Whole-genome sequencing in patients with precursor multiple myeloma conditions such as smoldering myeloma or monoclonal gammopathy of uncertain significance (MGUS) may help predict which patients will go on to develop the disease, according to study authors Ola Landgren, MD, PhD, and Francesco Maura, MD.

“In the past 2 or 3 years, we have shown that whole-genome sequencing has the potential to [identify] most myeloma-defining genomic events,” Maura, an assistant professor and principal investigator of the myeloma genomic lab at Sylvester Comprehensive Cancer Center, told 

. “If you [can] define events, you can see which patients with precursor disease have these events, and which do not. You can see that the presence of these events is associated with different clinical outcomes.”

, Landgren, Maura, and colleagues, explored the utility of whole-genome sequencing in patients with MGUS and smoldering myeloma to see whether they could identify genomic signatures that could predict progression to multiple myeloma. Results indicated that clinically stable cases of these 2 precursor conditions are characterized by different genomic landscapes and by variations in the temporal acquisition of myeloma-defining genomic events vs progressive entities.

One genomic signature of interest in the study was APOBEC, which has previously been observed in patients with relapsed multiple myeloma, according to Maura. Investigators noted that the patients who eventually progressed on the study already had this signature when they had MGUS, while those who did not progress did not have this signature.

“All of a sudden, we were able to lift off the lid on the Pandora's box of MGUS and see [those who will progress to] myeloma vs [those who will] not,” Landgren, the inaugural leader of the Experimental Therapeutics Program at Sylvester Comprehensive Cancer Center, told 

. “Many questions still need to be addressed. For example, [we know that] if a patient has [a specific] signature, that is a bad thing. However, if they do not have it, could they still develop it later? What is the rate of conversion? We do not know.” A large follow-up study is planned to examine this further, Landgren added.

, Landgren and Maura highlighted the evolution of genomic testing in multiple myeloma, further discussed their research with whole-genome sequencing in patients with precursor conditions, and spotlighted next steps for research.

What inspired this research to further examine myeloma precursor conditions?

: For a very long time, it has been recognized that some individuals who have proteins in the blood that are monoclonal do not have multiple myeloma. Others have multiple myeloma, [which] is the second most common blood cancer in adults. [This disease presents] in 35,000 people every year in the United States, and over 130,000 people are living with this disease without a cure. Years back, in the 1960s, there was a debate [regarding these] proteins; 1 group thought that there was no association between these proteins and the cancer, while others felt that maybe there was. In the 1970s, the consensus was that [the question remained open and up for debate].

That takes you into [the realm of] MGUS, which basically means we do not know. In reality, people show up with these proteins for various reasons. Doctors can order blood tests, and all of a sudden, you see these proteins. The patient wonders, ‘What is going to happen with me? Will I develop myeloma or not?’ People are living with this uncertainty. In the 1980s, [investigators were starting to realize that] some people have more protein than others; as such, they didn't fit with this terminology [of MGUS, so investigators] came up with the idea that they could call that smoldering myeloma. However, MGUS and smoldering myeloma are sort of the same thing; smoldering myeloma just has a little bit more of these proteins. For 40 years, blood tests [have been performed] every 3, 6, or 12 months and some people still develop myeloma, [while others] have [these proteins] and never progress. For many years, we have studied blood-based markers and other types of markers to determine whether we could identify those who are going to develop myeloma early on.

In 2009, I was the lead investigator on a study that definitively showed that any person who developed myeloma had these proteins in their blood years [in advance]. We had a collection of almost 100,000 blood samples that were drawn every year for many people. We identified all people who had myeloma, and then we went backward year by year and found [those proteins] in every person. That definitively showed that you need to have the protein to develop the cancer. However, the question that still puzzled us for more than 10 years was: Is there a better way to identify those who will [go on to] develop [the disease] vs those who will [not]?

To answer that question, we needed to first ask ourselves whether they were linked; the answer was, yes. There are [challenges to] doing these types of studies, because you need to have a lot of DNA if you are studying whole-genome sequencing. You need to have so many cells for the technology to work. You basically have people who already [are] halfway [to having] the disease. The real question is in those who have a very low level of disease, could you still address this question? Until now, that was not possible. This study takes advantage of a brand-new technology [that requires] low-input DNA. We were able to crack the code.

: This study aimed to answer 1 of the most important questions for the myeloma community. Some scientists [have] recently published very important studies showing that certain genomic drivers are associated with patients who progress. However, the limitation [in those] studies is that most of them are focused on smoldering myeloma because of the [number] of cells [they are able to collect]. [Others used] technologies that are focused on a small fraction of the genomes, so they are able to capture just a small fraction of events.

In the past 2 or 3 years, whole-genome sequencing has emerged and has shown the potential to reveal important myeloma-defining genomic events. [Whole-genome sequencing] is comprehensive and provides most of the answers that we were looking for, answers that the other previous studies could not; this is all possible with this technology.

Could you expand on the goals of this study and its key findings? What did the patient population look like?

: The study particularly focused on people with very low levels of disease; this is [those with] MGUS, which makes this study very unique. As you can imagine, if you study people with smoldering myeloma, they already have so many cells. If you have 1000 people, many will develop myeloma. However, if you have 1000 people with a MGUS, the proportion is going to be lower. For those individuals who are going to progress, [examining this is] equally important. This study, for the first time, focused on whole-genome sequencing, with a particular interest in people with very low disease burden.

What we showed was that we have an activation of certain genomic signatures. For example, a signature called APOBEC is known to be associated with aggressive, solid, and metastatic cancer. We have seen [this signature] in relapsed myeloma. However, when we look at these early disease cases, the patients who eventually progress already [had APOBEC] when they had the MGUS. The [patients] who did not progress, did not have [APOBEC]. That is a huge observation; that [shows us that we] can [predict] myeloma [before it occurs with these signatures]. Other single-variant hotspots, or templated insertions, [were also observed]. For example, chromothripsis also distinguishes these cases from each other.

