Sagar Lonial, MD, FACP

 When we think about patients in the refractory myeloma setting, it’s clear that new drugs have made a big difference. If we look at expected overall survival from patients in the DREAMM-2 study [NCT03525678], it’s well over 1 year. When we started this conversation, I told you that the anticipated survival of a triple-class refractory patient with a median of 6 prior lines of therapy was less than 1 year. These new treatments are already beginning to have an impact in terms of progression-free and overall survival. As with every other drug in the context of myeloma, our goal is to combine them with other drugs that are out there, and we’ve seen that in the context of belamaf being combined with pomalidomide, for instance, in the ALGONQUIN study [NCT03715478] and with bortezomib in the DREAMM-6 clinical trial [NCT03544281]. There are other studies on the horizon, combining it with combinations such as VRd [lenalidomide, bortezomib, and dexamethasone] or other potential agents or combinations in this setting. Figuring out the right dose and schedule will be important and give us additional treatment options. If we’ve learned anything [about] myeloma in the past 2 decades, it’s that combination therapy ends up being the answer because it’s not 1 plus 1 equals 2. It’s 1 plus 1 equals 4 or 5, and that is the goal of combination therapy. When we think about other drugs that are promising in terms of late-stage clinical development that have an opportunity to potentially improve or extend overall survival, the classes of agents that we’re excited about are CAR T cells, which can target BCMA [B-cell maturation antigen] right now. CAR T cells look exciting in the context of refractory myeloma, with high overall response rates and median durations of response right now of [approximately] 1 year. More importantly, the incidence of cytokine release syndrome and neurologic toxicity appears to be lower in patients [with myeloma] who received CAR T cells [as opposed to] CAR T cells [given to patients with] lymphoma or acute lymphoblastic leukemia. Those are exciting concepts, as well. Additionally, the use of bispecifics, or BiTE, targeting either BCMA or 

 for FCRH5 also look exciting, and when we get to mix in antibody drug conjugate, a bispecific, and a CAR T cell—all targeting BCMA because loss of BCMA is not the major mechanism of drug resistance in myeloma—we may be able to sequence these therapies in ways that patients can get the benefit of not just 1 drug in this class but 2 or even 3 drugs to potentially maximize the response duration and mechanism of action. For patients across the board, the future looks bright, with many new treatments coming in the context of refractory myeloma. We look forward to bringing those earlier and earlier in the disease course and hopefully increasing the fraction of patients we ultimately cure.

One of the key pieces of advice that I often offer to patients, as well as community oncologists when they’re treating patients with [challenging cases of] myeloma, is to partner early with an academic center that has access to many of these clinical or clinical trial options. The field, treatment scope, and treatment approach in myeloma are changing so fast that it’s hard to keep up. I don’t think any of us in the academic community want to take patients away from anybody. We would prefer patients to be treated closer to home and use their local community and doctors, but there may be situations or settings where that’s not possible because you’ve gone through all the available agents and patients need access to trials. The optimal time to refer for a trial is not when the counts are terrible, in extremis, and there aren’t many options left. It’s in the early relapse or earlier relapse setting, so that we can get to know the patient, they can understand what the potential treatment options are, and we can establish that relationship to allow them to get access to trials when they need them. It’s about getting as much treatment closer to home as possible, as well, so that partnership earlier in the patient’s disease is critical to maximizing the potential benefit patients may get from these new drugs.

