Coverage From the 2023 NCCN Annual Conference

NCCN Session Offers Considerations for Frontline, Second-Line Treatment Choices in CLL

The ALPINE trial (NCT03734016), which examined frontline use of the second-generation Bruton tyrosine kinase (BTK) inhibitor zanubrutinib (Brukinsa) in chronic lymphocytic leukemia and small lymphocytic leukemia (CLL/SLL), was the highlight of the 64th American Society of Hematology Annual Meeting and Exposition in New Orleans, Louisiana.¹ So, there was little surprise that an April 1 session at the 2023 National Comprehensive Cancer Network (NCCN) Annual Conference on updates in CLL/SLL featured these results, which led to the January 2023 approval of zanubrutinib in this setting.²

However, as Deborah M. Stephens, DO, director of the CLL and Lymphoma Program at the Huntsman Cancer Institute at the University of Utah, explained, that does not mean choices for treating newly diagnosed CLL are always straightforward. There are many considerations, including a patient’s age, whether the person has atrial fibrillation, other comorbidities, and whether a clinical trial is available.

Is a second-generation BTK inhibitor the best choice if it means indefinite use? Is the time-limited combination of venetoclax, a B-cell lymphoma 2 inhibitor, and obinutuzumab a better option for younger patients who may want to stop therapy at some point? Does the patient live close to the cancer center, making monitoring easy?

Always, Stephens said, physicians should ask, “Is there a great clinical trial available for these patients? If the answer is yes, I enrolled them—the reason being because we still haven’t cured chronic lymphocytic leukemia outside the setting of an allogeneic stem cell transplant,” and most patients are not candidates for that option.

If no trial is available, Stephens starts by checking immunoglobulin heavy chain variable (IGHV) status. “If there is a mutated copy of this gene, the next step would be looking at their FSH [follicle-stimulating hormone] results,” she said.

Then, for frontline therapy, it is a matter of identifying characteristics and comorbidities:

• For those with deletion 13q disorder only who are younger than 65 years, Stephens will consider the FCR combination (fludarabine, cyclophosphamide, rituximab).
• If deletion 17p or TP53 are present, second-generation BTK inhibitors acalabrutinib or zanubrutinib are preferred.
• If the patient has uncontrolled atrial fibrillation—which can be aggravated by BTK inhibitors—then the combination of venetoclax and obinutuzumab is appropriate.

For those with poor creatinine clearance—or without easy access to a lab facility—the second-generation BTK inhibitors are the best choice, “because [they] are not really impacted by poor kidney function,” Stephens said.

The BTK inhibitor drug class might also be considered “for folks who have extensive infections, as there is evidence of immune reconstitution after being on BTK inhibitors,” she said.

Data on combinations. Stephens reviewed data from the CLL13 study (NCT02950051), known as GAIA,³ performed by the German CLL Study Group, which examined 4 study arms: the first taking FCR or bendamustine and rituximab for 6 months; the second taking venetoclax and rituximab for 12 months; the third taking venetoclax and obinutuzumab for 12 months; and the fourth taking a triplet of venetoclax, obinutuzumab, and ibrutinib for 12 months, with the option to extend ibrutinib to 36 months. Patients with deletion 17p were excluded.

There have been some interesting takeaways, she said. It appears the patients taking obinutuzumab are more likely than those taking rituximab to achieve undetectable minimal residual disease. “It really just adds to the growing number of studies that show that obinutuzumab is a better antibody for patients who have CLL as compared [with] rituximab, so that was a little bit of a surprising result,” she said.

Also, the early returns do not show much benefit from adding ibrutinib to venetoclax and obinutuzumab, and no more patients are being added to that arm of the study. “However, this regimen is continued longer,” she said, “so this is something to watch.… A big question will be if the toxicity of adding ibrutinib outweighs any efficacy benefit.”

The GLOW study (NCT03462719) recently reported on treatment-naïve patients with CLL 65 years or older who were given obinutuzumab and chlorambucil vs fixed-duration ibrutinib and venetoclax.⁴ Although the second combination produced superior progression-free survival, Stephens suggested that a future combination would use second-generation BTK inhibitors. “I would hope that any future studies involving this combination would not be considered for patients with CLL because we have so many better drugs now.”

What comes next? Stephens noted the conundrum clinicians face if the most current therapies are used in a frontline setting: what happens when patients relapse?

It does appear that going first with time-limited therapy may limit the pressure on long-term use of BTK inhibitors, she said. Combinations that involved ibrutinib and showed toxicity may see different results with the second-generation BTK inhibitors. “There are multiple studies ongoing,” she said.

Insurance coverage may be a question mark, however.

“If any of you have prescribed these medications, you know that both [acalabrutinib and zanubrutinib] are very expensive medications. And so, I don’t know how the authorization process is going to work,” she said. “Hopefully, the [pharmaceutical] companies are far ahead of us and have already figured something out. But it’s unclear at this point which population might benefit the most from this combination therapy.”

Analyses of subgroups may follow, but as of now, “There’s still no evidence of a functional cure. And what do I mean by a functional cure?” If long-term data, including those for FCR, show patients diagnosed in their 70s live for up to 15 years and longer, “I think that is a functional cure.” These data do not yet exist, Stephens said.

