Targeted Oncology Staff

Associate Professor, Division of Hematology

Director, Hematology and Medical Oncology Fellowship Program

The James Cancer Hospital - The Ohio State University Comprehensive Cancer Center

Under what circumstances would you be most likely to use loncastuximab tesirine (Zynlonta) as third-line therapy for a patient with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL)?

What do you view as the pros and cons of loncastuximab as compared with other alternatives such as tafasitamab (Monjuvi)/lenalidomide (Revlimid), polatuzumab (Polivy)/bendamustine (Treanda)/rituximab (Rixutin), and selinexor (Xpovio)?

Do you foresee any barriers to using loncastuximab?

If loncastuximab were covered by insurance, would you use it in the second line for patients who decline stem cell transplant?

Would you use it for patients who may be eligible for chimeric antigen receptor (CAR) T-cell therapy?

Would you use it for patients who you consider not to be eligible for CAR T-cell therapy?

Consider the 46% response rate to CAR T-cell therapy in the 15 patients who received CAR T-cell therapy after loncastuximab.

 How does that factor into your opinions on sequencing therapeutics?

 For the participants that have used loncastuximab, what’s your experience like?

 We’ve used loncastuximab in 2 patients who had rapidly progressing disease. This was in the inpatient setting, and we were desperate to gain some control over the disease [to take them to CAR T-cell therapy after failure of other bridging therapies]. But we were unlucky in both patients; 1 patient received 2 cycles [of loncastuximab], and the other patient received 1 cycle before passing away.

 It sounds like the patients were on treatment for a relatively short time. Did you encounter any issues with edema or myeloid suppression?

 They experienced myeloid suppression for sure. As for edema, they had already been in the hospital receiving a lot of fluids and had the usual iatrogenic fluid overload. I don’t remember there being any pleural effusion, or anything outstanding that [we could attribute to] loncastuximab.

 Did the patients die because of cancer progression or adverse events of the drug?

 They died from the disease, which was just very refractory to everything, and we couldn’t really control it. It was one of those DLBCLs or high-grade B-cell lymphomas.

 In what circumstances would you be most likely to use loncastuximab as third-line therapy for a patient with R/R DLBCL?

 I haven’t used most of these therapies, and I think the reason for that is that I use R-GemOx [rituximab plus gemcitabine plus oxaliplatin] in most of my patients [who develop refractory disease] after first-line therapy. If the patient has an activated B-cell lymphoma then I am more likely to use zanubrutinib [Brukinsa] or lenalidomide. But the majority of my patients have had germinal cell [GC] disease.

In these patients, I generally use [a combination with] rituximab [Rituxan]. I think a platinum drug is important here. That’s when I go for a second-line [therapy] if the patient is not transplant-eligible. By then I’ve referred the patient for CAR T-cell therapy and they go on to our lymphoma team. But I know that I’m going to be getting some of these patients back. And for various reasons, some of them will go on to third-line or post-CAR T-cell therapy. There are all these [late-line] regimens, and we’ve seen some of the data. I think the polatuzumab vedotin, bendamustine, rituximab is something I lean towards, but I don’t completely grasp where and when to sequence these late-line treatments.

In your decision-making for sequencing, where are your inflection points in terms of using tafasitamab versus a polatuzumab-based regimen? How are you sequencing these in the late-line setting, [both in patients who have and have not received CAR T-cell therapy]?

 Some of the things I take into consideration are [the R/R DLBCL setting is] evolving and changing, and it’s really challenging right now to manage this condition. 

For my patients who have undergone prior CAR T-cell therapy; [these are usually] younger, fitter patients who weren’t eligible for autologous stem cell transplant or who relapsed after autologous stem cell transplant and received CAR T-cell therapy. One challenge that I encounter with these patients is that they often have prolonged cytopenia, whether that’s from transplant or from CAR T-cell therapy.

In my own practice, I’ve found that [cytopenia] can be somewhat of a barrier to using rituximab plus polatuzumab vedotin. I have had some patients where I started that therapy and then ultimately, I ended up converting it to polatuzumab alone, and I’ve seen some responses there. But I think low blood cell counts can be a challenge with that regimen.

One of the things that I take into account with tafasitamab/lenalidomide is the cell of origin. So, although the data in the phase 2 L-MIND study [NCT02399085] included patients with both non-GC and GC DLBCL, the responses [to lenalidomide] favored non-GC type disease.

 That is something that plays into my decision-making. I also find that the full dose of lenalidomide with tafasitamab/lenalidomide is not necessarily easy on blood counts. That’s something that I also consider when I am making choices about these treatments. And then finally, I think when it comes to loncastuximab, [one has to consider] the tolerability of it, in terms of the dosing schedule, and having to talk with patients and counsel them about the edema [associated with this drug]. There can also be some issues related to myelosuppression, but the dosing schedule does tend to be a little bit kinder [for loncastuximab] than for tafasitamab/lenalidomide.