A 72-Year-Old Man with Heavily Pretreated, R/R Multiple Myeloma

A 72-year-old man diagnosed with multiple myeloma 4.5 years ago returns for routine follow up

Initially treated with VRd for 12 months, followed by lenalidomide maintenance 15 mg daily; stable disease lasting 36 months

Rechallenged with VRd, stable disease lasting 20 months

Subsequently switched to KPd, achieved a partial response lasting 15 months

Started DVd; follow up at 12 months showed M protein increase by 0.5 g/dl; patient continues to feel well 

Currently, 3 months after his last visit, he returns to the clinic complaining of increased muscle weakness, fatigue and bone pain

PE: new bony tenderness appreciated on ribs, bruising, mild bleeding of the gums

Labs: Hb 8.8 g/dL, calcium 10.2 mg/dL, LDH 160 U/L, creatinine 2.1 mg/dL, albumin 3.0 g/dL, b2 microgloblulin 4.9 mcg/mL, serum M-protein 4.2 g/dL, lambda free light chains 4.1 mg/dL

Skeletal survey and MRI revealed stable lytic bone lesions in the left hip, pelvis and L2 vertebrae and new lytic lesions on the ribs 4 and 10 on the left side

Bone marrow shows 70% plasma cells IgG k

FISH: t(6;14) (p21;q32) at diagnosis; new del(17p)

Initiated treatment with belantamab mafodotin

Videos

Sagar Lonial, MD, FACP, discusses the management of heavily pretreated relapsed/refractory multiple myeloma and its future.

Current Status and Future Directions in RRMM

 As we evaluate how belantamab mafodotin [belamaf] fits into our current treatment paradigm, the FDA indication is for patients with 4 or more prior lines of therapy who are basically resistant to PIs, immunomodulatory agents, and an anti-CD38 antibody... I consider belamaf for most [of these patients] unless there’s a potential contraindication that may make the use of belamaf more challenging. Given that keratopathy represents the most common adverse event, you need to explain to patients that there is a chance that [it can affect] their vision or ocular comfort. If you look at patients in DREAMM-2 [NCT03525678], 72% of patients had some form of keratopathy. That’s an exam finding. That is not a clinical finding, meaning patients don’t complain of keratopathy. What they complain about are things, such as dry or itchy eyes, that represent the most common reason for keratopathy. Some patients may experience changes in visual acuity. If you look at data from DREAMM-2, only 18% of patients had significant changes in visual acuity and only 3% of patients had to come off the drug because of significant changes in visual acuity. It’s important to separate the impact of keratopathy by an ophthalmologist using a slit-lamp exam vs clinical impact of keratopathy, which occurs in a much smaller number of patients. From a practical perspective, there are some [treatment] strategies, but what we saw from Dr [Rakesh] Popat at his ASH [Alliance for Shared Health] presentation was that the quality of life data suggested there was no significant decrement in quality of life for patients who were treated with belamaf. This speaks to the fact that these are patients who have had a lot of treatment coming in. They understand the resistant nature of their disease, for the most part. Again, [approximately] 18% did not have significant impacts on visual acuity, their ability to drive, or their ability to read. From a dosing and frequency perspective, the treatment is given every 3 weeks, which means an office visit once every 3 weeks. The added wrinkle with belamaf is that you need an exam from an eye care professional, either an ophthalmologist or an optometrist, within 48 to 72 hours of each dose of belamaf. At our center, for instance, [patients will] see ophthalmology in the morning, us in the early afternoon, and if everything is OK, then we’ll dose them in the afternoon. The infusion is relatively well tolerated. It’s easy and quick to give... The next most common set of adverse events were hematologic, which were of much lower grade and severity than the keratopathy pieces that continue to be 1 of the more prominent adverse effects of this drug. From a dosing perspective, again, it is relatively easy to give. The office visits are relatively rare and the biggest problem is partnering with an eye care professional at the outset.

