Peter Voorhees, MD

Are there remaining unmet needs? Yes. In particular, high-risk patients continue not to fare as well as their standard-risk counterparts. Better understanding of why those patients aren’t doing as well and developing new strategies to treat their disease and overcome that high-risk status is going to be critical going forward. As far as interesting drugs or combinations in the pipeline, it goes without saying that there’s a tremendous amount of excitement, both in the CAR [chimeric antigen receptor] T-cell therapy space, as well as in the bispecific monoclonal antibody space. With regard to CAR T-cell therapy, we already have our first accelerated FDA approval of idecabtagene vicleucel, which is a BCMA-targeted CAR T-cell therapy. We’ll hear about potential accelerated approval of ciltacabtagene autoleucel later this year, another BCMA-targeted CAR T-cell product. There are other CAR T-cell products in development that are targeting other antigens on the surface of myeloma cells, which will definitely be of interest, and next-generation CAR T cell directed against BCMA.

With regard to the bispecifics, the BCMA bispecifics are performing incredibly well. We have new targets on plasma cells for bispecifics as well. There’s talquetamab, which targets GPRC5D, which is a very plasma cell–specific marker. That’s been performing exceptionally well in the initial clinical trial. Then we have cevostamab, which is also directed more specifically against plasma cells and has demonstrated very promising response rates in heavily pretreated patients. Then we’ve got the new version of IMiDs [immunomodulatory imide drugs], or CELMoDs [cereblon E3 ligase modulators]. There’s iberdomide—Cc220, as it was formally referred to—and then CC-92480. Those are performing very well also. What we’re going to see in the years ahead is all these things being moved to earlier therapy and eventually patients with newly diagnosed multiple myeloma in varying combinations. As far as the results are concerned, we’ll see if they’re going to be transformative.

As far as practical advice for community oncologists treating multiple myeloma, in the newly diagnosed space the number of treatment options is fewer than in the relapse space, and treating those patients is a lot easier. There are very good data emerging on incorporating the CD38 antibodies, both in transplant-ineligible and transplant-eligible myeloma patients. For relapse patients, it’s very daunting. When you look at the NCCN [National Comprehensive Cancer Network] Guidelines, for example, for relapsed myeloma, you have this gigantic menu of treatment options. That can be very daunting for someone who doesn’t treat myeloma on a day-in, day-out basis. In those circumstances, don’t hesitate to reach out to someone who treats multiple myeloma for a living and engage us. Ask for our advice as far as optimal therapy because it’s changing all the time.

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Considerations for future unmet needs and novel therapies in multiple myeloma, followed by practical advice for community oncologists.

Unmet Needs and Future Directions in the Management of Multiple Myeloma

From an efficacy standpoint, studies have made it clear that the triplet strategies in both the relapsed and up-front space have outperformed the doublets. With longer follow-up, we’re starting to see median overall survival improvements as well in many of these trials. There’s no situation in which a doublet will outperform existing triplets with regard to efficacy. When you’re looking at safety, obviously when you add a drug to a backbone, you’re going to increase adverse effects. When you add a CD38 antibody to lenalidomide and dexamethasone, for example, you’re going to increase the likelihood of grade 3 and higher neutropenia. That’s well established. You’ll increase the risk of infection. That’s also well established. In the MAIA trial, there was a slight increased risk of pneumonia in the triplet arm, compared with the doublet arm. When you add bortezomib to the lenalidomide-dexamethasone backbone, you’re going to increase the risk of neuropathy for those patients. That’s well established. There are safety issues that need to be discussed with each patient. But looking at the efficacy data, particularly overall survival advantage when you add either bortezomib or daratumumab to the lenalidomide-dexamethasone backbone, most of us feel that that improved efficacy outweighs the increased risk of those particular adverse effects.

