Part 2: Shah Discusses Challenges in Using Lenalidomide Plus Tafasitamab for Patients With DLBCL


Looking at the combination of lenalidomide plus tafasitamab for patients with diffuse large B-cell lymphoma shows promise for patients' treatment, but challenges remain that clinicians need to address.


Bijal Shah, MD, MS

Associate Member

Department of Malignant Hematology

Moffitt Cancer Center

Tampa, FL

During a live virtual event with other physicians, Bijal Shah, MD, MS, reviewed the efficacy and data for the combination of tafasitamab (Monjuvi) and lenalidomide (Revlimid) for patients with diffuse large B-cell lymphoma (DLBCL), Targeted OncologyTM had the chance to ask Shah about his rational surrounding this drug for patients who were relapsed or refectory to this disease.

Targeted OncologyTM: Can you discuss the combination of tafasitamab (Monjuvi) and lenalidomide (Revlimid)?

Tafasitamab was granted FDA approval in July 2020 based on data from the L-MIND trial [NCT02399085].1 L-MIND studied tafasitamab in combination with lenalidomide at 25 mg given orally on days 1 through 21 of a 28-day cycle.

Lenalidomide has been with us for a long time. When I was a resident, I remember doing a presentation on transplant-ineligible multiple myeloma, and this new crazy drug derived from thalidomide—lenalidomide—was showing activity in this space. Lenalidomide has a lot of mechanisms of action, and, honestly, I don’t think we even know them all. We know that [lenalidomide is associated with] T-cell and natural killer cell activation and expansion, which seems to be dependent on Ikaros and Aiolos transcription factors, and that same mechanism seems [to bring about] cell killing.2

We talk a lot about lenalidomide modulation of cereblon, [and how it affects treatment outcomes] in multiple myeloma, but in DLBCL it's less clear what else is driving that cytotoxicity signature. Certainly, lenalidomide [works as an E3 ubiquitin ligase inhibitor], affecting other proteins through the Ikaros and Aiolos ubiquitination system that drives degradation of [various] proteins and possibly cell death. This mechanism of degradation is important. [For example,] degraders targeting Bruton tyrosine kinase [BTK] or other cell signaling proteins use the same molecular system that we identified with lenalidomide.3

How does lenalidomide work for this patient population?

Lenalidomide induces T natural killer cell [expansion]. The question is whether we can use a monoclonal antibody to direct those T cells and natural killer cells, which is exactly what tafasitamab is [designed to] do. Tafasitamab is going to have antibody-dependent cellular cytotoxicity as well as antibody-dependent cellular phagocytosis, which are similar [mechanisms of action as in] daratumumab [Darzalex]. Tafasitamab may, in some cases, cause direct cell death through those mechanisms and will be synergistic with lenalidomide.2

In the phase 2 L-MIND trial, tafasitamab was given at 12 mg/kg weekly for three [28-day cycles] and then continued biweekly [for 9 cycles]. Lenalidomide was given at 25 mg/kg daily on days 1 through 21 [of all 12 cycles]. All patients included in the trial had had 1 to 3 prior regimens and were not eligible for transplant.4

I’ve given a lot of lenalidomide. I participated in the New England Journal of Medicine study [that evaluated] lenalidomide for mantle cell lymphoma.5 Lenalidomide is a great drug, but it's also not always an easy drug to deliver because of the AEs associated with it, such as cytopenias, rash, and gastrointestinal effects. [Nevertheless], I‘ve found that across lymphomas, including chronic lymphocytic leukemia, if the dose is above 10 mg/kg, [patients benefit]. Of course, if the patient has renal disease, the dose should be reduced to a bioequivalent dose of 10 mg/kg. The 10-mg dose seems to be the magic threshold for lenalidomide activity, and that’s what I try to keep my patients above.

What was the efficacy for patients in the L-MIND trial?

Patients enrolled in L-MIND were older patients [with a mean age of 72 years old]. A little more than half of them had an elevated LDH, [approximately] 20% of patients had primary refractory disease, and 44% [of patients had disease that was] refractory to last prior therapy. In total, 11% of patients had had a stem cell transplant, and the cell of origin was non-GCB or other in almost 90% of patients.4

At a median follow-up of at least 35 months, 40% of patients achieved a CR with lenalidomide/tafasitamab, and [an additional] 17% had PRs. The median DOR with extended follow-up was 43.9 months.2,6-8

Among patients who had a CR to the combination, PFS was quite long [median PFS, not reached], which is very reassuring. [However], as we saw with loncastuximab monotherapy in the LOTUS-2 trial, patients who had a PR [had a short duration of] response. For patients with a PR to lenalidomide/tafasitamab, the median PFS was 7.4 months. The median OS for patients who had a CR was fantastic [median OS, not reached], but for patients who didn’t, it was shorter [median OS, 22.5 months]. For patients with stable disease, progressive disease, or disease that was non evaluable, [OS was approximately] 10 months, and for patients with a PR, the OS was 22 months.2,6,7

What adverse events [AEs] should be noted with lenalidomide?