When it comes to ocular toxicities associated with belamaf, there are a couple of key pieces of information that patients and providers should be aware of. The first is that it does not occur in everybody, and an exam finding doesn’t always translate into clinical decrement in function. Although we do worry about changes in visual acuity, for many patients—particularly patients with myeloma who’ve been on a lot of steroids and may have cataracts that can interfere with vision, as well—it is important to put the potential in front of the patient and have them understand that although this could be an event, only 18% of patients in DREAMM-2 actually had visual acuity changes of 20/50 or greater. The majority of patients did not have that significant adverse event. What we also learned from DREAMM-2 is that corticosteroid eye drops used with cytarabine, for instance, do not offer significant benefit in risk reduction. This is an effect of MMAF, and steroids alone don’t address or mitigate the impact of that adverse event. We also learned that lubricating eye drops are quite helpful and are included in the pack for many patients who are starting on belamaf. That’s important because dry or itchy eyes may be 1 of the more common adverse effects that they experience. Having them use those lubricating eye drops frequently can be very helpful in minimizing the long-term potential issues with belamaf. The other thing we know about belamaf-associated keratopathy is that it is reversible. In almost every patient in DREAMM-2, it reversed, and in those whom we don’t have documented evidence of reversal, it’s because they came off with refractory myeloma and either withdrew additional follow-up or died in the context of refractory myeloma. Every patient that we do have a good follow-up on has had improvement and complete mitigation of their ocular issues. This does not cause long-term or permanent damage to the cornea. It is a reversible finding in patients, in general. These 2 things, along with partnership with your eye care professional, help you to manage and mitigate the potential toxicity. One of the other pieces that is important is the idea that just because you have to hold a dose because of the presence of keratopathy doesn’t mean that you’re going to lose control of the disease. If you look at the patients who had doses held of belantamab [during] therapy, only 20% or fewer had progression during the time of dose holding. That’s important because, unlike cytotoxic chemotherapy where if you hold the dose you often lose control, the half-life of the antibody can be so long you don’t actually lose control. In many patients, you deepen the response over time. You may learn that a patient may only need to be dosed every 6 weeks in instances where they keep having to miss that every-other-dose scheduling and their keratopathy continues to improve with each subsequent cycle of therapy.

An expert in multiple myeloma provides insight on the role of belantamab mafodotin in the treatment of heavily pretreated patients with relapsed/refractory multiple myeloma. 

Role of Belantamab Mafodotin In the Treatment of Heavily Pretreated RRMM

 Belantamab mafodotin [belamaf], was approved based on the DREAMM-2 study [NCT03525678]. DREAMM-2 was a randomized, phase 2 trial of belantamab mafodotin in patients with a median of 6 to 7 prior lines of therapy. In the context of this trial, patients were randomized to receive either 3.4 mg/kg of belamaf—which was the dose that was arrived at in the phase 1 study—or 2.5 mg/kg of belamaf, a dose that was suggested by the FDA as a way to try to reduce the incidence of keratopathy, the known and most common adverse event associated with the immunotoxin MMAF, which is what the BCMA [B-cell maturation antigen] antibody is linked with in belantamab mafodotin. We saw an overall response rate of [approximately] 30% in both arms, slightly higher with the higher dose. PFS [progression-free survival] was around 3 months for both arms… What was striking about this trial was that the duration of response [DOR] in the lower dose was 11 months [but it was] much shorter in the higher dose of belamaf. [Although] many may be perplexed by this, the reality is that the higher dose of belamaf was more difficult to give and was associated with more adverse events and higher-grade keratopathy. The reason the lower dose was chosen was that it appeared to be a safe, effective dose that did not [affect] how long responding patients could stay on therapy. It had a 30% response rate, median PFS of [approximately] 3 months, and a DOR of 11 months for the 2.5 mg/kg dose. When one looks at the FDA-approval trials for carfilzomib, daratumumab, and pomalidomide, they all look relatively similar. In fact, the 11 months with BCMA looks somewhat better, given that this was a median of 6 to 7 prior lines of therapy, and patients had all been exposed to carfilzomib, pomalidomide, and daratumumab prior to study entry. Overall, the safety and efficacy data from DREAMM-2 look favorable and led to the FDA approval of belamaf in the patient population. Additionally, what we did—and what was looked at ASH [Alliance for Shared Health] this year, as well as ASCO [American Society of Clinical Oncology Annual Meeting]—was look at responses based on prior therapy, and patients who had fewer than 6 lines of therapy were compared with patients who had more than 6 lines of prior therapy. We demonstrated that the response rate was similar between the 2, suggesting that because BCMA is a novel target, the efficacy of belamaf was not [affected] significantly by a lot of heavily pretreated patients vs less heavily pretreated patients across the board; remember, almost all the patients in this trial were triple-class refractory.