I don’t think there really is an optimal sequence [for late-line therapies for R/R DLBCL], but [when I make sequencing decisions] I try to take into account patient factors, [such as blood] counts, peripheral neuropathy, prior lines of therapy, [and] cell of origin.

 For the second line patients who are not transplant candidates, how do you select between, R-GemOx versus BR-pola [polatuzumab vedotin plus bendamustine plus rituximab] versus tafasitamab/lenalidomide.

 If I have a patient [with non-GC DLBCL] who is elderly and unfit, and I don’t think they’re eligible for transplant or CAR T-cell therapy, that is where tafasitamab/lenalidomide was approved in and has showed good results with sustained responses in some patients.

Patients with high-grade large B-cell lymphoma were excluded from L-MIND of tafasitamab/lenalidomide.

 But these patients were included in other studies, and so that is something I might take into consideration, as well as how rapidly I need a response, or how sick the patient is.

In terms of myeloid suppression, at least in my experience, the BR-pola can be a little bit of a tougher regimen if the patient has baseline cytopenias or is elderly or unfit, and I’m concerned about tolerance.

1. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. 

. 2021;22(6):790-800. doi:10.1016/S1470-2045(21)00139-X

2. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. 

. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4

Articles

During a live virtual event, Beth A. Christian, MD, discussed data on third-line loncastuximab tesirine treatment in patients with diffuse large B-cell lymphoma and how to sequence treatments for patients who may receive CAR T-cell therapy.  

Part 3: Third-Line Use of Loncastuximab for Relapsed/Refractory DLBCL

Case-Based Roundtable event, Mary Jo Fidler, MD, associate professor, Division of Hematology, Oncology, and Cell Therapy, Rush Medical College, discussed a 59-year-old man with non–small cell lung cancer. 

I do next-generation sequencing [NGS] with FoundationOne CDx, as well as a Guardant [Health] liquid biopsy prior to initiating treatment.

[Does] anyone else use both liquid biopsy and tissue biopsy at the same time?

Yes, I also do both at the same time, [using] Guardant liquid biopsy and then usually Caris [Life Sciences], unless an in-house [biopsy is] done. We’ll do them simultaneously and usually get the [results of the] liquid biopsy first so we can see if there’s an actionable mutation within a shorter period.

Usually, if the tissue is available, I will do FoundationOne testing with the tissue. I will only do the liquid biopsy if there is no tissue available. If I’m thinking of the second line, then [I am more likely to] do liquid [testing]. But I don’t do [both] combined.

The National Comprehensive Cancer Network [NCCN] guidelines recommend broad-based testing like everyone [here] is doing. I feel like these guidelines are evolving; [they now include molecular testing for] 

exon 14 skipping. The recommendation is that testing should be [conducted as part of] a broad molecular panel and also include PD-L1 plasma testing.

In this case, we already have [immunohistochemical] PD-L1 testing, but we know that plasma testing can [also] be done. We learned [from data presented] 2 years ago that whether the driver [mutation] was found in the plasma or in the tissue, it was equally actionable. [For a significant] percentage of the time, it was found only in the blood and not in the tissue, and vice versa.

 Especially for [patients for whom] I have high suspicion, I do both tests.

It sounds like most of us are using the next-generation panel; FoundationOne has this capability and we use Tempus quite a bit. However, to capture as many fusions as possible, [using an] RNA sequencing platform as part of the test is a little better. RNA sequencing can test for large fusions that can be missed by DNA sequencing; [in particular,] 

fusions can be missed by DNA [sequencing]. I’ve had times where I’ve had to order repeat biopsies, especially in patients with no nicotine dependence.

There was a presentation at [the] American Society of Clinical Oncology [(ASCO) Annual Meeting] this year, showing that testing for all these markers isn’t [very] common; there’s room for improvement. In a large community network [study, supported by electronic medical record] data, only about 50% of people with a diagnosis of stage IV nonsquamous cell carcinoma had [testing] for all 5 markers recommended at the time.

 There were also data at ASCO suggesting that if patients had NGS, they were more likely to enroll in clinical trials,

 and also data showing that African American patients were less likely to have NGS testing.

Did Oncotype develop an NGS [test] for lung or only for breast [cancer]?

There is a similar test that Medicare is paying for now, but it’s not called Oncotype. I think it’s called Oncocyte. It’s an Oncotype-like [test] for lung [cancer], looking at early-stage tumors. The [number] of patients used to create and validate the test wasn’t large; I don’t know if it’s quite ready for [mainstream use].