When patients relapse, a clinical trial is again the best option. Clinicians should review the prior treatment history, especially to see whether BTK inhibitors or venetoclax were used in the frontline setting. Obinutuzumab should be considered in a second-line setting. “Admittedly, this regimen has not been studied in [a] phase 3 study in the second-line setting,” Stephens said.

The MURANO study (NCT02005471) paired venetoclax and rituximab in second line,⁵ and many payers will look to those data—but Stephens emphasized how many studies now show the superiority of obinutuzumab to rituximab.

Clinicians should return to many of the same questions they asked with first-line therapy: what are the comorbidities? Can patients travel for monitoring? If a deletion 17p or TP53 mutation is present, “I lean toward the second-generation BTK inhibitors,” she said.

“Or if it’s been more than 12 months of remission, maybe you can give venetoclax and obinutuzumab again,” based on emerging data, Stephens added. “It’s not a hard and fast rule.”

As more studies are released, recommendations may be refined. The ELEVATE RR study (NCT02477696) showed noninferiority for acalabrutinib,⁶ whereas data from ALPINE showed superiority of zanubrutinib over ibrutinib in a head-to-head trial across multiple lines of care.¹ And data from the BRUIN study (NCT04965493) presented during ASH shows that a third-generation BTK inhibitor, pirtobrutinib—already approved in mantle cell lymphoma—may offer efficacy in CLL with the least toxicity yet.⁷ 

References

1. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332. doi:10.1056/NEJMoa2211582
2. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. January 19, 2023. Accessed April 12, 2023. https://bit.ly/3WrqH0A
3. Eichhorst B, Niemann C, Kater A, et al. Time-limited venetoclax-obinutuzumab +/- ibrutinib is superior to chemoimmunotherapy in frontline chronic lymphocytic leukemia (CLL): PFS co-primary endpoint of the randomized phase 3 GAIA/CLL13 trial. Presented at: European Hematology Association 2022 Congress; June 9-12, 2022; Vienna, Austria. Abstract LB2365. http://bit.ly/4159Zay
4. Kater AP, Owen C, Moreno C, et al; for the GLOW investigators. Fixed-duration ibrutinib-venetoclax in patients with chronic lymphocytic leukemia and comorbidities. NEJM Evid. 2022;1(7). doi:10.1056/EVIDoa2200006
5. Kater AP, Wu JQ, Kipps T, et al. Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations from the MURANO phase III study. J Clin Oncol. 2020;38(34):4042-4054. doi:10.1200/JCO.20.00948
6. Wolska-Washer A, Robak T. Acalabrutinib: a Bruton tyrosine kinase inhibitor for the treatment of chronic lymphocytic leukemia. Expert Rev Hematol. 2022;15(3):183-194. doi:10.1080/17474086.2022.2054800
7. Woyach JA, Wierda WG, Coombs CC, et al. BRUIN CL-314: a phase III open-label, randomized study of pirtobrutinib (LOXO-305 versus ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic leukemia. Blood. 2022;140(suppl 1):12427-12428. doi:10.1182/blood-2022-157589.

Early Recognition Is Key to Managing Immunotherapy Toxicities

A dozen years after the FDA approval of ipilimumab (Yervoy), developments in the management of immune-related adverse events have unfolded alongside the drugs themselves. As much as immuno-oncology (IO) therapies have been a leap forward, the ability to address immune-related adverse events (irAEs) is critical to making these therapies available beyond academic centers. To do so, the National Comprehensive Cancer Network (NCCN) offers clinical guidelines for management of toxicities.

Presenting updates on these guidelines¹ during the 2023 NCCN Annual Conference in March were:

• Marianne J. Davies, DNP, MSN, RN, APRN, ACNP-BC, AOCNP, FAAN, of the Yale Cancer Center/Smilow Cancer Hospital and the Yale School of Nursing in New Haven, Connecticut;
• Jordan McPherson, PharmD, MS, BCOP, of the Huntsman Cancer Institute, University of Utah, in Salt Lake City; and
• John A. Thompson, MD, of the Fred Hutchinson Cancer Center in Seattle, Washington.

Davies began with an overview of the phases of the immune cycle, from tumor degradation to the shedding of antigens, which are picked up by dendritic cells and brought to the lymphatic system during the priming and activation phase. From here, regulatory T cells reach the tumor microenvironment and can attack the cancer cells, leading to the release of more antigens, unless the tumor adapts and sets up blockades to stop this process. CTLA-4, for example, can put the brakes on a T cell; thus, the development of ipilimumab blocks that binding and keeps the T cell activated, Davies said. PD-1 and PD-L1 inhibitors have emerged in similar fashion.

“As we know, we are actually expanding the number of inhibitors that we have available in our arsenal,” she said, highlighting a list of therapies to manage solid tumors and hematological malignancies. “I think across the course of any of our careers, we’re all going to be exposed to an immune checkpoint inhibitor therapy.”

Davies noted that checkpoint inhibitors are used in multiple combinations with other drugs and that their use has moved from the metastatic relapsed setting to the first-line setting. “Now, we see the approval in the adjuvant and neoadjuvant setting for at least several diseases,” she said.