The question now is [whether a person who does not have these genomic signatures now] can develop them later. [We need to know the rate of conversion.] To this end, we are already planning to open a large follow-up study, here, in Miami, where patients with MGUS and smoldering myeloma will be welcome to come for this test. [The study] will also allow them to come back on an annual basis if they have the low-risk signatures [so that they can] be tested longitudinally to] definitively answer this question. We are also working to develop early intervention studies to treat [patients] based on these signatures.

: Where we are now in the field is that the prediction of the risk of whether patients will progress is based on indirect measurement of disease burden. We have a different prognostic score that was developed by Mayo Clinic and the Spanish group, that is effective in identifying patients [who are] very high risk. We consider these patients to probably already have multiple myeloma; it is just a matter of time [for the disease] to expand and [cause] symptoms. In just a few months, less than 2 years, most of these patients will progress. These scores are less [effective in] predicting [those with] intermediate and low risk. That is [why] our study is important. All our patients enrolled, [those with] MGUS and smoldering multiple myeloma, were all intermediate and low risk. We did not have any high-risk [patients]. The [patients] who progressed were those who did so from an intermediate or low risk to multiple myeloma. That is another important consideration.

Despite the limited cohort, because we're talking about less than 50 patients, the data were clean; the cohort was not contaminated by high-risk patients or by [those with] multiple myeloma that was not yet diagnosed. It is important because this population of myeloma without symptoms is a big problem when you try to extrapolate or understand a large population, particularly [through] retrospective studies. That is another advantage. APOBEC, chromothripsis, templated insertions—all these events can only be detected in an accurate way using whole-genome sequencing. That is why whole-genome sequencing is important. You can detect APOBEC with exome data, but it is less accurate, and you [are left with] a lot of uncertainty.

Whole-genome sequencing is pretty robust; [either] you have [it] or you don't have [it], and if you don’t have it, then you’re sure you don’t have it. That is another advantage.

Finally, we performed a bit of a complicated analysis using mutations that are constant over time and we showed that the first genomic-defining events that we were able to time are acquired in multiple myeloma around the second decade of life. [Patients with] smoldering myeloma and MGUS who progressed [did so] in a similar time window: the second or third decade of life. What was interesting is that in the [patients with] MGUS or smoldering myeloma who did not progress, [events were acquired] in the fifth and six decades of life. We don't know whether these patients will progress, but we can also [hypothesize] that most of these patients, if they take the same path that multiple myeloma requires, will progress when [they are] more than 100 years [of age].

Oben B, Froyen G, Maclachlan KH, et al. Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities. 

. 2021;12(1):1861. doi:10.1038/s41467-021-22140-0

This article was originally published on OncLive as, "

Whole-Genome Sequencing in Smoldering Myeloma and MGUS Could Predict Outcomes

Articles

Whole-genome sequencing may hold the answers for patients with myeloma precursor conditions.

Whole-Genome Sequencing Helps Predict MGUS and Smoldering Myeloma Outcomes

Following the FDA approval of idecabtagene vicleucel (ide-cel; Abecma) for patients with relapsed/refractory multiple myeloma,

 experts in the field are starting to navigate a new era of myeloma treatment featuring BCMA-directed CAR T-cell products, said Nina Shah, MD.

The potential integration of ciltacabtagene autoleucel (cilta-cel), she added, as well as the development of dual-targeted CAR T-cell therapies and allogeneic products could further improve treatment for heavily pretreated patients.

“The first cellular therapy is now approved for multiple myeloma,” said Shah. “We are very excited to see how the [therapy is used in the] real world, how patients are referred, how patients are managed, and whether we can keep pushing the progression-free survival [PFS] curve upward. [The goal is that] people can start living; instead of just being patients, they can be people.”

On March 26, 2021, the FDA approved ide-cel for the treatment of patients with relapsed/refractory multiple myeloma who received 4 or more prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

The regulatory decision was based on findings from the pivotal, phase 2 KarMMA trial, which demonstrated a 72% overall response rate (ORR) and a 28% stringent complete response (sCR) rate with ide-cel in 100 evaluable patients with heavily pretreated multiple myeloma.

Although ide-cel was the first BCMA-directed CAR T-cell therapy approved for this patient population, another product, ciltacabtagene autoleucel (cilta-cel) is poised to enter the paradigm as well, Shah explained.

In the phase 1b/2 CARTITUDE-1 trial (NCT03548207), cilta-cel elicited a 96.9% ORR and a 67% sCR rate in 97 patients with heavily pretreated multiple myeloma.

In April 2021, the rolling submission of a biologics license application to support the approval of cilta-cel for the treatment of patients with relapsed/refractory multiple myeloma was completed.

® during an Institutional Perspectives in Cancer webinar on multiple myeloma, Shah, a hematologist and oncologist, and an associate professor of medicine, Department of Medicine, at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, discussed the newfound role of BCMA-directed CAR T-cell therapies in multiple myeloma, how the field may select between ide-cel and cilta-cel if the latter is approved, and novel cellular therapies in clinical development.

®: What was noteworthy about the data from the KarMMa trial with ide-cel?

: Ide-cel was recently FDA approved for patients with relapsed/refractory multiple myeloma. The approval was based on the pivotal, phase 2 KarMMa study where 128 patients with relapsed/refractory multiple myeloma were infused with the BCMA-directed CAR T-cell therapy ide-cel. These patients were very sick; the median [number of] prior therapies was 6.