How does our choice of initial treatment impact subsequent choices for later lines of therapy? That’s a fantastic question. Most of the myeloma studies have utilized treatment until disease progression or the emergence of unacceptable adverse effects. Patients who don’t have unacceptable adverse effects on a particular regimen will eventually develop resistance or their myeloma will eventually develop resistance to that regimen. That’s going to impact best-therapy practices in that first relapse. In many instances, a transplant-eligible patient, for example, will go through an initial induction therapy followed by that up-front autologous stem cell transplant and subsequent lenalidomide maintenance therapy. For that patient who’s breaking through lenalidomide maintenance, you’re not going to want to use a lenalidomide-based triplet in that setting because although there are numerous studies looking at lenalidomide triplets in early relapsed myeloma, none of those studies allowed lenalidomide-refractory myeloma. We don’t know how well those regimens perform in the context of randomized trials. In the example that I’ve given, the choice comes down to whether you want to go to a completely… resistant mode of therapy, such as a CD38 antibody with carfilzomib and dexamethasone, or do you want to do a CD38 antibody with pomalidomide and dexamethasone? That’s just 1 example.

I monitor response to therapy as anyone else would. I utilized the International Myeloma Working Group uniform response criteria, and I’m assessing response with each cycle of therapy, determining whether a patient has achieved a partial response, a very good partial response, or a suspected complete response [CR]. For those who have achieved that suspected complete response, we’ll have a discussion with the patient about confirming that with bone marrow examination. As we’re doing that bone marrow examination, an assessment of minimal residual disease [MRD] status is an important consideration.

Generally speaking, achievement of deep response has been associated with improved progression-free and overall survival, so the best treatment response would be an MRD-negative complete response. That said, there are going to be patients who don’t achieve that level of response to therapy. What we don’t know is whether escalating treatment for those who don’t achieve MRD-negative complete responses changes their long-term outlook. Until we have randomized data that support that notion, I’ve been hesitant to escalate therapy simply to make the numbers look better. Those regimens that have a higher probability of achieving that MRD-negative CR are the regimens that are going to give you the best odds of a longer remission and progression-free survival.

In the context of multiple myeloma, Peter Voorhees, MD, considers the role of doublet vs triplet therapy, initial therapy selection, and monitoring treatment response. 

Practical Considerations for the Management of Multiple Myeloma

 The clinical implications of the updated results of the MAIA trial are very clear. Many of us were already convinced that daratumumab-lenalidomide-dexamethasone was a very important standard of care when all we had was a clear improvement in median progression-free survival, but now we have a clear improvement in overall survival as well. It’s very clear that daratumumab-lenalidomide-dexamethasone is a critical standard of care for patients with newly diagnosed transplant-ineligible [multiple] myeloma. As far as which patients I would consider for this regimen, any newly diagnosed patient who’s transplant-ineligible should be considered.

There’s this question that keeps arising: does the addition of a CD38 antibody to a backbone myeloma regimen provide meaningful benefit for high-risk patients? Unfortunately, when you look at each trial, the number of patients with high-risk cytogenetics is so small that it’s hard to infer any significance. When you look at metanalyses, in the relapsed and newly diagnosed settings, the pattern is very clear that there’s an improvement in progression-free survival in both high-risk and standard-risk patients. Anybody could be considered for this particular platform.

What are the implications of the MAIA data with regard to frontline transplant for those who are eligible? That’s an important question. I am 1 of the people who believes that there’s a role for high-dose melphalan consolidation supported by autologous stem cell transplantation. We have data from the IFM 2009 trial that looked at up-front transplant vs deferred transplant in the context of up-front RVd [lenalidomide, bortezomib, dexamethasone] therapy. As we know from that trial, the likelihood of achieving a deep response was higher with up-front transplant. That included an increased rate of MRD [minimal residual disease] negativity and translated into an improvement in median progression-free survival that was statistically and clinically significant.