“I’m sure you can all [see] these potential toxicities [and] you’re saying, ‘This is quite a large array of immune-related adverse events.’ In other words, [it means the] inflammation of any body system,” she continued. “We know the immune checkpoint inhibitors do not just target the tumor cell but can target healthy normal tissue as well, leading to a potential inflammatory kind of signal.”

The fallout? Toxicities can include fatigue, pruritus, rash, nausea, and vomiting. As Davies explained, this tends to happen in less than 20% of patients, and there’s a variety of responses, depending on the agent. “But in essence, every body system can be affected and thus must be assessed with each visit,” she said. The timing of these reactions can be unclear, she noted. Reactions can occur after several doses or even after therapy is complete, so monitoring must continue.

Pulmonary Toxicity

Davies focused on a case involving pulmonary toxicity in a 63-year-old man with non–small cell lung cancer. Previously, the patient had bullous emphysema, hepatitis C virus (HCV) managed with ledipasvir/sofosbuvir (Harvoni), Helicobacter pylori, and vocal cord paralysis from intubation for COVID-19 infection that led to his cancer being diagnosed. After concurrent treatment with carboplatin, paclitaxel, and radiation per NCCN guidelines, he was being treated with durvalumab (Imfinzi). Now on the third cycle of durvalumab, he had a worsening dry cough, dyspnea, right calf swelling when walking short distances, and heart palpitations. The patient was no longer able to work as a medical assistant.

Davies asked the audience to think about what was happening with this patient: Was cancer causing his pulmonary symptoms? Thompson took note of the vocal cord dysfunction, and McPherson noted that COVID-19 was likely complicating matters in a patient already at high risk for pneumonitis.

Davies agreed. “As you can see, COVID-19 certainly added to our challenges, particularly for our radiologists, [who were] trying to differentiate what exactly was causing a patient’s symptoms. And pneumonitis in the differential here is particularly challenging with patients who have pulmonary involvement [in] their malignancy,” she said.

First assessing a patient’s oxygenation status at rest is vital because a change in oxygen requirements is an early sign that pulmonary complications are emerging, she said. Ruling out other causes—such as infectious disease, pulmonary embolism, or disease progression—is next. Immune-mediated pneumonitis occurred in 3% to 7% of early trials, Davies said, and median onset was 60 to 90 days from the start of immune checkpoint inhibitor (ICI) therapy. Mortality rates were high, at 20% to 30%.

“Patients typically present with that dry cough, shortness of breath, chest pain, increased oxygen requirements,” she said. The patient in this case had an oxygen saturation of 94%, decreased from 97%. With ambulation, it dropped to 87% but improved with oxygen. Testing was negative for deep vein thrombosis, and a CT chest scan showed “new consolidation throughout the left lung with worsening ground glass opacities,” which were of concern for pneumonitis and may have been related to radiation therapy, Davies said.

Given the signs of pneumonitis, clinicians used NCCN guidelines to guide therapeutic decisions, Davies said. Physicians held immunotherapy and reassessed after 1 to 2 weeks while monitoring pulse oximetry; chest imaging can be used, but “in most cases, we would do that and repeat in 3 to 4 weeks for moderate toxicity…where there’s more of the lung involved,” and antibiotics can be considered, she said.

For patients with refractory disease, corticosteroids can be used. If there is no response, for severe toxicities checkpoint inhibitors are stopped for good and inpatient care is considered, Davies noted. “If the patient is not responding to the initial dose of steroids, then we escalate the methylprednisolone, and if refractory initiate a secondary immune suppressant such as infliximab,” Davies said.

Davies described the patient’s long monitoring period as well as considerations for use of infliximab. Once clinicians start methylprednisolone at 1 to 2 mg/kg per day, “if they do not have a response within 48 hours, we do want to consider starting that additional immunosuppressive agent. If you think a patient has high risk factors, you want to probably start to precertify them for infliximab,” because the process with an insurer can take 36 to 48 hours, she emphasized.

Evaluating in advance for possible risk factors and being ready to act is important, Davies said. This patient had been treated for HCV, and testing for tuberculosis up front is also recommended, because it can be reactivated. Knowing where your patient has traveled matters. “You shouldn’t delay the initiation of the immunosuppressive agent” while waiting on test results, Davies said.

Myocarditis

McPherson then presented a very recent case of myocarditis involving a 74-year-old man with stage IIIA resected melanoma. The patient had been treated with adjuvant pembrolizumab 2 weeks prior. His medical history included hypertension, osteoarthritis, stroke, and stage III melanoma resection 8 years prior, as well as a resection 1 year ago and a local excision 6 weeks prior.

A week earlier, the patient had presented at an urgent care center with cold symptoms. Two days prior, he had myalgia in the shoulder, back, and thighs and said his muscles felt “overworked” despite a sedentary lifestyle. An exam revealed leg swelling, back pain, dizziness; he tested positive for influenza A virus; and his cardiovascular rhythm was irregular, with bilateral lower extremity pitting edema. The patient was given acetaminophen. McPherson said the patient’s provider noted the recent start of immunotherapy but that “it would be rare to see toxicity this soon after initiating therapy.”