From those data, we learned that more than 70% of patients responded [to ide-cel], which was remarkable considering how advanced these patients’ diseases were. In the 450 million [cell]–dose, which is the dose that will be carried forward for the ide-cel product [per] the FDA label, these patients actually had greater than an 80% response rate and a median PFS of about 1 year. We haven’t seen such strong data like this for patients with [heavily] relapsed/refractory multiple myeloma previously.

Are similar toxicity challenges observed with BCMA- and CD19-directed CAR T-cell therapies? What did the safety data reveal regarding cytokine release syndrome (CRS) and neurotoxicity with ide-cel?

CRS and neurotoxicity are [toxicities] that happen with the CD19-directed CAR T-cell therapies and the BCMA-directed CAR T-cell therapies. However, [these adverse effects] seem to be a little bit different [in terms of] characteristics for myeloma [compared with other hematologic malignancies].

According to the ide-cel data, about 84% of patients had CRS, but it was mainly grade 1 and 2. The median time to onset [of CRS] was 1 day. Neurotoxicity [occurred] in around 18% of patients and was also low-grade. [Neurotoxicity] was easily treatable. It is not only that the CRS and neurotoxicity qualities are different and a little less severe with the BCMA-directed therapies, but we are also more comfortable managing [these toxicities compared with those of the CD19-directed products].

How does cilta-cel appear to compare with ide-cel in terms of efficacy?

Cilta-cel is a really exciting possible CAR T-cell therapy for patients with multiple myeloma. [Cilta-cel] is also a BCMA-directed CAR T-cell therapy that works slightly differently [than ide-cel]. The extracellular domain that binds to BCMA, binds to 2 epitopes of BCMA instead of 1, the latter of which is the case with ide-cel.

The data from the CARTITUDE-1 study have been unprecedented. All patients were heavily pretreated; the median number of prior therapies was 6, which was very similar to the ide-cel group.

In this dataset, 97% of patients responded and 94% had a very good partial response or better [with cilta-cel]. Also, [we saw] very deep responses [with cilta-cel]. The minimal residual disease data look very good as well.

We do not have the long-term follow-up data, but it seemed as though more than half of patients were still in remission as of the 12-month cut-off. Of course, these are not mature data, so we don’t know exactly [how durable these responses are]. Preliminarily, [the data with cilta-cel] appear to be even better than the data we’ve seen with ide-cel.

Did the safety data from the CARTITUDE-1 trial reveal anything unique about CRS and neurotoxicity with cilta-cel?

Almost all patients [developed] CRS [with cilta-cel], but again, these were mainly grade 1 or 2 toxicities and were very treatable. A good portion of patients had some sort of neurotoxicity. However, what was interesting is that not all of the [neurotoxicities observed] are what we consider immune effector cell–associated neurotoxicity syndrome. [Patients had] some cognitive [toxicity] and other types of motor neuropathy. These were a little bit mysterious but were too [infrequent] to really understand a pattern. This is something that [providers] will have to look out for when [cilta-cel] is brought to a wider variety of patients.

Something interesting about the CRS was that the median time to onset was 7 days, with a range of 1 to 14 days. That means that [the CRS with cilta-cel] is a little less predictable, but that maybe not all patients need to be in the hospital for all 14 days [following infusion with cilta-cel]. The same is also true for ide-cel.

How do you anticipate the field will select between ide-cel and cilta-cel if cilta-cel receives an approval?

If the PFS [with cilta-cel] blows [the data seen with ide-cel] out of the water, a lot of people are going to be excited to use [cilta-cel]. There will be some pause to make sure that the neurotoxicity is well recognized and work to see ultimately what predicts for [neurotoxicity] so that we may prevent it. Again, [neurotoxicity] didn’t happen all that often, but for the select few patients in which it did happen, it was significant.

Otherwise, we are very excited to have not 1 but maybe 2 CAR T-cell therapy options out there for our patients with multiple myeloma. More options are always better when it comes to patient care.

What is next for cellular therapies in relapsed/refractory multiple myeloma?

Although we have done a good job of treating [patients with] multiple myeloma with BCMA-directed CAR T-cell therapies, we haven’t cured multiple myeloma and there is not a plateau on that [survival] curve. Therefore, we are always looking for new ways to treat [patients], particularly when we consider the CAR T-cell therapy field. There are some changes and advances going on.

One is that other targets are being explored, including GPRC5D. There are also dual-targeting CAR T-cell therapies [under investigation], such as [therapies targeting] CD38 and BCMA or CD19 and BCMA.

Also, there are different ways to culture the CAR T cells to bring out the memory population and improve persistence and potentially duration of response.

Something else that is going to be a different kind of splash from a different direction is the allogeneic CAR T-cell therapies, which will allow patients to avoid the step of apheresis and go straight to getting CAR T cells. That is something that is going to have a niche in the market because it is hard to do all the logistics [that are required of current autologous products]; that is sometimes what prevents people from getting this type of therapy. If [allogeneic CAR T-cell therapies] are pretty effective and tolerable as far as toxicity goes, they will be another option for patients.

FDA approves idecabtagene vicleucel for multiple myeloma. FDA. News release. March 26, 2021. Accessed May 5, 2021. 

Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): initial KarMMa results. 

 2020;38(suppl 15):8503. doi:10.1200/JCO.2020.38.15_suppl.8503

Madduri D, Berdeja JG, Usmani SZ, et al. CARTITUDE-1: phase 1b/2 study of ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor t cell therapy, in relapsed/refractory multiple myeloma. Presented at: 47th Annual Meeting of the European Society for Blood and Marrow Transplantation; March 14-17, 2021; virtual. Accessed May 5, 2021.

Form 20-F Legend Biotech Corp: Annual and transition report of foreign private issuers [sections 13 or 15(d)]. Accessed April 6, 2021. https://bit.ly/3fLKJ4h.