Also, they don’t test [for] EGFR in the early stage [in which there might be] benefit from the osimertinib mesylate [Tagrisso] adjuvant.

Yes. It’s a good point that we should probably be testing in the [neo]adjuvant setting [for] EGFR, but I’m recommending that for all patients [with disease stage] IB and above. We may have immunotherapy approved too; the benefit for atezolizumab [Tecentriq] post operation seemed more focused on patients with PD-L1 expression.

 More data are coming out [regarding] the combination of chemotherapy plus immunotherapy, [suggesting that PD-L1 expression could be] useful in identifying 25% of pathological complete responses. We don’t yet know about overall survival and progression-free survival [PFS] results.

The combination of carboplatin, nab-paclitaxel [Abraxane], and atezolizumab is FDA approved. Interestingly, the regimen did not meet the end point in [patients with squamous non–small cell lung cancer (NSCLC) in IMpower130 (NCT02367781)], but it is an FDA-approved choice [for patients with nonsquamous NSCLC].

 I use quite a bit of the carboplatin, pemetrexed [Alimta], plus pembrolizumab [Keytruda] combination. I think what’s left for us to figure out is how to incorporate nivolumab [Opdivo] and ipilimumab [Yervoy]. That [combination is] FDA approved for PD-L1–positive NSCLC.

 I would not start with single-agent pembrolizumab.

[According to the NCCN guidelines], there are quite a few treatment options for NSCLC with PD-L1 expression that ranges from at least 1% to 49%. The preferred regimen is pemetrexed and pembrolizumab plus either carboplatin or cisplatin. Another category 1 regimen is the quadruplet with carboplatin, paclitaxel, bevacizumab [Avastin], and atezolizumab. The combination of carboplatin, nab-paclitaxel, and atezolizumab [is also recommended].

The [regimen studied in] CheckMate 9LA [(NCT03215706), nivolumab, ipilimumab, plus platinum chemotherapy and pemetrexed,] is also listed. Additionally, nivolumab and ipilimumab [used as a stand-alone combination] is listed as “useful in certain circumstances” and is supported by category 1 data.

Could you describe how you pick 1 option over the other?

[In my] experience, the carboplatin, pemetrexed, and pembrolizumab combination is very well tolerated. I used nivolumab plus ipilimumab when the approval came out [for that combination]

 for people who really didn’t want to have chemotherapy [and who] also weren’t necessarily the best chemotherapy candidates. I did not [find] that the nivolumab and ipilimumab combination was any easier [on patients] than was the carboplatin, pemetrexed, and pembrolizumab combination. I do like the choice of the nab-paclitaxel [combination], because patients who are fit for chemotherapy but have renal dysfunction cannot get the pemetrexed, so it’s still less than the platinum doublet plus an immune checkpoint inhibitor.

 I, ultimately, base [my choice] on the adverse event [AE] profile.

Usually, I pick the carboplatin, pemetrexed, and pembrolizumab combination because we have been [using] it longer and have more experience [with it].

Do you think there’s a role for bevacizumab if [a patient is] immunotherapy eligible?

 was the only large phase 3 trial that included patients with a history of driver mutations. There are good preclinical data to suggest synergy [between] antiangiogenic drugs (like bevacizumab) and immune checkpoint inhibitors, so I think there is a rationale to combine [bevacizumab with immunotherapy]. Paclitaxel is usually not as palatable as carbo[platin] plus [pembrolizumab because of accompanying] neuropathy and hair loss, but I do [discuss] it with patients who have driver mutations and need to switch from their tyrosine kinase inhibitors.

I have [used a single-agent immune checkpoint inhibitor], rarely, for [patients with] low PD-L1 expression.

The NCCN guidelines, [as mentioned, recommend several different regimens] for patients with PD-L1 expression that ranges from at least 1% to 49% [in the context of] nonsquamous [disease].

 [These include] single-agent pembrolizumab, which was based on category 2B data from the KEYNOTE-042 study [NCT02220894]. This was a randomized 1:1 trial in patients who had a TPS [tumor proportion score] of greater than or equal to 1%, and the [treatments were] pembrolizumab vs carboplatin plus paclitaxel or carboplatin plus pemetrexed for [patients with nonsquamous disease].

The primary end point was overall survival [OS] in cohorts [defined by TPS] as greater than or equal to 50%, greater than or equal to 20%, and greater than or equal to 1%.

The cohort defined by a TPS of greater than or equal to 1% and the whole trial population [showed that], technically, this was a positive trial with respect to median OS in the experimental arm vs the control arm at 16.7 months vs 12.1 months, respectively [HR, 0.81; 95% CI, 0.71-0.93; 

= .0018]. However, it appears that most of the benefit was in the cohort with [the highest] PD-L1 expression and OS at 20 months vs 12.22 months, respectively [HR, 0.69; 95% CI, 0.56-0.85; 

In an analysis of patients similar to the one we are discussing here [with a TPS of 1% to 49%], there was not a great difference between the arms. One could argue that the benefit of pembrolizumab may be like that of chemotherapy alone for patients with low PD-L1 expression, [so it is] probably not the best treatment. The [survival] curves do cross, suggesting that some patients may get sicker more quickly [when treated with] single-agent pembrolizumab vs chemotherapy.