McPherson asked Thompson to weigh in on that statement. “Is this accurate?”

Thompson called the provider’s comment “interesting” and added, “It does illustrate that there are multiple possibilities…for what’s going on,” he said. “This is not unusual for a flu or other viral process. However, after we start the checkpoint inhibitor, I think that one of the take-home messages at today’s session is that we have to be very concerned that…these symptoms may represent the beginnings of a potentially serious immune-related adverse event directly related to the immunotherapy. And I think as this case unfolds, you’ll see that that’s what going on.”

McPherson agreed, and noted that in the case of ICI-induced myocarditis, the median onset is 30 days from the start of therapy, so this patient’s symptoms—weakness, muscle pain, dyspnea, fatigue—appeared early. “The incidence, obviously, is very rare,” he said. “But it is something that we should discount because of the rarity? Absolutely not.”

The mortality rate of this irAE is even higher than the pneumonitis case—25% to 50%. Patients with these symptoms should undergo extensive cardiologic evaluation, including electrocardiogram (ECG), echocardiogram, and a brain natriuretic peptide test.

“If a patient is suspected to have myocarditis, [because of] the mortality of this condition it is recommended that we pulse them with the novel prednisone dosing—that is, the highest that we recommend in the guidelines, with 1000 mg [intravenously] daily for 3 to 5 days, then transition them if they respond to lower doses,” he said. If there’s no improvement after 2 days, patients should get a secondary immunosuppressant, he said. McPherson pointed to an algorithm for treatment and noted that the ECG should be compared with one taken at baseline.

This patient showed initial improvement with steroids but then started worsening again. Davies noted that the patient didn’t quality for an available clinical trial and had an ejection fraction that was too low for infliximab, which might be an option.

“Unfortunately, this is not a good news story,” McPherson said. “At the end of this particular case, the myasthenia gravis work-up was not initiated until several days into the case. And even the antibodies were negative. But the patients started to decline, having eyelid dysfunction [and] starting to have respiratory dysfunction.”

McPherson said other secondary agents were used in an attempt to reverse the patient’s rapid decline, to no avail. This led to hypotension, respiratory failure, and death on day 15—after the patient first showed up with symptoms that looked like a cold.

“This is a cautionary tale for each one of us. We are not doing a great job with these cases; we need to identify them earlier. It’s going to be a challenge for us to do that. But I think the beginning, the first step is to be aware of the fact that it’s a risk,” McPherson said. “This will lead to early identification, earlier treatment, earlier intervention, and, hopefully, data on what works and what is effective in the secondary setting past steroids for this life-threatening condition.”

Oral Toxicities

Thompson said oral toxicities are increasingly recognized in the NCCN guidelines, and Thompson’s tale of a case that unfolded as the COVID-19 pandemic hit Seattle showed how oral toxicities can linger well after immunotherapy is withdrawn.

The case involved a woman with vaginal and mucosal melanoma who had been treated in 2008 with a radical lobectomy and then had a recurrence at the original site after 11 years. The lesion was again excised. Genetic testing was negative for actionable mutations, and PET/CT scans showed no evidence of distant metastasis. After a tumor board discussion, “we deemed her at high risk of recurrence,” Thompson said, and “she took the recommendation to do adjuvant immunotherapy with pembrolizumab.”

The patient’s first dose was 200 mg, anticipating 1 year of treatment, but that turned out to be the only dose she could tolerate. She had nausea, diarrhea, mild plasmacytic colitis, and diffuse esophagitis. She tested negative for herpes simplex virus and other infections and was started on prednisone 1 mg/kg per day with planned slow taper. She continued to experience severe lip and mucosal mucositis, as well as gum and tongue mucositis.

“We were fortunate in Seattle to have a strong oral medicine consult team, because of our transplant program largely, but we availed ourselves of this and the oral medicine consultant confirmed severe mucositis—and again confirmed that viral studies were negative,” Thompson said.

The patient received oral dexamethasone swipe, swishes, and clobetasol steroid to the lips. This did not help much, Thompson noted, and oral tacrolimus was not tolerated. “And so, at this point we felt like we were in a bind with the patient. She was still on prednisone; she did not tolerate topical steroid therapy,” he said.

The team opted to increase the prednisone from 0.5 to 1 mg/kg per day and started infliximab. The patient tolerated the first 2 doses and the increased steroid dose. She did not take the third infliximab dose because of rising concerns about immunosuppression and COVID-19 risk, and she was improving. Her lips had improved, as Thompson showed on a slide. He outlined an update of the NCCN guideline on how to handle a severe oral reaction to immunotherapy, including dexamethasone rinses and use of clobetasol gel.

“So, this raises the question of what is causing the mucositis: Is it the chemotherapy or is it the IO therapy? One of the points of today’s discussion is we can’t just automatically attribute oral mucositis to the cytotoxic therapy, we have to also consider that IO may be the causative factor,” he said. 