Adoption of BCMA-Directed CAR T-Cell Therapy Kickstarts A New Era in Multiple Myeloma

BCMA-directed CAR T-cell therapy is drastically changing the multiple myeloma treatment landscape.

CAR T-Cell Therapy Ushers in New Era for Myeloma Treatment

The FDA has granted an accelerated approval to loncastuximab tesirine (Zynlonta) for the treatment of adult patients with relapsed/refractory large B-cell lymphoma following 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma.

The approval for loncastuximab tesirine is based on findings from the pivotal phase 2 LOTIS 2 study, in which the CD19-directed antibody and alkylating agent conjugate elicted a 48.3% objective response rate (ORR), which included a 24.1% complete response (CR) rate in patients with relapsed/refractory disease who had received 2 or more previous lines of systemic treatment.2

In the multicenter, open-label, single arm phase 2 LOTIS 2 study, investigators evaluated the safety and efficacy of 

 in patients with relapsed/refractory DLBCL who had received 2 or more previous lines of systemic treatment; all patients received a median of 3 lines of prior therapy.

Loncastuximab tesirine was administered as a 30-minute infusion at a 150-μg/kg dose once every 3 weeks for the first 2 cycles. In subsequent cycles, the drug was administered at a dose of 75 μg/kg. Treatment was given for 1 year, or until disease progression, unacceptable toxicity, or when other discontinuation criteria were met.

At the April 6, 2020 data cutoff, 145 participants were enrolled to the trial; these patients had received a mean of 4.3 cycles of the ADC (range, 1-15). Additional data revealed during the 

2020 European Hematology Association (EHA) Congress

 showed that loncastuximab tesirine induced an ORR of 37.9% in patients who were refractory to their frontline treatment; this rate was 36.9% in patients who were refractory to their last-line previous treatment. The median duration response achieved with the ADC was 10.25 months.

Regarding safety, loncastuximab tesirine was found to be tolerable and no new safety signals had been observed. The most common grade 3 or higher treatment-emergent adverse effects reported with the ADC in 10% or more patients comprised neutropenia (25.5%) with low incidence of febrile neutropenia (3.4%), thrombocytopenia (17.9%), increased gamma-glutamyl transferase (16.6%), and anemia (10.3%).

Loncastuximab tesirine is also under examination in combination with ibrutinib

 (Imbruvica) in patients with relapsed/refractory DLBCL or mantle cell lymphoma (MCL). In the phase 1/2 trial, the ADC was administered in 30-minute IV infusions as part of a standard 3+3 dose-escalation trial design. Patients received doses of 60 μg/kg or 90 μg/kg. Loncastuximab tesirine was given every 3 weeks for the first 2 doses, with concurrent fixed-dose oral ibrutinib given at 560 mg/day for up to 1 year.

At the April 6, 2020 data cutoff of, a total of 25 participants had been enrolled to the trial; 23 of these patients had DLBCL, while 2 patients had MCL. Eighteen patients were evaluable for antitumor activity. Interim data from the phase 1 portion of the research, which were also presented during the 2020 EHA Congress, demonstrated that the combination elicited an ORR of 66.7% with a CR rate of 50.0% across the dose levels. Moreover, at the recommended phase 2 dose of 60 μg/kg, the combination induced an ORR of 75.0% with a 58.3% CR rate.

The phase 3 confirmatory LOTIS 5 trial (NCT04384484) is assessing the combination of loncastuximab tesirine and rituximab (Rituxan) vs chemoimmunotherapy in patients with relapsed/refractory DLBCL.3

ADC Therapeutics announces maturing data from pivotal phase 2 clinical trial and phase 1/2 combination clinical trial of loncastuximab tesirine (Lonca) in patients with relapsed or refractory diffuse large B-cell lymphoma. News release. ADC Therapeutics SA. June 12, 2020. Accessed November 20, 2020. 

Study to evaluate loncastuximab tesirine with rituximab versus immunochemotherapy in participants with relapsed or refractory diffuse large B-cell lymphoma. Clinicaltrials.gov. Updated September 17, 2020. Accessed November 20, 2020. 

https://clinicaltrials.gov/ct2/show/NCT04384484

FDA Approves Loncastuximab Tesirine for Relapsed/Refractory Large B-Cell Lymphoma.

FDA Approves Loncastuximab Tesirine for Relapsed/Refractory DLBCL

A walking program dramatically increased the number of steps walked by patients being treated for hematologic malignancies at City of Hope National Medical Center in California, according to a poster on the program presented at this year’s Oncology Nursing Society (ONS) Annual Congress.

After noticing decreased ambulation by patients during their hospitalization, in addition to increased fall rates and a decrease in documentation of ambulation in electronic medical records, presenter Kimberly Mercado, MSN, RN, BMTCN, and her colleagues decided to implement a walking program for patients to increase ambulation and decrease falls.

“We really wanted to give them a program that would help them to get motivated to exercise on the unit and kind of get out of their rooms, and keep up their stamina while they're receiving this treatment. Because as we all know, these treatments can be quite debilitating as in especially during COVID,” Mercado said during her poster presentation. “When the visitor policies don't allow for very many visitors, we wanted to make sure they had something to look forward to during their day and kind of get out and move.”

Additionally, Mercado explained, a walking program could also potentially be beneficial to patients suffering from cancer-related fatigue, as exercise had been previously shown to improve this side effect.

To start, Mercado and her colleagues created a brochure that explained the program to newly admitted patients and used foot-shaped necklace charms as incentives that patients could earn with each milestone they achieved. “Anytime a patient walked a lap, they could get a foot charm and hang it on their IV pole on a little chain to kind of remind them how much they've walked,” Mercado explained, “And it became nice for them to collect and understand how just how well they were doing.”