More recently we have the FORTE trial, which looked at the KRd [carfilzomib, lenalidomide, dexamethasone] backbone with up-front transplant vs delayed transplant with additional 4 cycles of KRd [carfilzomib, lenalidomide, dexamethasone]. In that trial, we found that although the rates of MRD negativity were similar between those 2 arms of the trial, sustained MRD negativity was clearly higher in the up-front transplant arm, and that led to an improvement in progression-free survival for the transplant arm. That’s with the best of what we have to bear in the frontline setting.

If you want to increase your odds of the longest remission possible in the first line, transplant still has a role. Can we use a quadruplet, for example, to obviate the need for transplant? That’s an open question or will the bispecifics of the CAR [chimeric antigen receptor] T-cell therapies that are emerging replace transplant? It’s possible, but we’ll need those randomized trials to determine that, and we don’t have that data. My advice is to get the transplant in frontline. Patient preference is absolutely critical in decision-making, and patients may have very strong preferences about when or if they’ll do transplant. For those who have low-risk disease, perhaps hyper diploid myeloma with no high-risk cytogenetics, who very strongly want to avoid transplant, it would be very reasonable to collect stem cells for that patient and reserve transplant for first relapse.

Peter Voorhees, MD, reflects on practical implications of the MAIA trial and how best to manage a patient with newly diagnosed multiple myeloma.

Multiple Myeloma: Clinical Implications of the MAIA Trial

 The MAIA trial was a randomized phase 3 trial that looked at lenalidomide and dexamethasone with or without the CD38 monoclonal antibody daratumumab in newly diagnosed patients with transplant-ineligible multiple myeloma. Patients were assigned 1:1 to the 2 arms, and patients were treated until disease progression or the emergence of unacceptable adverse effects. The primary end point of the study was progression-free survival [PFS]. Other key secondary end points include depth of response, including MRD [minimal residual disease] negativity, overall survival, progression-free survival, as well as safety. 

As far as baseline characteristics, the 2 arms of the trial were well matched. It’s important to note that close to 45% of the patients in the trial were 75 years of age and older, so this is representative of an older patient population. Interestingly, 30% of patients in both arms had ISS [International Staging System] stage III disease. High ISS stage is well represented in this trial. As far as high-risk cytogenetics are concerned, that was seen in about 15% of patients in both arms of the trial. The addition of daratumumab to the lenalidomide-dexamethasone backbone improved overall response rate. With long follow-up, overall response rate in the triplet arm was 93% in contrast with 82% for those on the doublet arm; that was statistically significant. When you look at CR [complete response] rates, that was 51% in the triplet arm vs 30% for those in the lenalidomide-dexamethasone arm, so that’s very clear improvement in complete response or better. When you look at MRD negativity at 10-5 level of sensitivity, there were much higher rates in the triplet arm vs the doublet arm. When you look at sustained MRD negativity over 12 months, there were much higher rates in the triplet arm vs the doublet arm.

Dr Thierry Facon of the University of Lille [in France] updated the MAIA results at the European Hematology Association Congress [EHA] earlier this year. Remarkably, with long follow-up, the progression-free survival for daratumumab, lenalidomide, and dexamethasone at 60 months, or 5 years, was 52.5%. We still haven’t hit median progression-free survival 5 years out. That’s in contrast with a 5-year progression-free survival rate of 28.7% for those assigned to lenalidomide-dexamethasone. The median progression-free survival was 34.4 months, so that’s a dramatic improvement in progression-free survival with the addition of daratumumab. The hazard ratio for PFS was 0.53, so you’re looking at a 47% reduction in the risk of progression or death with the addition of daratumumab to the lenalidomide-dexamethasone backbone. Importantly, overall survival was also updated at EHA. Looking at the 60-month overall survival rate, it was 66.3% in the triplet arm in contrast with 53.1% in the doublet arm, and that was highly statistically significant. The hazard ratio was 0.68, so you’re looking at a 32% reduction in the risk of death of any cause with the addition of daratumumab to the lenalidomide-dexamethasone backbone. What we’re seeing is that the addition of that CD38 antibody improves overall response and depth of response, which translates into progression-free survival and, with long enough follow-up in many instances, overall survival.