Reference

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines. Management of immunotherapy-related toxicities. Version 1.2023. Updated March 10, 2023. Accessed April 24, 2023. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf

Characteristics of Relapse Affect Treatment Choices in Multiple Myeloma

Natalie S. Callander, MD, director of the University of Wisconsin Carbone Cancer Center Myeloma Clinical Program, reviewed the treatment landscape at the National Comprehensive Cancer Network (NCCN) 2023 Annual Conference.

The number of patients with a diagnosis of multiple myeloma is rising worldwide, and not solely because of an aging population, noted Callander, as she opened her talk. With this increased incidence in multiple myeloma comes a rise in patients living with myeloma after initial treatment—approximately 150,000 in the United States alone, according to National Cancer Institute data.¹

A defining pattern of multiple myeloma is that patients relapse, and “we’re going to be seeing more and more relapsed patients,” Callander said. The number of ways to treat these patients also has expanded, and examining the characteristics of each relapse is key to deciding what to do, she added.

Defining relapse. As Callander noted, disease progression can be characterized by laboratory parameters—specifically, thresholds of myeloma protein (> 0.5 mg/dL), urinary monoclonal protein (> 200 mg/24 hours), or of involved light chain (> 10 mg/dL). Progression also can be defined by an event such as anemia, renal insufficiency, bone lesions or fractures, or new medullary deposits. She noted that a refractory relapse occurs when a patient progresses while on therapy or within 60 days of completing therapy.

Standard vs high risk. In some cases, patients at standard risk can be observed before starting treatment after relapse, but those at high risk need to be treated quickly, usually with a triplet combination. Previously collected stem cells may be used for an autologous transplant if this treatment was not used in the past (or if the patient’s last transplant was more than 24 months ago), Callander said. A “functional high-risk” patient would be one whose transplant lasted only about 1 year, which she noted “is considered a bad prognostic sign.”

Early vs late relapse. This is the key point of departure in deciding treatment options, as Callander explained. Often, patients will be receiving lenalidomide maintenance at the time of a first relapse; increasing the dose offers “no real benefit,” she pointed out, but adding dexamethasone may provide some. “Now, [pomalidomide with dexamethasone] is not a bad choice,” she said, “but you have to be prepared that only [one-]third of patients are going to respond to that maneuver and that it’s not necessarily going to last very long.”

Instead, Callander continued, data from recent trials show that “introduction of a monoclonal antibody in a triplet should be a strong consideration.”

She reviewed multiple FDA-approved triplet combinations for patients who had received 1 to 2 prior treatments, including the following:

Daratumumab, lenalidomide, and dexamethasone, as seen in the phase 3 POLLUX trial (NCT02076009), for relapsed or refractory (R/R) patients who have received lenalidomide but are not lenalidomide refractory. Patients who received the combination with daratumumab had progression-free survival (PFS) of 44.5 months compared with 17.5 months for those who received lenalidomide and dexamethasone only.²

Daratumumab, carfilzomib, and dexamethasone, as seen in the phase 3 CANDOR trial (NCT03158688), involving R/R patients who had received 1 to 3 prior treatments. Median PFS was 28.6 months for patients who received the triplet therapy vs 15.2 months for patients who received carfilzomib and dexamethasone only.³

Isatuximab, pomalidomide, and dexamethasone, as seen in the phase 3 ICARIA-MM trial (NCT02990338), for R/R patients previously treated with at least 2 lines of therapy including lenalidomide and a proteasome inhibitor (PI). Median overall survival (OS) was 24.6 months for the isatuximab group and 17.7 months for the group administered pomalidomide and dexamethasone only.⁴

Isatuximab, carfilzomib, and dexamethasone, as seen in the phase 3 IKEMA trial (NCT03275285), for R/R patients previously treated with 1 to 3 lines of therapy but not carfilzomib. After a median follow-up of 44 months, median PFS was 35.7 months for the isatuximab arm vs 19.2 months for patients receiving carfilzomib and dexamethasone only.⁵

Elotuzumab, pomalidomide, and dexamethasone, as seen in the phase 2 ELOQUENT-3 trial (NCT02654132) for R/R patients treated with 1 to 3 lines of therapy, including lenalidomide and a PI. Compared with patients in the pomalidomide/dexamethasone only group, those in the elotuzumab group had 46% improved PFS and 38% improved OS.⁶

Callander noted that in addition to the clinical trial data, physicians take into account factors such as how the drug is administered and the ability to give the drug once a week—or, in some cases, once a month. “Isatuximab combined with carfilzomib probably has the highest response rate in terms of PFS here—35.7 months, which is just great,” she said. However, this therapy is still given intravenously. “Most patients tolerate it pretty well in my experience. There is an on-body formulation that seems to be coming…that may make the choice between daratumumab and isatuximab not as clear-cut for many people.”

She also reviewed multiple combinations for early-relapsed patients previously exposed to monoclonal antibodies, which included the following:

• pomalidomide, carfilzomib, and dexamethasone
• pomalidomide, bortezomib, and dexamethasone
• bortezomib, panobinostat, and dexamethasone
• selinexor, bortezomib, and dexamethasone
• lenalidomide, carfilzomib, and dexamethasone
• lenalidomide, cyclophosphamide, and dexamethasone
• carfilzomib, cyclophosphamide, and dexamethasone

Callander said treatment with an antibody has other considerations: data show that using it at the first relapse does not preclude its use later on, “which is obviously something we want to know.” And data show carfilzomib seems to be a better choice for higher-risk patients, she added.