“Another incentive we gave was a reusable City of Hope mask that if anybody walked to 5K (3.1 miles) while they were on the unit, they would be given this to take home with them,” Mercado added.

Mercado and her colleagues also hung motivational posters throughout the unit to help keep patients motivated and moving.

A staff education component was implemented through emails, flyers, and in meetings, with the goal of explaining the program and offering tips how to encourage patients to participate.

One of the biggest interventions in the program, Mercado noted, was a change in workflow that asked night shift nurses to chart the amount of feet walked by patients throughout their day with the intention of standardizing charting and recording accurate ambulation data.

At baseline, patients walked an average of 136 steps in a 24-hour period. After implementing the program, that number was up to an average of 847 steps a few weeks into the program, and further increased to an average 1,018 steps per day at the end of one month.

While fall data is still being collected, the number of inpatient falls decreased from 6 in Q1 of 2020 to 4 in Q1 of 2021 thus far. Additionally, the number of falls with injury was 0, compared to 1 in 2020. To Mercado and her colleagues, this data, coupled with the dramatic increase in daily steps, signaled a success. “Patients seem to really take to it and enjoy it as well,” she noted.

“So as we go along, we obviously want to keep doing this program on our floor. Maybe it could even go house-wide at some time,” she said.

In addition to evaluating fall data, going forward, Mercado concluded that she and her colleagues plan to gather patient feedback to further improve upon the walking program and add additional incentives such as challenge coins, pins, and patches for completing milestones such as distances of 10 kilometers (6.2 miles), a half marathon (13.1 miles) or even marathons (26.2 miles).

“If you can walk a marathon while you're getting cancer treatment, that's incredible,” Mercado said.

Mercado K. Implementation of A Walking Program For Hematology Patients. Presented at: Oncology Nursing Society 46th Annual Congress; April 20, 22, 27, and 29, 2021. ePoster 1880. 

https://ons.confex.com/ons/2021/qi/eposterview.cgi?eposterid=1880

A walking program dramatically increased the number of steps walked by patients being treated for hematologic malignancies. 

Walking Program Improves Ambulation in Patients with Hematologic Cancer

Five-year follow-up data from the pivotal phase 3 ECHELON-1 trial suggest that peripheral neuropathy is not a prohibitive toxicity for the majority of patients with newly diagnosed stage III/IV Hodgkin lymphoma who receive brentuximab vedotin (Adcetris) plus doxorubicin, vinblastine, and dacarbazine (A+AVD), explained Mendel Goldfinger, MD. However, further studies are needed to determine whether vinblastine could be omitted from the brentuximab vedotin–containing regimen to mitigate some of the risk for peripheral neuropathy.

Findings from the 5-year analysis, which were presented virtually during the 2020 ASH Annual Meeting and Exposition, showed that treatment-emergent peripheral neuropathy completely resolved in 84% of patients treated with A+AVD and 86% of patients treated with AVD plus bleomycin (ABVD). The median time to complete resolution of peripheral neuropathy was 30 weeks and 16 weeks, respectively.

Moreover, the majority of patients with ongoing peripheral neuropathy had low-grade events, explained Goldfinger.

“Neuropathy [is] the major toxicity of brentuximab vedotin, and the majority of patients [who develop neuropathy] are young. It [is] concerning that we are going to cure them [of their Hodgkin lymphoma] but [leave them with] neuropathy that could be a lifelong debilitating issue,” said Goldfinger.

® during a 2020 Institutional Perspectives in Cancer webinar on hematologic malignancies, Goldfinger, director of the Hematology-Oncology Montefiore Network Program at Montefiore Medical Center and an assistant professor at the Albert Einstein College of Medicine, discussed some of the key points of the ECHELON-1 trial data.

®: Why has A+AVD become the new standard of care for patients with stage III/IV Hodgkin lymphoma?

: ECHELON-1 was a large, phase 3 trial [conducted] in many countries at many centers in patients with advanced Hodgkin lymphoma to try to change [what had been the standard of care] for over a decade. The standard [arm] was ABVD, which over 600 patients received, and the other half of patients received AVD with brentuximab vedotin, which was substituted for bleomycin.

For a long time, we had tried to get away from bleomycin because it is known to cause potentially short- and long-term toxicity. We also looked at ways to improve efficacy.

ECHELON-1 nicely showed at 2-, 3- and 4-years that the A+AVD arm had much better progression-free survival [rates] compared with ABVD. In addition, the toxicity of bleomycin [was absent].

There was initial concern about peripheral neuropathy, which is an adverse effect that we see more with brentuximab vedotin. However, the good news was that [with longer follow-up], the majority of patients’ neuropathy subsided over time. The vast majority of patients who had sustained neuropathy had very low-grade neuropathy.

Clearly, this was a large trial that was able to change the standard of care for advanced-stage Hodgkin lymphoma. The community has accepted [A+AVD] as the new standard [for this patient population].

Did A+AVD decrease the need for salvage therapy compared with ABVD?

It’s always been challenging to demonstrate survival benefits in Hodgkin lymphoma because we get another chance at [treatment] if our patient doesn’t do well and recurs. However, even though we could salvage patients, that requires an additional year of chemotherapy or an autologous stem cell transplant with high-dose chemotherapy. [Chemotherapy] by itself has short- and long-term complications. Therefore, even though some patients don’t do well with ABVD, we can salvage the majority of them, but at a very big price.

[ECHELON-1] showed that not only does the short-term data look better with A+AVD, but the reason the data look better is because we get it right the first time. A subgroup of these patients who would have likely required additional therapy can be cured [with A+AVD].

All subgroups except for patients from Asia benefitted from the A+AVD regimen compared with ABVD. Why might that be?

