Update on the Treatment of Heavily Pretreated, Relapsed Refractory Multiple Myeloma

Multiple myeloma is the second most common hematologic malignancy in the United States, accounting for approximately 17% of all blood cancers.¹ It is characterized by unchecked production of monoclonal plasma cells in the bone marrow, leading to high levels of dysfunctional (monoclonal) immunoglobulins in the blood and urine.^2,3 According to recent estimates, more than 32,000 individuals will be diagnosed with multiple myeloma in the United States in 2020.⁴ Therapeutic advances over the last decade have led to prolonged survival, but the prognosis remains poor and the disease is incurable.⁵ In an interview with Cancer Network, Cesar Rodriguez Valdes, MD, clinical assistant professor of Hematology and Oncology at Wake Forest University School of Medicine and a myeloma specialist at the Wake Forest Baptist Comprehensive Cancer Center in Winston-Salem, North Carolina, commented on the impact of new therapies for patients with multiple myeloma. “Historically, multiple myeloma has been a disease that is hard to treat,” he said. “Previously we had very few treatment options, which had a lot of [adverse] events (AEs) and little efficacy, so the overall survival [rate] of patients was pretty grim. On average, people could live up to 3 years with the treatments that we had about 15 years ago. Over the last 10 to 15 years, there has been a large number of drugs that have been approved for treatment in multiple myeloma that are very effective at controlling the disease and also have decreased AEs compared [with] the old treatments that we used for myeloma. This has translated into better responses and better control of the disease. Before, while patients would live on average up to 3 [additional] years, now the average is approximately 5 years based on SEER [Surveillance, Epidemiology, and End Results] data.⁶”

The course of multiple myeloma is heterogeneous, but relapse and disease progression are inexorable features of the disease for most patients.⁷ Multiple relapses are common, and lead to relapsed/refractory multiple myeloma (RRMM). Over the course of repeated relapses, resistant clones emerge that contribute to shorter periods of remission and reduced response (or resistance) to standard salvage therapies.^5,7,8 Patients with RRMM who have failed multiple prior therapies are becoming more common and more challenging to treat, according to Rodriguez, who described the challenge of treating this patient population: “In myeloma, we know that the disease tends to come back, and every time the disease comes back, it tends to be more aggressive and harder to treat. Each time we control this disease, the time we have it controlled tends to shrink as the disease comes back over and over again. We have patients currently who have had 4 relapses, 5 relapses, 6 relapses, or [who] have had many different lines of therapy to try to control the disease. Whenever we deal with [someone] who has heavily pretreated myeloma or who has undergone multiple lines of therapy—more than 4 prior lines of therapy—then we are dealing with a unique situation where we are starting to run out of the drugs that we normally [use] to treat multiple myeloma.”

The general approach to treating RRMM is to use doublet or triplet regimens that include some combination of a proteasome inhibitor (PI) (eg, bortezomib, carfilzomib, ixazomib), an immunomodulatory drug (IMiD) (eg, lenalidomide, pomalidomide),and a monoclonal antibody (mAb) (eg, daratumumab, elotuzumab), usually on a dexamethasone backbone, and autologous stem-cell transplantation in eligible patients.1 Other treatment approaches, such as CAR-T cell therapy, are in development. Within the last several years, the treatment paradigm for RRMM has changed to one in which patients can be treated at each relapse phase, resulting in prolonged survival.⁸

Selinexor is specifically indicated for patients with heavily pretreated disease. Selinexor is indicated in combination with dexamethasone in adult patients with RRMM who have received at least 4 prior therapies and whose disease is refractory to at least 2 PIs, at least 2 IMiDs, and an anti-CD38 mAb.^1,9 It has a novel mechanism of action in that it selectively inhibits nuclear transport of tumor suppressor proteins, glucocorticoid receptors and oncoprotein mRNAs by exportin 1 (XPO1). XPO1 overexpression in myeloma cells is associated with poor prognosis (ie, shorter overall survival).¹⁰ Rodriguez explained that clinical trials have shown favorable results with selinexor as part of a combination regimen in patients who have received 4 or 5 prior therapies.¹⁰ “[In the STORM trial,] selinexor in combination with dexamethasone had an overall response rate of approximately 26%.¹⁰ Even though this number seems to be low, we need to keep in mind that these are patients who have been heavily pretreated and who are refractory or who have been exposed to the most common agents that we normally use for multiple myeloma. (These include bortezomib or carfilzomib, lenalidomide, pomalidomide and daratumumab.) [Therefore,] seeing a response such as this in [a patient] who has had this [high] amount of therapy in the past is actually a very promising thing. When we combine it with other agents, we are seeing preliminary data that actually increase this response rate up to 60% or higher.”¹¹