For the patients in the KEYNOTE-189 study [NCT02578680], if you’re doing maintenance with pembrolizumab plus pemetrexed and somebody is having an AE, which [drug] ends up getting pulled off first?

It depends on the [AEs]. If it’s an immune [-related AE, I stop] the immuno-oncology agent [IO]. But usually [I need to stop] the chemotherapy [pemetrexed].15,16 I think I would stop the chemo before the IO unless it was an IO-related toxicity.

We’ve had patients [who have been] on pembrolizumab and other IOs for months or even years and who are doing incredibly well. When to stop, I think, is more difficult [to determine] than how long to [continue]. If the patient is doing well and is tolerating [the regimen], you keep going.

Some of the [regimens] that [have to be discontinued because of] toxicity tend to [still] add benefit for a while [after they have been discontinued] because the patient just had a better immune response. I do know of patients who had to be put on steroids and who continued on low-dose steroids but who then went back to the IO, and some of them are still doing well. Every person is individual.

I try to keep [patients on maintenance] until it works, basically, unless there are toxicities. I have a patient [with] squamous [disease] who has been [on] single-agent nivolumab for the past 3 to 4 years and is doing very well.

1. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 7.2021. Accessed November 3, 2021. https://bit.ly/3HjNx4f

2. FDA approves atezolizumab for first-line treatment of metastatic NSCLC with high PD-L1 expression. FDA. May 18, 2020. Accessed November 7, 2021. https://bit. ly/3CbRVhC

3. FDA approves atezolizumab with nab-paclitaxel and carboplatin for metastatic NSCLC without EGFR/ALK aberrations. FDA. Updated December 5, 2019. Accessed November 4, 2021. https://bit.ly/3c5C5KS

4. West H, McCleod M, Hussein M, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. 

. 2019;20(7):924-937. doi:10.1016/S1470-2045(19)30167-6

5. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%). FDA. May 15, 2020. Accessed November 8, 2021. https://bit.ly/30flYb6

6. FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC. FDA. Updated May 27, 2020. Accessed November 4, 2021. https:// bit.ly/3osxmZP

7. Reck M, Ciuleanu TE, Cobo Dols M, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. 

. 2020;38(suppl 15):9501. doi:10.1200/JCO.2020.38.15_suppl.9501

8. Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. 

2021;22(2):198-211. doi:10.1016/S1470-2045(20)30641-0

9. Socinski MA, Jotte RM, Cappuzzo F, et al; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. 

. 2018;378(24):2288-2301. doi:10.1056/NEJMoa1716948

10. Socinski MA, Jotte RM, Cappuzzo F, et al. Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) + chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. 

. 2018;36(suppl 15):9002. doi:10.1200/JCO.2018.36.15_suppl.9002

11. Lopes G, Wu YL, Kudaba I, et al. Pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: open-label, phase 3 KEYNOTE-042 study. 

. 2018;36(suppl 18):LBA4. doi:10.1200/JCO.2018.36.18_suppl.LBA4

12. Mok TSK, Wu YL, Kudaba I, et al; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. 

. 2019;393(10183):1819-1830. doi:10.1016/S0140-6736(18)32409-7

13. Akinboro O, Vallejo JJ, Mishra-Kalyani PS, et al. Outcomes of anti-PD-(L1) therapy in combination with chemotherapy versus immunotherapy (IO) alone for first-line (1L) treatment of advanced non-small cell lung cancer (NSCLC) with PD-L1 score 1-49%: FDA pooled analysis. 

14. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. 

. 2018;378(22):2093-2104. doi:10.1056/NEJMoa1801946

15. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. 

. 2018;378(22):2078-2092. doi:10.1056/NEJMoa1801005

16. Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated analysis from KEYNOTE- 189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non–small-cell lung cancer. 

. 2020;38(14):1505-1517. doi:10.1200/JCO.19.03136

Oncologists discuss a 59-year-old man with poorly differentiated adenocarcinoma of the lung.

Roundtable Discussion: Fidler Breaks Down the Steps for Targeted Treatments in Metastatic NSCLC

Ajai Chari, MD, associate professor Medicine, Hematology, and Medical Oncology, The Mount Sinai Hospital, discussed the case of a 51-year-old patient with multiple myeloma during a Targeted Oncology

Targeted OncologyTM: What are the data for using autologous stem cell transplant (ASCT) in patients such as this?