Considerations after third-line treatment. But what happens once patients start to run through treatments, including various antibody drugs? There are many questions to ask: Is the patient now “triple-class refractory,” to antibodies, PI, and immunomodulatory drugs? Does the patient need a quick response? What is their fitness level—are they still walking 3 to 4 miles a day? And how close is an academic center that might offer cellular therapy? Callander reviewed the following agents:

• Selinexor, an XPO1 inhibitor
• Belantamab mafodotin, which Callander discussed even although GlaxoSmithKline has begun the process of withdrawing the therapy from the market after phase 3 results confirmed data that supported accelerated approval
• Idecabtagene vicleucel (ide-cel), one of a pair of chimeric antigen receptor (CAR) T-cell therapies that target BCMA, the other being ciltacabtagene autoleucel
• Teclistamab, a bispecific T-cell engager, the first of its kind

Callander explained that CAR T-cell therapy in multiple myeloma is not the same as in large B-cell lymphoma. “One of the things to remember is, right now, it’s not curative,” she said. CAR T has a useful role, but patient selection is crucial here, because the manufacturing time is 4 to 6 weeks and reports of manufacturing challenges in the multiple myeloma space have been significant. Therefore patients who cannot wait are not candidates for this therapy.

Callander reviewed the data for the trials, which show that CAR T-cell therapies do give patients “this nice break,” but patients are told “we are anticipating at some point we are going to have to do something else. Now that is something that might give you a little bit of a pause if you consider that these therapies are coming in at about a half a million dollars each.”

“Now, how about cellular therapies for early relapse?” she asked, “This has been a theme in my entire career in myeloma—newer drugs get moved up.”

She reviewed data from KarMMa-3 (for ide-cel, which showed a survival advantage of 13.3 months vs 4 months for standard of care. Some clinicians looked at the data and were impressed whereas others were unmoved. “So I guess it’s in the eye of the beholder,” she said.

“Stay tuned.” Bispecific antibodies, both the approved product and those in development, offer the advantage of being “off the shelf,” meaning patients do not have to wait for a manufacturing process. Results for talquetamab were presented in December 2022 at the American Society of Hematology annual meeting.⁷

Callander is excited about some newer treatments under development. Among these are next-generation immunomodulatory drugs called cereblon E3 ligase modulators or CELMoDs, including iberdomide and mezigdomide, as well as modakafusp alfa (TAK-573), which is a first-in-class immunocytokine that delivers attenuated interferon in a laser-like manner to immune and tumor cells.⁸

And, she noted, there are improvements in the works to existing therapies. “There [are] so many CAR Ts out there under development. One of the things that’s being looked at…is a shorter production time,” she said. “Patients are just not healthy enough to last through that 6-week period, and you really can’t find what we call bridging therapy that makes sense—or that they respond to.”

Some treatments under study could have a turnaround time of a week or less, “which would actually change things quite a bit,” Callander said. “Just stay tuned is probably the answer.” 

References

1. Cancer stat facts: myeloma. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed April 24, 2023. https://seer.cancer.gov/statfacts/html/mulmy.html
2. Dimopoulous MA, Oriol A, Nahi H, et al; POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331. doi:10.1056/NEJMoa1607751
3. Dimopoulous M, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020;396(10245):186-197. doi:10.1016/S0140-6736(20)30734-0
4. Attal M, Richardson PG, Rajkumar SV, et al; ICARIA-MM study group. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019;394(10214):2096-2107. doi:10.1016/S0140-6736(19)32556-5
5. Moreau P, Dimopoulous MAC, Mikhael J, et al. Updated progression-free survival (PFS) and depth of response in IKEMA, a randomized phase III trial of isatuximab, carfilzomib and dexamethasone (Isa-Kd) vs Kd in relapsed multiple myeloma (MM). Ann Oncol. 2022;33(6):P664-665.:doi:10.1016/j.annonc.2022.04.0130
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As More Patients Survive Cancer, Issues With Sleep, Fatigue, and Cognitive Function Are on the Rise

As a nurse practitioner at Fred & Pamela Buffett Cancer Center in Omaha, Nebraska, Jennifer Schmitz, MSN, APRN, FNP-BC, knew fatigue came with cancer. But she did not fully grasp it until she received a diagnosis of acute lymphoblastic leukemia (ALL) in 2017. Over the next several years, all the symptoms patients had described—the insomnia, the cognitive issues, restless legs syndrome—slowly became real.

“Restless leg is a real thing,” Schmitz said, “I used to think that was kind of a funny thing when patients would tell me they had restless leg. I never really understood it until I had it myself.”

Schmitz opened the April 2 plenary session at the National Comprehensive Cancer Network (NCCN) 2023 Annual Conference, entitled Sleep Disorders, Fatigue, and Cognitive Function in Cancer Survivors. Moderated by Andrew T. Day, MD, MPH, of UT Southwestern Harold C. Simmons Comprehensive Cancer Center and vice chair of the NCCN Survivorship Panel, the session covered NCCN guidelines for handling symptoms that have become increasingly common as the survivorship ranks grow.