Novel Treatment Targets for RRMM

There have been ongoing efforts to identify novel treatment targets for RRMM, with the goal of developing more effective therapies with fewer AEs. A novel target that has recently been the subject of considerable attention is the multiple myeloma cell-surface receptor B-cell maturation antigen (BCMA).¹² BCMA is preferentially expressed on multiple myeloma cells, and is important to the long-term survival of plasma cells in the bone marrow and can affect disease progression.5 The level of BCMA expression has been shown to remain stable across the different stages of the disease, from diagnosis through relapse, underscoring its potential as a treatment target.^2,5 Rodriguez discussed the potential of BCMA as a treatment target. “The unique thing about BCMA is that it is highly expressed in myeloma cells, and it is seen in other B-cells; [however,] it is rarely seen in other types of cells [in the body],” he said. “If we identify a therapy that is effective at killing the cells that have the surface antigen, we can reduce the toxicity and zone in on the cells that we want: the myeloma cells. BCMA is a protein that helps modulate B-cell proliferation. It can activate the cells and promote B-cell survival. Whenever you have a myeloma cell that is overexpressing BCMA, this confers to the myeloma cell advantage of survival, proliferation, and activation. If we find a therapy that can actually neutralize that, then we can have better control at the proliferation and the control of the cell survival of that cell. BCMA has been studied as a target in mAB therapy, antibody-drug conjugate therapy, and CAR T-cell therapy. There are many options that we can use in terms of immunotherapy [that] can focus on BCMA as a target so that we can reduce toxicities and AEs.”

The BCMA-directed antibody and microtubule inhibitor conjugate, belantamab mafodotin, was granted accelerated approval by the FDA in August 2020 for the treatment of patients with RRMM who have received at least 4 prior therapies, including an anti-CD38 mAb, a PI, and an IMiD.13 Belantamab mafodotin is a first-in-class afucosylated, humanized immunoglobulin G1 anti-BCMA mAb linked with a tubulin polymerization inhibitor, monomethyl auristatin F.^5,12 Upon binding to the BCMA cell surface receptors, belantamab mafodotin leads to multiple myeloma cell death through multiple mechanisms, including apoptosis, cytotoxicity, cellular phagocytosis, and immunogenic cell death.¹² According to Rodriguez, there are some definite advantages to targeting BCMA with an antibody-drug conjugate. “Using an antibody-drug conjugate gives us many benefits in addition to just the mAb,” he said. “The monoclonal antibody part is going to help identify the myeloma cell and it is going to help inhibit the BCMA that is in that myeloma cell that helps with proliferation and survival. At the same time, it is going to help identify the cancer cell by the T cells. But the added benefit is that, in addition to those things, it is also going to deliver a drug that is in the antibody once it attaches to the BCMA. And that way, you’re going to have the drug delivered straight to the cancer cell while also taking the benefit of inhibiting the BCMA and helping the T cells identify the myeloma cells.”

Lonial et al evaluated the efficacy and safety of belantamab mafodotin in patients with RRMM in the DREAMM-2 study (NCT03525678), the results of which were published in the Lancet in February 2020. DREAMM-2 was a 2-arm, randomized, open-label, phase 2, international study of adult patients with RRMM. Among other eligibility criteria, patients had disease progression after 3 or more lines of therapy and were refractory to IMiDs and PIs, and refractory and/or intolerant to an anti-CD38 monoclonal antibody. Patients were stratified by number of previous lines of treatment ( ≤ 4 vs > 4) and whether they had high-risk cytogenetic findings, and then randomized in a 1:1 ratio to receive either 2.5 mg/kg or 3.4 mg/kg belantamab mafodotin. They received treatment intravenously once every 3 weeks. The number of cycles was determined by disease progression and/or toxicity. The primary end point was the overall response, defined as the percentage of patients who achieved partial response or better, as assessed by an independent review committee.¹²

Patients in both dose groups had a median of 3 treatment cycles. Thirty of 97 patients (31%) in the 2.5 mg/kg group and 34 of 99 patients (34%) in the 3.4 mg/kg group achieved an overall response. Approximately 20% of patients in each dose group achieved a very good partial response or better. The median duration of response had not been reached at the time of this study’s publication. At the time of data cutoff, 18 of 97 and 25 of 99 patients in the 2.5 mg/kg and 3.4 mg/kg groups, respectively, had a duration of response of at least 4 months and were continuing with treatment. The authors estimated a 78% probability of having a similar duration of response in the 2.5 mg/kg group and 87% in the 3.4 mg/kg.¹²