Some brief data from the IFM/DFCI2009 study [NCT01191060] that had VRd [lenalidomide (Revlimid), bortezomib (Velcade), dexamethasone] for 3 cycles, after which they got ASCT in the consolidation phase or got more VRd, then lenalidomide maintenance for a year. These are the French data. In the United States [DFCI (Dana-Farber Cancer Institute)] version, the lenalidomide is given until progression of disease [PD].

[After 44 months of follow-up], the control arm without ASCT had a 36-month median PFS [progression-free survival] vs 50 months for the ASCT arm, so an extra 14 months. After 90 months of follow-up, the PFS didn’t change much, and the OS [overall survival] rate is not different [either], at 60.2% without ASCT vs 62.2% with ASCT.

 This is important because people make their decisions based on OS.

I would say that, although we always look for OS end points, our outcomes in myeloma are getting so good. If you’re going to wait for an OS end point to make treatment decisions, you’ll be waiting a long time because this was with a long follow-up of 90 months.

In 90 months, there wasn’t an OS difference, despite a significant PFS difference, which speaks to the impact of salvaged therapies. Although we can risk stratify multiple myeloma, there are high-risk patients who relapse and might be able to demonstrate OS outcomes, but not for the typical patients with multiple myeloma. The FDA routinely accepts PFS as a surrogate end point, particularly for less heavily treated patients and those with newly diagnosed multiple myeloma [NDMM], because of the prohibitive duration of follow-up. Sometimes people talk about molecular data and whether somebody should get a particular treatment. In the IFM/DFCI2009 study, relative to the hazard ratio, ASCT was better in all patients. Although [there was] a wide confidence [interval in those with high-risk cytogenetics], which is not surprising because they had [only approximately] 40 patients.

I don’t think ASCT harms patients. But [to know] whether it overcomes patients, you need well-designed prospective studies with an adequate number of patients.

There’s a lot of debate about the use of MRD [minimal residual disease] status, especially coming from chronic myeloid leukemia, where you have these deep molecular remissions, and you may think this is really practice-changing. The ASCT arm always does better than the arm without ASCT.

Whether you’re looking at standard-risk or high-risk [cytogenetics] based on transplant, standard-risk seems to do better.

What do you consider the standard-of-care regimen for induction?

In speaking to the potential utility of MRD, the FORTE study [NCT02203643] from the Italian group is a very important study. They used a 1:1:1 randomization. There were several questions being asked, [such as] what the best induction regimen was. It was 4 cycles of KCd [carfilzomib (Kyprolis), cyclophosphamide, dexamethasone] for 1 arm vs 4 cycles of KRd [carfilzomib, lenalidomide, dexamethasone] for 2 arms.

All 3 arms got mobilized, 2 arms got ASCT, and 1 KRd arm did not get ASCT, but went on with 8 more KRd cycles. The dosing of carfilzomib is 36 mg/m

 twice weekly. Keep that in mind because many of you [probably] do weekly chemotherapy, but here it is twice weekly for an entire year. That’s a pretty dose-intensive regimen, and we need to think how many patients, physicians, and nurses would adhere to a year of chemotherapy twice weekly. The other 2 arms received ASCT followed by KCd or KRd consolidation, and the second 1:1 randomization was to either KR or R alone maintenance.

Francesca Gay, MD, PhD, presented some updated [data at the American Society of Hematology 2020 meeting and later published in 

 Interestingly, after a 1-year follow-up, there was no big difference between the ASCT and the non–ASCT arms. This is one of the limitations of MRD because it is a surrogate, but OS and PFS can also be difficult, and MRD doesn’t preclude you from needing to follow up patients with these survival-based end points that are being used as surrogates.

Based on median PFS, the winner—by far—is the KRd plus ASCT, then the arm with 12 cycles of KRd [KRd12], then KCd plus ASCT. KRd12 without ASCT did better than KCd.

 This is an important take-home message because it confirms the older IFM2013-04 study [NCT01971658] that VTd [bortezomib, thalidomide (Thalomid), dexamethasone] was superior to VCd [bortezomib, cyclophosphamide, dexamethasone] by efficacy. It seems a better partner for a PI [proteasome inhibitor] is [an immunomodulatory drug (IMiD)], whether in Europe you use thalidomide [or] in the United States you use lenalidomide.

It seems like the IMiD plus PI combination is better. I still think there may be slight exceptions for somebody who is admitted in the hospital with renal failure or cord compression, and you need to start treatment immediately. You may have some issues with getting [an IMiD]. In the real world, just because you start somebody on a [cyclophosphamide]-based regimen, doesn’t mean with the next cycle you couldn’t switch, but in the European policy, they’re pretty much locked into it.