Principal investigator Sagar Lonial, MD, FACP, discusses the DREAMM-2 trial and relapsed/refractory multiple myeloma.

The DREAMM-2 Trial in RRMM

 When we think about treatment options for a patient who has had 4 or more prior lines of therapy, the approved options are limited and speak to the fact that the PFS [progression-free survival] and overall survival rates are quite short for these patients. What often happens is the use of cytotoxic chemotherapy regimens, such as DCEP [dexamethasone, cyclophosphamide, etoposide, cisplatin] or VDT-PACE [bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide] and hyper-CVAD [cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone], that use combinations of alkylating agents and steroids that historically represented early line therapy—given the advance of novel agents in the [treatment] of patients—have moved forward into this situation. Alternatively, one can recycle other novel agents that have been used, particularly retreatment with an anti-CD38, an IMiD [immunomodulatory imide drug], and/or a proteasome inhibitor. Unfortunately, what we know about that is although one may get an initial response, the duration of response ends up being quite short. In this situation, the patient was offered treatment with belantamab mafodotin [belamaf], which is a BCMA [B-cell maturation antigen]-directed antibody drug conjugate that has a very novel and unique mechanism of action.

Functionally, the immunotoxin is different than one that we’ve seen in any other antibody drug conjugate molecules in all of oncology. The immunotoxin is something called MMAF, which is different from MMAE, which is more commonly used in this clinical situation. This allows the direct targeting of chemotherapy agent toward 2 cells that express BCMA. Because BCMA is a little less ubiquitously expressed than other antibody targets in myeloma, such as CD38 or SLAMF7, what this means is that you’re effectively delivering local chemotherapy to the tumor cell itself because BCMA is not expressed on many cells beyond plasma cells. This immunotoxin is somewhat unique and represents the first antibody drug conjugate approved in myeloma and the first BCMA-directed drug in the context of myeloma, as well.

BCMA is a target that has not been used, and this patient has not been exposed to that target to date. This offers a significant benefit, particularly in patients who may have significant comorbidities or difficulty traveling back and forth between the clinic and their home, because belamaf has to be given only once every 3 weeks; this means visits to the office are relatively few. On the other hand, the other approved agent in this context is selinexor, which is an XPO1 inhibitor, an FDA-approved combination with dexamethasone in the context of refractory myeloma—particularly penta-refractory or myeloma. In this context, selinexor given on a twice-weekly dosing schedule is a treatment that could potentially be given at home; however, the twice-weekly dosing schedule that was approved by the FDA in the basis of the STORM trial [NCT02336815] made office visits frequent and required for supportive care—particularly nausea, vomiting, diarrhea, and anorexia. With once-weekly dosing of selinexor—either with dexamethasone or in partnership with bortezomib or carfilzomib, or even combining with pomalidomide—the incidence of the GI [gastrointestinal] toxicity has dropped markedly but remains an issue in supportive care. Hydration, energy, fatigue, and asthenia are all adverse effects that persist and require interventions with additional supportive care measures. It’s clear that both belantamab mafodotin and selinexor have significant activity in the population of patients with refractory myeloma. If patients can tolerate therapy, they may gain significant clinical benefit, but the idea of trying to anticipate and manage the potential adverse events is quite different between these 2 approved agents in the context of refractory myeloma.

Sagar Lonial, MD, FACP, reviews and comments on the treatment options for patients with triple-class relapsed/refractory multiple myeloma (RRMM).

