of some standard treatments in more frail, older populations or in those who would not otherwise qualify for clinical trials.

“There is a real need to understand both the burden of infectious outcomes as well as the consequences to patients who suffer from these infections. This is, unfortunately, a common and severe problem to date in our field,” Pianko said. “There have been some interesting data out of the UK looking at antibiotic prophylaxis, but there are some challenges there [because they] don’t necessarily reflect what we use in real practice in the United States.”

Some of the most pressing concerns with using antibiotic prophylaxis in this patient population stem from their possible impact on treatment outcomes and survival. In some data sets, broadly applying antibiotic prophylaxis reduced the rates of fever and death, yet more patients died of progressive myeloma than did those of a standard-of-care group. Additionally, Pianko said some evidence from his own research has pointed to potentially more abundant microbiota in patients who are MRD negative, which could have implications for who ends up receiving prophylaxis.

“A randomized clinical trial to understand that seems like a tall order,” Pianko said. “There’s a need for real-world data to understand how infections interact with treatments that we use.”

Cytogenetics and Risk Status

No conversation regarding real-world outcomes would be complete without also looking at risk stratification, with the panelists first visiting the use of cytogenetic risk factors such as deletion (del)17p; translocations t(4;14), t(14;16), t(14;20); and 1q gain (1q+). However, not all classification systems consider these factors equally. In his experience, Fonseca noted, patients presenting with those cytogenetic risk factors rarely have good outcomes in the clinic.

Pianko had concerns with classification of disease risk using only cytogenetics, as he has seen patients with favorable baseline characteristics who still behave as though they harbor these genetic biomarkers. “You meet your patient and treat them with what you think is the best therapy based on their presentation. Over time, a standard-risk patient behaves in a functionally high-risk way. They have an early relapse, and you are surprised,” he said, adding that MYC amplification always makes him “raise an eyebrow” about disease prognosis.

Another challenge that may limit the use of cytogenetics in risk assessment is the lack of standardization in the reporting of pathology results, which is particularly poignant in the evaluation of 1q+. The number of copies of 1q is important in determining risk, but most patients have their bone marrow evaluated several months prior to seeing their medical oncologist and the appropriate information is lacking.

Future Directions

To conclude, the panelists considered what is needed in the immediate future to clarify some of their outstanding questions. “If you look at the RVd data set from the Emory group [discussed by Nooka earlier], we can’t [always] wait 10 years to get those data to be offering the best therapy to our patients. Because there has been adoption of 4-drug regimens both in academia and the community, there’s an opportunity to look at real-world data and the impact of those therapies outside sometimes too-rigid confines of randomized clinical trials to observe the potential benefits,” Pianko concluded.

References

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2. Cancer stat facts: myeloma. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed July 19, 2022. https://bit.ly/2JYrWUc
3. Costa LJ, Chhabra S, Callander NS, et al. Daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd), autologous transplantation and MRD response-adapted consolidation and treatment cessation. Final primary endpoint analysis of the Master trial. Blood. 2021;138(suppl 1):481. doi:10.1182/blood-2021-145494
4. Durie BGM, Hoering A, Sexton R, et al. Longer term follow-up of the randomized phase III trial SWOG S0777: bortezomib, lenalidomide and dexamethasone vs lenalidomide and dexamethasone in patients (Pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT). Blood Cancer J. 2020;10(5):53. doi:10.1038/s41408-020-0311-8
5. Mateos MV, Dimopoulos MA, Cavo M, et al; ALCYONE Trial Investigators. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378(6):518-528. doi:10.1056/NEJMoa1714678
6. Facon T, Kumar SK, Plesner T, et al. Overall survival results with daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in transplant-ineligible newly diagnosed multiple myeloma: phase 3 MAIA study. HemaSphere. 2021;5(suppl 2):LBA1901. doi:10.1097/HS9.0000000000000566
7. Facon T, Venner CP, Bahlis NJ, et al. Oral ixazomib, lenalidomide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma. Blood. 2021;137(26):3616-3628. doi:10.1182/blood.2020008787
8. Fonseca R, Usmani SZ, Mehra M, et al. Frontline treatment patterns and attrition rates by subsequent lines of therapy in patients with newly diagnosed multiple myeloma. BMC Cancer. 2020;20(1):1087. doi:10.1186/s12885-020-07503-y
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10. Fonseca R, Facon T, Hashim M, et al. First-line use of daratumumab, lenalidomide, and dexamethasone confers survival benefit compared with second-line use of daratumumab-based regimens in transplant-ineligible patients with multiple myeloma: analysis of different clinical scenarios. Blood. 2021;138(suppl 1):118. doi:10.1182/blood-2021-144914