[The] first message is [that] the KRd is superior. The second message is [that], although MRD [initially] suggested relatively comparable results—with the notable exception that even early on there would seem to be a benefit for high-risk patients going to transplant— with a longer 45-month follow-up, ASCT with KRd did the best and was statistically significantly better than the non–ASCT group.

Pretty much everybody benefited from ASCT, so KRd with ASCT is favored, and the HRs are well below 1 [across the board], with a few crossing the 1 threshold because, again, smaller numbers. The message here is [that] if KRd 36 mg/m

 twice weekly for an entire year did not beat ASCT, then that gives us pause as to the utility of MRD as a surrogate for decision-making and the importance of how you get to a particular remission.

Now we have both the French data for VRd with ASCT with a 90-month follow-up and KRd with a 45-month follow-up, and both studies show that, even in 2021, ASCT has not gone away. If you want to displace ASCT, I argue that you need to show that novel regimens are doing better than it. Not only have we not seen that they’re not doing better but they are also not keeping up with it, so we still have work to do. We’ll see what the newer regimens are, but we should still be considering ASCT, [especially] for patients below age 70.

One of the tricky parts is, for patients over age 70 or 75, you need to reduce the melphalan [Alkeran] dose typically to condition for the ASCT. Then you are in a [murkier] situation.

The second randomization was the KR vs R, and the KR [seemingly] did better across all subgroups, showing the utility of doublet maintenance therapy.

The carfilzomib dosing for the maintenance is 36 mg/m2 on day 1, 2, 15, and 16. So it’s still 4 visits per month, which is a big ask, but it is an option for patients.

Can you discuss trials looking at quadruplet therapy?

In the CASSIOPEIA study [NCT02541383], everybody was transplant eligible. All patients received 4 cycles of VTd or VTd plus daratumumab [Darzalex; D-VTd], stem cell collection, ASCT, then 2 cycles of consolidation with VTd or D-VTd.

There was an important difference in the United States version of this study. In the CASSIOPEIA study, there’s a possibility a patient could get daratumumab up front in induction and consolidation but not get it in maintenance. In the United States version, it is daratumumab throughout, and there is no double randomization. Another difference is, in this study, the daratumumab maintenance started off every 8 weeks. That’s important because we now have pharmacokinetic data, and we all know daratumumab is a monoclonal antibody, but the trough level is quite below where we think efficacy is maintained. In the United States study, daratumumab also started off at 8 weeks, then it was modified to go to monthly for every-4-week dosing of maintenance. Those are the 2 major differences other than [lenalidomide use in the United States one].

The CASSIOPEIA study was a large study with 1000 patients that had 2-part end points. One randomization before induction, and [the second randomization before maintenance].

What was the efficacy in the CASSIOPEIA trial?

The [first] primary end point was stringent complete response [sCR], and that was favorable. It was 29% for the quadruplet arm vs 20% for the triplet arm, which was statistically significant [

MRD negativity status was 64% in the quadruplet arm vs 44% in the triplet arm, which was also statistically significant [

< .0001]. The take-home message is [that] we currently have deeper responses with the addition of daratumumab. Everybody seemed to benefit in [the subgroup analysis], except the high-risk patients.

In the high-risk population, there was a difference between improving, overcoming, and hurting. The addition of daratumumab didn’t overcome high-risk, but it also did not hurt those patients. The high-risk group remains an unmet need, and we still need to do better. With continuing therapy, both arms have a deepening of response, but the quadruplet arm always seems to do better.

Whether you look at MRD using next-generation flow cytometry or next-generation sequencing, D-VTd did better than the VTd.

Perhaps the most important thing from this study is the Kaplan-Meier curve after a 2-year follow- up. There was already a median PFS separation favoring the quadruplet over the triplet therapy [HR, 0.47; 95% CI, 0.33-0.67; 

< .0001]. That’s an important message because it is not just sCR and MRD that are the primary end points, but it translates into PFS benefit, which, barring OS, is the most important end point.

The 2021 American Society of Clinical Oncology meeting had an update about the second randomization in all-comers.

 As you might suspect, many people would criticize that the control arm was observation, and if it is already established that lenalidomide is a better maintenance than placebo, then why are we doing this? Keep in mind that, when studies are designed, there’s always a lag in what we learn. In this study, the observation arm was the control. [At a median follow-up of 35.4 months, median PFS was not reached with daratumumab and was 46.7 months with observation [HR, 0.53; 95% CI, 0.42-0.68; 

< .0001], so almost a 50% reduction in the risk of PD or death with the addition of daratumumab on maintenance.

This was consistent across most subgroups. However, one notable exception is that this only appeared in the patients who got VTd in induction and consolidation. If you got daratumumab up front, there didn’t seem to be any benefit of getting it as maintenance again [HR, 1.02; 95% CI, 0.71-1.47], but if you got only VTd, there was a benefit [HR, 0.32; 95% CI, 0.23-0.46].