It’s a great question. This trial wasn’t statistically powered to look at that subgroup [of patients from Asia]; however, subsequent studies will have to look into that with more detail. In general, we try to look at subgroups [to determine] whether we can study [those patients] in more detail later on. Is it the disease biology? Is it the pharmacokinetics of the drugs? These are questions that will have to be answered in subsequent trials.

Could you speak to the PFS benefit observed in patients independent of PET2 status and in patients younger than 60 years?

ECHELON-1 was not what we would call a PET-adapted approach. Patients did get a PET scan after 2 cycles [of A+AVD or ABVD], but as long as they were not progressing, they continued on their assigned treatment regimen.

The data demonstrated that even the patients who had a Deauville score of 4, which we routinely consider for treatment escalation or switch to a different therapy, had benefit with A+AVD vs ABVD. It wasn’t as pronounced as the patients [with lower Deauville scores], but clearly there was benefit.

One point that should be made is that a minority of patients had a positive PET scan after 2 [cycles of therapy].

Additionally, the study doesn’t give clear guidance as to whether we should do an [interim] PET scan after 2 cycles. When using A+AVD, my personal approach has been to [do] the interim PET scan to make sure the patient is heading in the right direction. The vast majority of patients will have a negative PET with a Deauville score of 3 or less. If they do have a Deauville score of 4, there is not clear guidance.

Clearly, the [ECHELON-1] study showed there was a benefit [with A+AVD] compared with ABVD. However, whether [we should] change the treatment course at that point is a case-by-case [decision]. There are data emerging that the delta comparing the baseline PET scan with the repeat PET scan does matter. That’s usually a question of tumor boards with colleagues.

As far as age [as a stratification point], the data were striking. Hodgkin lymphoma [affects] a heterogenous group of patients. There is bimodal distribution [between] younger and older [patients]. Clearly the benefit [of A+AVD] was there for the young patients as well.

Does peripheral neuropathy remain a concern with A+AVD? How could this toxicity potentially be prevented?

As oncologists, we deal with [the risk of neuropathy] with other drugs as well. As the data [from ECHELON-1] mature, we see that the vast majority of patients’ neuropathy disappears. [Patients with] remaining neuropathy have low-grade toxicity.

Another point is that there are currently studies ongoing to [answer] the question: If we omit vinblastine, which is another microtubal inhibitor that can cause neuropathy, can we minimize toxicity and maximize efficacy? Boston researchers has published some early reports from that study. The data look good, but it is not ready for primetime. We will have to wait for the full study to mature. Going forward, we believe there will be ways to try to mitigate this toxicity even further.

How is peripheral neuropathy currently mitigated in practice?

The key is to ask the patient all the time about [whether they are experiencing] neuropathy and whether we need to dose reduce [brentuximab vedotin]. Generally, [A+AVD] is a curative therapy, so we try to keep going [with treatment]. The biggest tip that I have found to be helpful is to see if the neuropathy gets better in week 2, prior to [initiating] therapy [in that cycle].

Then I know we are going in the right direction. If a patient still has [neuropathy] on day 14 or day 28 prior to starting the next dose that hasn’t gotten better than the week before, there are good guidelines on how to grade [the neuropathy] and dose reduce if needed. I honestly haven’t had a patient whose neuropathy has not gotten better as they got closer to the next dose, but that is usually a warning sign that we should consider dose reduction.

Is the addition of granulocyte colony-stimulating factor (G-CSF) warranted with A+AVD and what is your approach to navigating that decision?

Investigators learned early on when there was no G-CSF support that a number of neutropenic patients had neutropenic sepsis and [eventual] death. Once the G-CSF support was added, that was no longer an issue. For me, I give patients long-acting G-CSF with pegfilgrastim [Neulasta] with each therapy. It is basically [given] on day 2 and day 16 in whatever formulation [of pegfilgrastim] is available in the clinic. I’ve seen clinicians give [pegfilgrastim] once a cycle; my approach has been to give it with each treatment.

Can A+AVD be sequentially administered for elderly patients with Hodgkin lymphoma?

Certainly, we have bimodal distribution in Hodgkin lymphoma. There is an elderly population of patients who gets this disease that have not historically been well represented in the data. A+AVD could be very toxic for these patients.

A small but practical study was published in the 

 that gives good guidance wherein patients get 2 cycles of single-agent brentuximab vedotin, followed by 6 cycles of AVD, followed by 4 more cycles of brentuximab vedotin. This approach has multiple benefits. [Brentuximab vedotin] is better tolerated as it is sequenced. The vast majority of patients [on the study] did well in terms of remission. Personally, using this regimen [allows me to have] the ability to test what my patients can tolerate. I’ve had patients who haven’t finished a full course of treatment, but I was able to learn as I was sequencing how much they could tolerate.

The downside [of this approach] is that it takes a long time to get through [a cycle]. However, the results are good, and it is one of the biggest contributions [to the Hodgkin lymphoma armamentarium], specifically for elderly patients with Hodgkin lymphoma who have not historically been well represented in the literature.

What efforts are underway to improve A+AVD as a treatment for patients with advanced-stage Hodgkin lymphoma?

There are other incredibly effective agents in Hodgkin lymphoma, including immunotherapy. Checkpoint inhibitors have shown really good responses in the relapsed/refractory setting. A clinical trial is looking A+AVD compared with a checkpoint inhibitor plus AVD. It will be a number of years before we have the readout of that trial.

Another remaining question that I alluded to earlier is: Can we omit vinblastine or decrease the amount of vinblastine that we give to mitigate neuropathy? We will have to answer that question in ongoing clinical trials.

The addition of G-CSF was a game-changer. We have to wonder if we had [given G-CSF with A+AVD] from the get-go whether the data would have looked even better than it does. The real-world data might be slightly better than the data from the trial because we are learning how to manage toxicities.

