For Multiple Myeloma, Choosing Optimal Therapy in Second, Later Settings Challenges Clinical Decision-Making

Krina K. Patel, MD, MSc

With new and previously available agents and combinations, selecting the optimal sequence of therapies for patients with early relapsed multiple myeloma is daunting. Decision-making for the second to fourth lines of therapy can depend on many factors, and clinicians still face unanswered questions, according to Krina K. Patel, MD, MSc.

At the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022), Patel—center medical director and associate professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston—discussed recent developments affecting our understanding of sequencing agents in patients with early relapsed multiple myeloma during an interview with The SOHO Daily News before the conference. Patel is addressing these challenges during the Meet the Professor session at 6:45 am on September 28, 2022.

“There [are] over 25 different [regimens] that are mentioned in the NCCN [National Comprehensive Cancer Network] guidelines—which is great that we have all these options, but how do you decide which is the best one for your patient?” Patel said. Her presentation highlights the current landscape of regimens for early relapsed multiple myeloma, which she says includes 11 regimens preferred by the NCCN guidelines and another 15 recommended regimens (Table).¹ Among these options, the treating physician’s choice may vary widely. Patient outcomes, adverse events (AEs) associated with previous regimens, comorbidities, and patient goals can influence choice of treatment in the second, third, and fourth lines of therapy.

Many treatment options are better for frail patients vs others that are better tolerated by those who are more fit; age is not necessarily the key factor in determining what patients can tolerate. “We want to use our best regimens up front and not try to save anything for the end,” Patel said, “because…patients do much better when they get the best regimens earlier.”

Another key question is which therapies and combinations are the top treatments for most patients and which sometimes need to be avoided. For example, Patel notes that physicians may want to avoid the use of alkylating agents prior to chimeric antigen receptor (CAR) T-cell therapy because evidence suggests that alkylators can decrease their efficacy.²

The introduction of anti-CD38 monoclonal antibodies such as daratumumab (Darzalex) and isatuximab (Sarclisa) have influenced the front line and later lines of therapy. Patel says most patients now receive an anti-CD38 in the front or second lines, but patients who have not should get it in the second or third lines. Now that patients are receiving quadruplet regimens including an anti-CD38 antibody, and even patients who are frail and transplant ineligible receive CD38-based regimens, there are new questions on what to do when they relapse. Patel says new options for patients who are refractory to CD38-based therapy are a key area of development in patient treatment.

B-Cell Maturation Antigen

B-cell maturation antigen (BCMA) is a target that has a growing number of therapies with multiple mechanisms of action, Patel says. Data from clinical trials have supported the use of BCMA-targeted CAR T-cell therapies and bispecific T-cell engagers. The phase 3 KarMMa-3 trial (NCT03651128), the first randomized clinical trial of a CAR T-cell therapy in multiple myeloma, recently reported positive interim results for idecabtagene vicleucel (ide-cel; Abecma) vs standard-of-care regimens.3 The CARTITUDE-1 (NCT03548207) trial of ciltacabtagene autoleucel (cilta-cel; Carvykti) led to a second CAR T product being approved for multiple myeloma after showing strong efficacy in later lines of therapy. Accessing these therapies in earlier lines is vital. “When patients are relapsed/refractory, it’s much harder to make T cells and get them through, [whereas] we know that when you do it earlier, it’s probably going to be a lot easier,” said Patel.

The first bispecific T-cell engager for multiple myeloma, teclistamab, has been submitted for FDA approval, and Patel anticipates further data supporting the use of bispecifics in patients with early relapse. The BCMA-targeted antibody-drug conjugate belantamab mafodotin (Blenrep), currently used as monotherapy, has also reported data from combination therapies in the first 3 lines of therapy. There remains an important question of whether BCMA-targeted therapies can be sequenced after one another; a retrospective study of patients who received bispecific antibodies following BCMA-targeted CAR T-cell therapy showed potential for durable responses.⁴

According to Patel, managing and sequencing these new therapies with all the others currently available is a major challenge. More research on antigens and biomarkers could shape sequencing of patients in the early relapsed setting. Venetoclax (Venclexta) has shown promising efficacy for patients with a translocation 11;14, and she anticipates that more molecular-targeted treatments could affect this field.⁵ “Finding a way to, hopefully, use a biomarker in clinic will help us in the future. But I do think we’re still far away from that.”

Even with the introduction of new agents, there are still critical unmet needs in this setting due to clinical trials lacking coverage of certain patients. Most trials do not allow patients with kidney failure, and data on the efficacy of new therapies are also limited when it comes to patients with very aggressive disease and those with central nervous system disease. Patel says clinical trials in this setting tend to lack representation of Black and Hispanic patients. “We really need to make sure that they are getting appropriate access to care.”

Another key concept Patel feels is critical to discuss in her presentation is supportive care. “We have all these amazing therapies, but each has different potential risks,” she says. Multiple myeloma treatment regimens have different AE profiles compared with chemotherapy, but they include risks of serious AEs such as clotting, deep vein thrombosis, pulmonary embolism, and infection due to hypogammaglobulinemia, as well as negative interactions with vaccines during treatment.

Patel is looking forward to giving her presentation in person this year. “I’m in Houston, and SOHO is in Houston. But I don’t get to see my colleagues, even within my own department, but [also] all our other leukemia and lymphoma and transplant colleagues, very often anymore. I think everyone’s really excited about finally being able to see each other and talk in person.”

Table. Preferred Regimens in Early-Relapse Multiple Myeloma (1-3 Prior Therapies)¹

REFERENCES:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 5.2022. Accessed August 15, 2022. https://bit.ly/2T0mDYS}

_{2. Rytlewski J, Madduri D, Fuller J, et al. Effects of prior alkylating therapies on preinfusion patient characteristics and starting material for CAR T cell product manufacturing in late-line multiple myeloma. Blood. 2020;136(suppl_1):7-8. doi:10.1182/blood-2020-134369}

_{3. Bristol Myers Squibb and 2seventy bio announce topline results from KarMMa-3 trial showing Abecma (idecabtagene vicleucel) significantly improves progression-free survival versus standard regimens in relapsed and refractory multiple myeloma. News release. Bristol Myers Squibb. August 10, 2022. Accessed August 16, 2022. https://bit.ly/3C7bR95}