The message here is, if you didn’t get daratumumab up front, it’s a good maintenance, but it doesn’t answer the question of how it compares with lenalidomide maintenance. The second [unanswered] question is: If you had been giving daratumumab as intended, which is every 4 weeks, how it might have worked for those who had it up front?

What was the version of the quadruplet regimen investigated in the United States?

The United States randomized phase 2 trial, the GRIFFIN study [NCT02874742], had transplant-eligible patients with NDMM. [Randomization was 1:1 with 4 cycles of] VRd, ASCT, VRd consolidation, then R maintenance in the control arm and [4 cycles of D-VRd, ASCT, D-VRd consolidation, and DR maintenance] in the experimental arm. There’s no double randomization. [Initially], the daratumumab [maintenance] was every 8 weeks, but then it moved to every 4 weeks.

Another consideration that was different from the European version was that they used [cyclophosphamide] for mobilization, whereas they used granulocyte colony-stimulating factor [in the GRIFFIN study]. If that failed to get adequate cells, they could go back and use cyclophosphamide, but it was not permitted as a mobilization strategy from the get-go. The median age in the GRIFFIN study was 60, ISS III [was approximately] 13%, and high-risk was 15%, which was comparable with the CASSIOPEIA study. [The issue in the United States] randomized studies is adherence. In the D-VRd arm, 90% of those patients got ASCT, whereas [only 76% did] in the VRd arm.

If you did an intention-to-treat analysis vs actual treatment, you might get different results. The primary end point of sCR after consolidation was statistically significant at 63.8% in D-VRd vs 47.4% in VRd [

= .0253] and CR or better was [approximately] 82% vs 61% [

= .0014]. This is after the induction, ASCT, and consolidation. There is a deepening of responses in both but, again, the depth is maintained with the addition of daratumumab.

[In the subgroup analyses] for sCR, most are in favor of D-VRd, with the exceptions of ISS III and high risk. But again, the sample sizes for them were exceedingly small. Remember this is a randomized phase 2 study with much fewer patients than CASSIOPEIA. ISS III only had [approximately] 13 patients in each arm, and the same for high risk, so you have a wide confidence interval.

For MRD negativity status, everything is favoring D-VRd, too. In the ISS III [subgroup], you have more MRD negativity [favoring D-VRd], and in the high-risk [subgroup, too], but it also still has a wider confidence interval. Overall, MRD negativity was 62.5% for the quadruplet therapy vs 27.2% [for the triplet therapy].

OS is not surprising. The VRd arm is a great regimen. Many of you are using that and have been using that for the past decade for good reason. If you were an early adopter of VRd, you were doing that based on a single-arm, phase 2 study with [approximately] 60 patients. The randomized studies did not report until maybe a few years ago.

We don’t have long enough data, and I’m not surprised we’re not seeing OS difference with a great triplet regimen to begin with. For PFS, there seems to be a potential separation, but it’s premature to say anything. There were very few patients in that follow-up. There are [approximately] 7 patients who are still relapse free vs the VRd. We clearly need more follow-up. We saw from the FORTE [study], and all those other studies, that you need more follow-up to see if these translate. If you believe in MRD, then there [was favoring of the quadruplet therapy] pretty much across all subgroups.

[For me,] the one use of MRD is as a surrogate when PFS is prohibitively long. My crystal ball would say that if the MRD negativity is deeper with the addition of daratumumab [across the board], this should pan out through PFS benefit with more time.

How did adverse events (AEs) affect the patients on the GRIFFIN trial?

For safety, we know daratumumab and isatuximab [Sarclisa] targets CD38, which is expressed on myeloid precursor cells. So we do see neutropenia of all grades at 58% for D-VRd vs 35% for VRd, and grade 3 and higher [neutropenia] is 41% vs 21%. Thrombocytopenia is also higher in D-VRd.

 A lot of the [numbers on] AE tables— which I find challenging—are always absolute and never adjusted for time on therapy. Although it’s less of an issue here because the follow-up is relatively short.

[Of course,] the question is [whether] the cytopenia translated into any significant clinical problems. From an infection point of view, upper respiratory tract infection [URTI] of grades 3 and 4 are not high grade, so those were not different. All grades of URTI were 63% for D-VRd vs 44% for VRd.

Of course, subcutaneous daratumumab has very little infusion-related reactions. It started off with IV [intravenous], and later in the study during maintenance, we were allowed to switch. Initially, all grades of infusion reactions were 42% because it was IV. Typically, with subcutaneous daratumumab, we’re getting around 10% for all grades and very few for grade 3 and 4.