According to 2023 data from the American Cancer Society, there were 18.1 million cancer survivors in the United States in January 2022, which is 5.4% of the population. Cancer survivors will number 22.5 million by 2032.¹ And yet, panelists acknowledged, most oncologists were trained in the days when the focus was simply on keeping people alive rather than helping them to live well, much less work or care for a family.

Schmitz was a busy working mother with children aged 2 and 5 years when the bone pain, mouth sores, and other symptoms led her to look for answers that led to her ALL diagnosis. That led to a very long protocol mostly of intravenous chemotherapy. But as the audience knew, “It’s not just the cancer treatment—the medications, the chemo[therapy] itself—that really affects you; it’s everything else.”

Blood transfusions. Trips to the intensive care unit. Drug reactions. Blood clots around her port. Early menopause. The antifungal medication voriconazole “is not my friend,” she said, and it caused hallucinations.

Just being in a hospital itself makes it hard to sleep. And “you’re on a whole lot of steroids,” Schmitz said. “I would get up and clean my hospital room all night long, because I couldn’t sleep.”

She was an inpatient for 6 months, a very long time, “especially when you have 2 little kids and you can’t see them every day. Your brain really starts to play tricks on you.”

Schmitz was finally able to leave and continue chemotherapy on the POMP protocol (6-mercaptopurine + vincristine + methotrexate + prednisone), and after 3 months she returned to work. “It was a blessing,” she said. “But it was also really hard.”

Walking 6 or 7 miles a day around a hospital is not easy with neuropathy in your feet. It led to falls. It meant Schmitz had to rest, sometimes right on the floor. People knew her story and were kind. But even as her treatments eased, her fatigue continued. And then, at the moment of excitement when her treatment ended, COVID-19 had already begun to spread. “I couldn’t even hug my oncologist, which was really awful…. And it was quite the experience. But my bone marrow did confirm I was in remission.”

Schmitz still struggles with short-term memory loss. She has gone back to running. She lifts weights to rebuild her strength. She brings a new perspective to her work with people with cancer. “I get to work with other cancer survivors now and help them through their journey,” she said. “I’ve really learned to just slow down and truly not sweat the small stuff.”

“Life is a blessing. It just looks a little bit different now.”

“No Bloody Clue”

Eric S. Zhou, PhD, an assistant professor of pediatrics in the Division of Sleep Medicine at Dana-Farber Cancer Institute, Harvard Medical School, said there are 83 different types of sleep disorders across 7 different categories in the International Classification of Sleep Disorders, including breathing disorders, circadian rhythm disorders, parasomnias, and sleep-related movement disorders. And yet, in a recent review looking at sleep disorders among cancer survivors, the authors concluded that “the prevalence of overall particular types of sleep disorders and cancer cannot be ascertained.”

“[This] means we really have no bloody clue how many of our patients are survivors [who] really have diagnosable sleep disorders,” Zhou said.

A major challenge here is that many sleep studies rely on self-reported data, but some disorders require a sleep study or a polysomnography to be performed. “But these are really labor-intensive or costly things,” Zhou noted, and have not been prioritized.

This means that science has few answers about sleep and cancer, even though it is one of the largest issues that patients will face during treatment as well as later, as survivors.

Better sleep leads to better survival, and NCCN guidelines recommend cognitive behavioral therapy for insomnia (CBTI) as the preferred treatment for poor sleep. This 5-component treatment is also endorsed by the American College of Physicians and the American Academy of Sleep Medicine. The key elements are stimulus control and sleep restriction.

“Sleep restriction simply gets to the heart of insomnia, which is [that] patients are in bed trying to get more sleep rather than good-quality sleep. That’s the right amount of sleep,” Zhou said. “Sleep stimulus control gets to the idea that patients who have insomnia try really hard to sleep. And what that results in [is] their inability to fall asleep.”

Cancer centers are not doing a good job. Findings from a survey by the National Cancer Institute revealed that the 25 best programs were only getting good insomnia treatment to 50% of survivors. How can this be improved? Zhou recommended 3 things:

• Screen for sleep disorders, within the existing workflow.
• Embed care within the treatment site, because when the referral is to another location, patients are less likely to go.
• Train providers to address sleep issues, starting in medical school.

Fatigue: The Most Distressing Symptom

Kristin Dickinson, PhD, RN, OCN, an assistant professor of nursing at the Fred & Pamela Buffett Cancer Center, said that although there is no single agreed upon definition for cancer-related fatigue, it is the most common symptom reported by patients. “And it’s often reported to be the most distressing symptom, even more so than other symptoms such as pain [and] nausea, where they’re often able to have medications to control those symptoms,” she said.

As Schmitz had noted, Dickinson said fatigue doesn’t stop when treatment ends. “We can have up to 50% of patients still reporting fatigue in long-term survivorship, 5 or more years from diagnosis,” she said. “We’re seeing on average 30% of patients reporting that fatigue is a distressing symptom in their life. In terms of quality of life, fatigue is often underreported, underdiagnosed, and undertreated.”