Treatment Options for Heavily Pretreated RRMM 

Let’s start off with a case of heavily pretreated relapsed/refractory myeloma. A 72-year-old man [received an initial diagnosis of] myeloma about 4.5 years ago and returned for routine follow-up. His treatment history included initially being treated with bortezomib, lenalidomide, and dexamethasone [VRd] for about 12 months, followed by lenalidomide maintenance daily. He achieved stable disease that lasted for approximately 36 months. After progression, he was subsequently rechallenged with VRd and achieved stable disease again, [which lasted] about 20 months. He was then switched to carfilzomib with pomalidomide and dexamethasone [KPd] and achieved a partial response that lasted approximately 15 months. Then he was switched to daratumumab, bortezomib, and dexamethasone [DVd]. His follow-up at 12 months showed an M protein increase of approximately 0.5 g/dL, but he continued to do well. However, 3 months after that visit, he came back to the clinic complaining of increased muscle weakness, fatigue, and bone pain. His physical exam showed new bone tenderness on his ribs, as well as bruising and mild bleeding of his gums. His clinical work-up at that time showed a hemoglobin of 8.8, calcium of 10.2, and LDH of 160; [his] creatinine was 2.1, albumin was 3.0, β-2 microglobulin was 4.9, and the M protein was now 4.2 g/dL with λ free light chains of about 4.1 mg/kg. Hepatitis B was negative. Skeletal survey and MRI demonstrated stable lytic lesions in the left hip, pelvis, and L2, as well as new lytic lesions on ribs 4 and 10 on the left side. Bone marrow showed about 70% plasma cells with IgG [immunoglobulin G] κ restricted, and FISH [fluorescence in situ hybridization] analyses demonstrated 6/14 translocation, which was present at diagnosis but now demonstrated the presence of 17p deletion. Diagnosis at this time was R-ISS [Revised

Multiple Myeloma International Staging System] stage 2. He had an ECOG performance status of 1. Initiation of treatment with belantamab mafodotin was started based on this history and the need for initial therapy.

[A case such as this] is not uncommon in routine clinical practice. Despite the fact that we have improved the overall survival median for most patients to greater than 10 years, patients who are not potentially eligible or offered high-dose therapy and transplant often have a shorter initial duration of response and often have a shorter overall survival. The fact that this patient has been exposed to all approved classes of drugs and has developed what we call triple-class refractory myeloma is an unfortunate scenario that’s occurring with increasing frequency. What we know from retrospective data analyses is that patients with triple-class refractory myeloma have a median overall survival of less than 1 year and have a median progression-free survival with their next line of treatment in the absence of new drugs of less than 3 months; that includes recycling combinations of cytotoxic agents or recycling of old agents in the past.

One of the main challenges that remains when we see these kinds of patients relates to the fact that their performance status may be limited; their counts may be low as a consequence of progression of disease, as well as multiple rounds of therapy, so they have less bone marrow reserve. These factors together cultivate the idea that although we like to achieve complete remissions or MRD [minimal residual disease] negativity in many of our patients, in patients such as this, achieving stable disease or better with a treatment that is well tolerated can often be a big win and represents a major step forward. The goals of treatment and challenges of patients in this situation are different, and they need to be handled differently. Even if they weren’t frail at the [time they received the] initial diagnosis, they often fall into a frail patient category by the time they’ve reached 4 prior lines of therapy and are triple-class refractory.

Sagar Lonial, MD, FACP, summarizes the case of a 72-year-old man with heavily pretreated, triple-class relapsed/refractory multiple myeloma (RRMM).

72-Year-Old Man with Heavily Pretreated RRMM

Sagar Lonial, MD, FACP, presents a case of a 72-year-old man with heavily pretreated relapsed/refractory multiple myeloma and discusses treatment options for patients with this diagnosis who have failed multiple prior lines of therapy.

Sagar Lonial, MD, FACP | Authors

Articles

Current Status and Future Directions in RRMM

Role of Belantamab Mafodotin In the Treatment of Heavily Pretreated RRMM

The DREAMM-2 Trial in RRMM

Treatment Options for Heavily Pretreated RRMM

72-Year-Old Man with Heavily Pretreated RRMM

A 72-Year-Old Man With Heavily Pretreated, Relapsed/Refractory Multiple Myeloma