Nearly all patients (98% and 100%) in each group experienced at least 1 AE.¹² Eight percent of patients in the 2.5 mg/kg group and 10% in the 3.4 mg/kg group discontinued treatment indefinitely due to AEs, most commonly keratopathy. AEs of interest were grade 3-4 keratopathy (27% and 21%), thrombocytopenia (20% and 33%), and anemia (20% and 25%, respectively). Rodriguez discussed the important AEs in this study. “Toxicities were something that were somewhat concerning at the beginning because the most common toxicities included eye keratopathy, anemia, thrombocytopenia, and infusion reactions.¹² The eye keratopathy [was] a new AE that we had not normally seen in multiple myeloma therapies,” he said. “It was seen in a good number of myeloma patients [who] were receiving this drug [as were eye blurriness and dryness]. [Keratopathy] is the toxicity that concerned the FDA at the beginning and required the drug company to find ways to mitigate this so that it does not become a serious problem for myeloma patients. Fortunately, after our studies, we have seen that people who do develop any eye symptoms can have reversal of their symptoms if they are closely monitored by an eye specialist. For this reason, people who receive therapy with belantamab mafodotin need to be seen by an eye doctor every 3 weeks prior to each therapy to monitor the cornea of the eye and make sure that there are no toxicities. If there are early signs of toxicities, then the drug can be held or can be dose reduced so that those toxicities do not get worse. About 20% of the patients [21% at the 2.5 mg/kg dose and 16% at the 3.4 mg/kg dose] developed some infusion-related reaction.¹² For this reason, people need some premedications to try to reduce the risk of [AEs].”¹³

The results of the DREAMM-2 study are encouraging for patients with heavily pretreated RRMM. The efficacy of belantamab mafodotin monotherapy was comparable to the efficacy observed in previous studies with approved combination treatments in this patient population.¹² Data from the 13-month follow-up, recently presented at 2020 American Society of Clinical Oncology (ASC0) virtual annual meeting, showed a median duration of response of 11 months and a median overall survival of 13.7 months in heavily pretreated patients who received single-agent belantamab mafodotin 2.5 mg/kg.¹⁴

DREAMM-6 (NCT03544281) is an ongoing, phase 1/2, open-label, dose escalation and expansion study investigating whether adding belantamab mafodotin (2.5 mg/kg) to 1 of the current standard-of-care combination therapies (lenalidomide + dexamethasone or bortezomib + dexamethasone) increases the efficacy observed with monotherapy in DREAMM-2. As of the May 2020 ASCO virtual annual meeting, 18 patients with a median of 3 prior therapies had been treated. The overall response rate was 78%, with 50% of patients achieving a very good partial response.¹⁴ Infusion reactions, thrombocytopenia, and corneal events were the most common AEs at a median of 18.2 weeks of treatment.¹⁵

When asked to summarize his thoughts about the potential role of belantamab mafodotin in the treatment of patients with heavily treated RRMM, Rodriguez stated: “This is a game changer in the myeloma world because it expands our armamentarium that we can have to treat myeloma, especially [in] people who have been heavily pretreated, where we are seeing responses by using this drug. It would be very interesting to see how this therapy is going to make headway as we use it in earlier lines of therapy or earlier in the diagnosis of myeloma and how this is going to impact when we combine it with other agents.”

Conclusions

RRMM is a difficult-to-treat hematologic malignancy with a generally poor prognosis. Advances in treatments and therapeutic approaches over the last decade have extended overall survival, but the 5-year relative survival rate is only 53.9%,⁶ and more research is urgently needed. Several novel treatment combinations are being explored, as are potential new treatment targets. BCMA is a promising cell-surface receptor preferentially expressed in multiple myeloma cells that plays a key role in their survival. Anti-BCMA therapies, including bispecific antibodies, antibody-drug conjugates, and CAR T-cell therapy, have the potential to change the landscape for patients with RRMM.

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14. DREAMM-2 and DREAMM-6 data at ASCO reinforce the potential of GSK’s investigational belantamab mafodotin in patients with relapsed/refractory multiple myeloma. News release. GlaxoSmithKline. May 27, 2020. Accessed October 12, 2020. https://www.gsk.com/en-gb/media/press-releases/dreamm-2-and-dreamm-6-data-at-asco-reinforce-the-potential-of-gsk-s-investigational-belantamab-mafodotin/

15. DREAMM-6: evaluating belantamab mafodotin and bortezomib plus dexamethasone in relapsed/refractory myeloma. ASH Clinical News. July 15, 2020. Accessed October 1, 2020. https://www.ashclinicalnews.org/on-location/other-meetings/dreamm-6-evaluating-belantamab-mafodotin-bortezomib-plus-dexamethasone-relapsed-refractory-myeloma/