Also shocking is that only 20% of patients believe anything can be done for fatigue, so this may mean many are not even reporting it. Patients do not want to be seen as complaining, Dickinson said.

And yet, fatigue can affect the ability to manage symptoms. NCCN guidelines call for screening at the initial visit—because fatigue can start even before treatment—and at every recurring visit. “NCCN recommends using a valid and reliable tool to screen and they have an appendix that lists and recommends different tools that are available,”’ she noted.

Dickinson pointed to the NCCN algorithms that recommend using validated tools that determine whether fatigue is mild, moderate, or severe, and what are the treatable or contributing factors. If medical management steps are taken and the patient still reports fatigue, “then we move into the general management strategies. And these strategies are stratified by those undergoing active treatment, those in post treatment, and those at the end of life.”

She highlighted the evidence categories for the NCCN guidelines. “This speaks to the strength and rigor at which these guidelines are developed,” she said. Nonpharmacologic management strategies, particularly exercise, are emphasized before patients rely on pharmacological solutions. Dickinson highlighted resources from the American College of Sports Medicine and Livestrong, which are specific to cancer survivors.

Guidelines are in line with general recommendations for physical activity: 150 minutes a week, spread over 2 to 3 days per week of strength training. However, similar benefits have been seen with 30 minutes 3 times a week of aerobic activity only to address cancer-related fatigue.

Cognitive effects of cancer and its treatments can be varied, said Halle C.F. Moore, MD, of Cleveland Clinic Taussig Cancer Institute. People may feel they cannot complete tasks; they cannot find words; they need to leave themselves notes. “Sometimes these concerns can be severe enough to affect performance at work. And these symptoms can make an individual feel very isolated,” she explained.

As with fatigue, there are no standard diagnostic criteria for cognitive impairment related to cancer, and this makes studying cognitive impairment a challenge.

Moore often hears the term “chemo brain,” relating to the “fog” that individuals experience during or after chemotherapy. “However,” she said, “we know that cancer-related cognitive changes can go well beyond that. There’s a more general term––cancer treatment–associated cognitive changes––taking into account that other cancer treatments, endocrine treatments, target therapy, [and] radiation surgery can all contribute to cognitive changes.”

Even before chemotherapy starts, surgery and anesthesia can cause cognitive issues for up to one-third of patients with cancer, Moore said, although those may be short-lived. “While inflammatory processes that are occurring might be contributing, or the anxiety that surrounds a cancer diagnosis, the sleep issues associated with that anxiety could affect one’s cognitive function, or perhaps there [are] common risk factors for whatever caused the cancer. And that might also cause cognitive impairment.”

Among patients, 50% to 70% will have cognitive issues during treatment, and one-third will experience lingering symptoms, Moore continued. “If you look at long-term cross-sectional data, if cancer survivors in the general population have about a 14% reporting of memory problems—which compares with about 8% in the general population without a cancer history—and if you look at those individuals who had chemotherapy, that rate is even higher.”

So what are the risk factors? Age, hormonal factors such as menopause, and certain central nervous system (CNS) therapy delivery systems are among the risk factors. And it is known that quality of life is affected, whether or not that is reported.

“In terms of assessment, some patients may need to undergo formal neuropsychological evaluation and particularly if there’s a disability that’s suspected, and they may need disability benefits,” Moore said. “Again, these tests don’t always correlate with the patient experience, so they need to be used selectively,” For example, CNS imaging might not be needed to diagnose cancer related to cognitive impairment.

Moore discussed the concept of cognitive reserve, which addresses individuals who were high-functioning before they received their cancer diagnosis. “They can increase activity and other parts of the brain. And they can maintain that high performance, even though that person’s perception is that this is very hard.”

But for an older patient, or someone already taking many medications, pain or chemotherapy can rob them of what limited function they had. This is different from dementia, which tends to be progressive.

“The vast majority of individuals with cancer-related cognitive impairment will actually experience improvement in symptoms over time, rather than worsening. And these changes are often subtle,” Moore said.

What can a patient do? As with addressing fatigue and sleep, trying to maintain one’s prior level of function may not be attainable. But doing what is possible is a good idea. “Jennifer’s instinct to keep running I think is right on. Go keep doing it,” Moore said.

Finding resources for patients can be challenging. “These may be at your institutions; you may not even know about them. Often these are found in [the] occupational therapy [department]. At my institution. It’s our speech therapy department that does the cognitive rehabilitation.”

For some patients, the psychotherapy department can offer CBTI, which helps with sleep. A memory clinic may be a resource if symptoms persist. NCCN guidelines suggest that a trial of methylphenidate modafinil be considered, but Moore said the data for the pill “are less than convincing.”

Schmitz said the disconnected nature of survivorship resources was consistent with her experience.

“I think there’s a lot more room for growth in the survivorship world. I really didn’t have a lot of people helping with that [and] a lot of the resources I had to find on my own,” she said. “And I’m really hoping that, as practitioners and providers in the oncology world, we’re going to continue to get better at that, because there’s a lot more people like me out there.” 

Reference

Cancer Treatment & Survivorship Facts & Figures 2022-2024. American Cancer Society; 2022. https://www.cancer.org/research/cancer-facts-statistics/survivor-facts-figures.html