As I mentioned before, lenalidomide is not always an easy drug to give. In L-MIND, the most common nonhematological AEs included fatigue, diarrhea, cough, [peripheral] edema, and respiratory tract infections.2 In my experience, the infections associated with lenalidomide have largely been mild. Some patients on lenalidomide develop hypogammaglobulinemia and some [may develop] sinonasal, upper respiratory, and lower respiratory infections. This is something [clinicians should] be aware of when using lenalidomide. I want to make sure to mention thrombosis; it's rare in patients with lymphoma, but it can happen. [To reduce the risk of thrombosis], I give my patients baby aspirin when I put them on lenalidomide therapy.

Serious AEs occurred in 50% [of patients in L-MIND], of which a little fewer than half were thought to be treatment-related. [Some treatment-related AEs] culminated in treatment discontinuations. Approximately half of the patients had to have at least 1 dose reduction, but [77% of patients] were able to receive lenalidomide at 20 mg/kg or higher for the duration of treatment.

How does the combination of tafasitamab (Monjuvi) and lenalidomide (Revlimid)compare with lenalidomide alone?

The RE-MIND study [NCT04150328] evaluated this question by conducting a propensity score-based, matched comparison of patients using real-world data. [Results of RE-MIND] showed that tafasitamab adds a considerable benefit to lenalidomide-based therapy, leading to [a dramatic] increase in the complete response [CR] rate from 13% to 39% [and an increase in the PR rate] from 21% to 27%.9 These increases were significant, and we can anticipate the addition of tafasitamab to lenalidomide.

What I would have loved to [have seen] and what wasn’t evaluated in this analysis was the effect of adding rituximab to lenalidomide in patients with relapsed/refractory diffuse large B-cell lymphoma [R/R DLBC]. It also would have been interesting to see the effects of lenalidomide plus other monoclonals, such as obinutuzumab [Gazyva], ublituximab, ofatumumab [Arzerra], [or other] monoclonals targeting CD20 that are in the pipeline.

We know that lenalidomide activates T cells, but without a monoclonal drug such as rituximab or obinutuzumab to direct them [to the tumor cells], the impact of lenalidomide isn’t being optimized.


1. FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. FDA. Updated August 3, 2020. Accessed June 6, 2021.

2. Salles G, Duell J, González Barca E, et al. Primary analysis results of the single-arm phase II study of MOR208 plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (L-MIND). Presented at: 15th International Conference on Malignant Lymphoma; June 18-22, 2019; Lugano, Switzerland.

3. Dobrovolsky D, Wang ES, Morrow S, et al. Bruton tyrosine kinase degradation as a therapeutic strategy for cancer. Blood. 2019;133(9):952-961. doi:10.1182/blood-2018-07-862953

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

5. Ruan J, Martin P, Shah B, et al. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015;373(19):1835-1844. doi:10.1056/NEJMoa1505237

6. Duell J, Maddocks KJ, González-Barca E, et al. Long-term outcomes from the phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Haematologica. 2021;106(9):2417-2426. doi:10.3324/haematol.2020.275958

7. Düll J, Maddocks KJ, Gonzalez-Barca E, et al. Long-term analyses from L-MIND, a phase II study of tafasitamab (MOR208) combined with lenalidomide (LEN) in patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL). J Clin Oncol. 2021;39(suppl 5):7513. doi:10.1200/JCO.2021.39.15_suppl.7513

8. Salles G, Duell J, González Barca E, et al. Long-term outcomes from the phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Haematologica. 2021;106(9):2417-2426. doi:10.3324/haematol.2020.275958

9. Nowakowski GS, Rodgers RD, Marino D, et al. RE-MIND study: a propensity score-based 1:1 matched comparison of tafasitamab + lenalidomide (L-MIND) versus lenalidomide monotherapy (real-world data) in transplant-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). J Clin Oncol. 2020;38(suppl 15):8020. doi:10.1200/JCO.2020.38.15_suppl.8020

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