Straus DJ, Dlugosz-Danecka M, Connors JM, et al. Brentuximab vedotin with chemotherapy for patients with previously untreated, stage III/IV classical Hodgkin lymphoma: 5-year update of the ECHELON-1 study. 

. 2020;136(suppl 1):26-28. doi:10.1182/blood-2020-137089

This article was originally posted on OncLive as, "

Mitigating Peripheral Neuropathy Is Still Focus of Ongoing Research in Hodgkin Lymphoma

Mendel Goldfinger, MD, discusses some of the key points of the ECHELON-1 trial data.

Expert Discusses Neuropathy in Hodgkin Lymphoma Treatment

A simplified geriatric assessment offers a validated objective tool to assess fitness status and should be considered the new Elderly Prognostic Index (EPI) standard to predict overall survival (OS) in older patients with diffuse large B-cell lymphoma (DLBCL), according to findings from the Elderly Project study (NCT02364050) published in the 

The tool incorporates activities of daily living, instrumental activities of daily living, Cumulative Illness Rating Scale for Geriatrics, and age (≥80 or <80) to refine and improve the original geriatric assessment tool adopted by the Fondazione Italiana Linfomi (FIL) that categorized patients into 3 categories of fitness: fit, unfit, and frail.

Utilizing the simplified tool that also categorized patients into the same fitness categories as the original tool, the 3-year median OS was 65% (95% CI, 62%-68%) in the overall patient population (n = 1163); however, the median OS varied significantly based on fitness. The hazard ratio (HR) was 1.98 for unfit vs fit patients (95% CI, 1.55-2.54; 

 < .001), 3.27 for frail vs fit patients (95% CI, 2.52-4.22; 

 < .001), and 1.65 for frail vs unfit patients (95% CI, 1.26-2.14; 

 < .001). This translated to 3-year OS rates of 87% (95% CI, 81%-91%), 69% (95% CI, 63%-73%), and 42% (95% CI, 36%-49%) for fit, unfit, and frail patients, respectively.

“The development and validation of the EPI [Elderly Prognostic Index] on an independent series of patients provides clinicians with a unique tool to better account for the complexity of each older patient with DLBCL,” lead study author Francesco Merli, MD, managing director of the Department of Oncology and Advanced Technologies at Azienda Osperdaliera Santa Maria Nuova di Reggio Emilia in Italy, and co-authors wrote.

DLBCL is the most frequently occurring lymphoma subtype. Moreover, about 70% of patients with DLBCL are over the age of 65 years.

The integration of rituximab (Rituxan) to standard anthracycline-containing regimens has significantly improved survival for patients with DLBCL; however, older patients with DLBCL have poorer outcomes compared with younger patients. Moreover, age-related comorbidities limit available treatment options, which are associated with increased risk of treatment-related toxicity. Notably, despite this disparity, elderly patients are largely underrepresented in clinical trials, so physician preference plays a significant role in treatment selection.

The integration of geriatric assessment has provided a useful tool to gauge multiple geriatric conditions and subsequently tailor therapies in terms of patient goals, intensity, tolerance, and prognosis.

“FIL has been using the same [original geriatric assessment] in its studies on older patients with DLBCL for several years,” the authors wrote.

The Elderly Project was a prospective, multicenter, observational study aimed at evaluating how simplified geriatric assessment affected OS in older patients with newly diagnosed DLBCL.

The 3-step study prospectively validated the original geriatric assessment, refined the new, simplified geriatric assessment to account for confounding factors, and developed and validated a prognostic model that integrated patient- and lymphoma-related factors.

The study evaluated 1163 patients from 36 hematology/oncology centers of the FIL in Italy.

Patients had to have histologic confirmed DLBCL, be 65 years of age or older, provide informed consent, and have original geriatric assessment results available. Patients who had a diagnosis other than DLBCL, including grade 3b follicular lymphoma or high-grade lymphoma were not eligible for evaluation.

Patients were classified as fit, unfit, or frail per the simplified geriatric assessment criteria and the results of a Web-based calculator.

Overall, patients were a median age of 76 years (range, 65-94; 

 < .001), and 32% were over the age of 80 years (

 < .001). Half of the patients (50%) were male (

 = .032), 67% had stage III or IV disease (

 = .217), 29% had more than 1 extranodal site (

 = .795), and 20% had an ECOG performance status greater than 1 (

 < .001). Most patients’ (55%) lactase dehydrogenase was above the upper limit of normal (

 = .180), and 56% of patients had an International Prognostic Index (IPI) score between 3 and 5 (

Notably, the protocol for simplified geriatric assessment did not include any recommendations for patient management, and treatment selection was left to the provider’s discretion and did not need to be informed by the results of the assessment.

Of the overall population, 54% (n = 652) were classified as fit at baseline, 28% (n = 334) were unfit, and 18% (n = 221) were frail. Additionally, 63% of patients previously received full-dose chemotherapy, 24% received prior reduced-dose chemotherapy, and 13% received prior palliative care. The full-dose chemotherapy was administered to 86%, 48%, and 16% of fit, unfit, and frail patients, respectively.

“The prognostic score was obtained [by] giving a weight to each variable according to its relative importance, derived from the z-Wald values found in the Cox PH [proportional-hazards] model. The weights were obtained [by] rounding the ratio, and the score was the sum of [the] weights. We thus obtained a score ranging from 0 to 8 that showed a good correlation with OS,” wrote the authors.

At a median follow-up of 30 months (range, 1-59), 354 deaths were reported from causes included lymphoma progression (n = 243), treatment-related toxicity (n = 74), secondary malignancy (n = 10), and unknown (n = 27).

Fitness level, IPI score, and hemoglobin level were found to be the most significant prognostic factors in building the EPI score. The EPI model was developed based on a 1065-patient cohort with a 3-year OS rate of 66% (95% CI, 62%-69%); the cohort excluded patients with incomplete data.