What are your thoughts on the trials you have mentioned overall?

The IFM/DFCI2009 study and the CASSIOPEIA were phase 3, and the others were phase 2. Median follow-ups were remarkably different for all, and for the CASSIOPEIA and GRIFFIN [studies], they were relatively short.

One of the most important things we don’t talk about enough is how much chemotherapy was given. For the IFM/DFCI2009 study, it was about 4 cycles of induction to post consolidation. The control arm VRd had a total of 6 cycles lasting [approximately] 6 months. The FORTE study had 8 and 12, CASSIOPEIA [had] 6, and GRIFFIN [had] 4.5.

All studies, apart from the GRIFFIN study, use cyclophosphamide mobilization. Because the end points are very different, if you look at post consolidation very good partial response, usually the experimental arm does better. It was 78% vs 69% [in the IFM/DFCI2009 study], but the FORTE [study was] quite comparable at 89% vs 87%. In CASSIOPEIA, it was 83% vs 78%, and in the GRIFFIN study, it was highest at 91% vs 73%.

For the PFS differences, the data are not mature enough. But all 3 studies, apart from the GRIFFIN study, show an improvement. VRd plus ASCT was superior by PFS. KRd plus ASCT was superior. D-VTd was superior as well.

Attal M, Lauwers-Cances V, Hulin C, et al; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myelom

ed. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750

Perrot A, Lauwers-Cances V, Cazaubiel T, et al. Early versus late autologous stem cell transplant in newly diagnosed multiple myeloma: long-term follow-up analysis of the IFM 2009 Trial. 

. 2020;136(suppl 1):39. doi:10.1182/blood-2020-134538

Gay F, Cerrato C, Petrucci MT, et al. Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: results from the FORTE trial. 

. 2019;37(suppl 15):8002. doi:10.1200/JCO.2019.37.15_suppl.8002

Gay F, Musto P, Scalabrini DR, et al. Survival analysis of newly diagnosed transplant-eligible multiple myeloma patients in the randomized Forte trial. 

 2020;136(suppl 1):35-37. doi:10.1182/blood-2020-136907

Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. 

. 2019;394(10192):29-38. doi:10.1016/S0140-6736(19)31240-1

Moreau P, Hulin C, Perrot A, et al. Daratumumab maintenance or observation after treatment with bortezomib, thalidomide, and dexamethasone ± daratumumab and autologous stem cell transplant in patients with newly diagnosed multiple myeloma: CASSIOPEIA Part 2. 

2021;39(suppl 15):8004. doi:10.1200/JCO.2021.39.15_suppl.8004

Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. 

. 2020;136(8):936-945. doi:10.1182/blood.2020005288

Kaufman JL, Laubach JP, Sborov D, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of Griffin after 12 months of maintenance therapy. 

 2020;136 (suppl 1):45-46. doi:10.1182/blood-2020-137109

The case of a 51-year-old with multiple myeloma, standard risk, stage II was the topic of discussion during a recent Targeted Oncology Case-Based Roundtable moderated by Ajai Chari, MD.

Chari Discusses Prominent Trials For Newly Diagnosed Multiple Myeloma

Robert and Margarita Louis-Dreyfus professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research, 

Hospital of the University of Pennsylvania, led a discussion about a 75-year-old patient with diffuse large B-cell lymphoma. 

: Outside of a clinical trial, what treatment options are there for this patient?

If you’re going to use chimeric antigen receptor [CAR] T-cell therapy, you have to have a strategy, because until we have data from a randomized trial you won’t to be able to get coverage for this therapy, which is expensive. Low-intensity chemotherapy is not unreasonable, particularly if it’s a bridge to CAR T-cell therapy. I don’t think that high-intensity chemotherapy is a great option. [Regarding] patients in the rituximab era that relapsed at this time, even the data from the CORAL trial [NCT00137995] showed only about 20% of them are long-term survivors.

The National Comprehensive Cancer Network [NCCN] guidelines [for second-line and subsequent therapies in transplant-ineligible patients]

 include [a regimen] approved by the FDA, polatuzumab vedotin [Polivy] and bendamustine, to be used after 2 or more prior regimens.

 [Regimens listed as] “useful in certain circumstances” include lenalidomide [Revlimid] with or without rituximab and ibrutinib [Imbruvica], which has about a 30% to 40% chance of response in the activated B-cell type [disease].

 [Of all the regimens listed], the only 1 that is approved for patients who have received 1 line of therapy [and are ineligible for transplant] is tafasitamab-cxix [Monjuvi] plus lenalidomide,

Following 6 well-tolerated cycles of R-CHOP, a 75-year-old patient with diffuse large B-cell lymphoma showed complete remission on a PET scan. But 1 year later, the disease relapsed.

Targeted Oncology Staff | Authors

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