In addition to OS, the prognostic role for the EPI model was validated for progression-free survival and disease-free survival, the authors wrote.

External validation of 456 cases with a median follow-up of 30 months was conducted in Italy (n = 172), Australia (n = 204), and Brazil (n = 80). Complete data were available in 78% of cases. A total of 117 patients died on study, and the 3-year OS rate was 61% (95% CI, 55%-67%).

In the validation cohort, 22% were classified as low risk, 46% were intermediate risk, and 32% were high risk. The 3-year OS rates were 85% (95% CI, 71%-93%), 65% (95% CI, 55%-73%), and 44% (95% CI, 34%-54%), respectively. The HR was 2.14 in the intermediate-risk group vs the low-risk group (95% CI, 1.08-4.24; 

 = .029) and 2.18 in the high-risk group vs the intermediate-risk group (95% CI, 1.49-3.21; 

Notably, the simplified geriatric assessment takes less than 10 minutes to complete by the oncologist/hematologist during a patient’s regularly scheduled visit, the authors wrote.

“The time has come to consider the fitness status of older patients with DLBCL to better identify their treatment goals. The EPI is the first prognostic index to integrate fitness evaluation into prognosis in older patients with DLBCL, which contributes to improving patient assessment,” concluded the authors.

Merli F, Luminari S, Tucci A, et al. Simplified geriatric assessment in older patients with diffuse large B-cell lymphoma: the prospective Elderly Project of the Fondazione Italiana Linfomi. 

 Published online February 12, 2021. doi:10.1200/JCO.20.02465

Simplified Geriatric Assessment Validated as OS Predictor in Elderly Patients With DLBCL

A simplified geriatric assessment offers a validated objective tool to assess fitness status and should be considered the new Elderly Prognostic Index standard to predict overall survival in older patients with diffuse large B-cell lymphoma.

Assessment Predicts Survival In Elderly Patients with DLBCL

The FDA has approved idecabtagene vicleucel (ide-cel; Abecma) as the first BCMA-directed chimeric antigen receptor (CAR) T-cell therapy for patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

The approval is based on findings from the pivotal, phase 2 KarMMA trial, in which ide-cel elicited an overall response rate (ORR) of 72% (95% CI, 62%-81%) and a stringent complete response (sCR) rate of 28% (95% CI, 19%-38%) in an efficacy evaluable population (n = 100) of patients with relapsed/refractory myeloma who had received at least 4 prior treatments.

Ide-cel is approved as a one-time infusion with a recommended dose range of 300 to 460 x 106 CAR-positive T cells.

“In the KarMMa study, ide-cel elicited rapid responses in the majority of patients, and these deep and durable responses were observed in patients with triple-class exposed and refractory multiple myeloma,” said Nikhil C. Munshi, MD, associate director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute. “As a treating physician, I often work with patients with relapsed or refractory multiple myeloma who are in critical need of new therapies. Now, with the approval of ide-cel as the first anti-BCMA CAR T cell therapy, we are excited to finally be able to offer patients a new, effective personalized treatment option that is delivered through a single infusion.”

KarMMA included a total of 128 patients with relapsed/refractory multiple myeloma who had received at least 3 previous therapies, including an IMiD, a PI, and an anti-CD39 antibody. The median age of the participants was 61 years, and 35% of patients had high-risk cytogenetics. About half of patients, or 51%, had high tumor burden, while 39% had extramedullary disease and 85% had 50% or higher tumor BCMA expression. Forty-five percent of participants had an ECOG performance status of 0, 53% had a status of 1, and 2% had a status of 2. R-ISS stage disease was I in 11% of patients, II in 70% of patients, and III in 16%. Overall, participants had received a median of 6 previous treatments (range, 3-16).

The majority of patients, or 94%, had undergone 1 previous autologous stem cell transplant; 34% had undergone more than 1 of these procedures. Moreover, 88% of participants had been given bridging therapies during CAR T-cell manufacturing, but only 4% responded to that treatment. Ninety-four percent of patients proved to be refractory to anti-CD38 antibodies, and the majority, or 84%, were determined to be triple refractory.

In the trial, participants were given at the following CAR T cell doses: 150 x 106 (n = 4), 200 x 106 (n = 70), or 450 x 106 (n = 54). The median follow-up was 18 months for the first dosing cohort, 15.8 months in the second, and 12.4 months in the third. Across the entire study population, the median follow-up was 13.3 months. The primary end point of the trial was ORR, and key secondary end points were comprised of CR, DOR, PFS, overall survival (OS), and quality of life.

Additional findings showed that responses with ide-cel were rapid and durable; the median time to response was 30 days (range, 15-88) and the median duration of response was 11 months (95% CI, 10.3-11.4) for all responders and 19 months (95% CI: 11.4–not estimable [NE]) for those who achieved a sCR. Of the 28 patients who achieved a sCR, approximately 65% (95% CI, 42%-81%) had remissions that lasted at least 1 year.

Ide-cel does come with a Boxed Warning for cytokine release syndrome (CRS), neurologic toxicities, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged cytopenia.

The FDA has approved idecabtagene vicleucel as the first BCMA-directed CAR T-cell therapy for patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

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FDA Approves Loncastuximab Tesirine for Relapsed/Refractory DLBCL

Walking Program Improves Ambulation in Patients with Hematologic Cancer

Expert Discusses Neuropathy in Hodgkin Lymphoma Treatment

Assessment Predicts Survival In Elderly Patients with DLBCL

FDA Approves Idecabtagene Vicleucel for Relapsed/Refractory Multiple Myeloma

Better Outcomes, Less Toxicity With Axi-Cel in Large B-Cell Lymphoma

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