Updated results from the MAIA trial, which tested the addition of daratumumab to lenalidomide-dexamethasone therapy in patients with transplant-ineligible newly diagnosed multiple myeloma. 

Transplant-Ineligible Newly Diagnosed MM: Results From the MAIA Trial

 What available frontline treatments can be used for transplant-ineligible patients? We have several. The 1 used most commonly in the United States is the combination of RVD, or lenalidomide, bortezomib, and dexamethasone. For those patients who are truly transplant ineligible, perhaps as a result of increased frailty, the RVD [lenalidomide, bortezomib, dexamethasone]–lite regimen or some iteration of that is commonly used in these patients. We have newer data supporting the role of the CD38 monoclonal antibody—daratumumab in combination with lenalidomide and dexamethasone—for patients with newly diagnosed myeloma who are not undergoing the initial transplant. In some instances, if the patient does not have significant cardiovascular risk factors, the carfilzomib, lenalidomide, and dexamethasone triplet can also be used. In select instances, we may use the cyclophosphamide-bortezomib-dexamethasone regimen. For example, let’s say a patient newly diagnosed in the hospital with acute renal failure Given the increasing body of literature supporting proteasome inhibitor triplets in this patient population, we will typically transition those patients to a PI [proteasome inhibitor]–IMiD [immunomodulatory imide drug] or CD38-IMiD-dexamethasone triplet on the outpatient side of things. Increasingly the literature supports that the doublet regimens are inferior to the triplet regimens and should be used only in exceptional circumstances.

What’s my approach to treatment duration, and why? As I explain to patients and to community oncologists: when in Rome, do what the Romans do. If you want to recapitulate the results we’re seeing in randomized trials that inform practice for multiple myeloma, do what they did in the trials, as long as you can do it in a way that’s tolerable for patients. For example, going back to the RVD [lenalidomide, bortezomib, dexamethasone] regimen in the transplant-ineligible patients, the SWOG-S0777 study utilized the triplet for 24 weeks, or eight 3-week cycles followed by lenalidomide maintenance. That’s what I’ll do in that circumstance. And just like what was done in the protocol, I’ll treat until disease progression or the emergence of unacceptable adverse effects that I can’t manage by dose reductions or supportive care. Similarly, with the daratumumab-lenalidomide-dexamethasone triplet in patients with transplant-ineligible myeloma, the way that study was designed is patients were either assigned to the lenalidomide-dexamethasone doublet or daratumumab-lenalidomide-dexamethasone triplet until disease progression or the emergence of unacceptable adverse effects. My intent is to continue to treat patients until their disease has developed resistance to that regimen or they’ve developed unacceptable adverse effects that I’m not able to manage with those reductions and optimal supportive care.

What do I do if a patient requests a drug holiday, or doesn’t want to resume treatment after an adverse effect? Patient preference is critical and has to be first in any decision-making that occurs. In that circumstance, I’ll try to better understand the particular adverse effect. What have we done to manage it? How severe is it? Are there any other strategies up our sleeves that can mitigate that adverse effect that’s leading to the patient wanting to come off therapy? If the answer is yes, then I’ll work with the patient to try and achieve that goal. If an adverse effect has had a significant impact on quality of life, despite optimal supportive care and modifications to the regimen, then in that circumstance it’s absolutely appropriate to hold therapy. If the patient requests a drug holiday in the absence of unacceptable adverse effects, then it’s a discussion. You have to help them understand that the success of these regimens that we were using was in the context of treatment until disease progression. They have to understand that a drug holiday could potentially impact the effectiveness of the regimen in the long term. I always tell patients that duration of remission for that first treatment is absolutely critical. With all the advances occurring in myeloma right now, with the standard of care for both newly diagnosed and relapsed disease changing at lightning pace, the longer you’re in remission that first time around, the more opportunities you’ll have at the time of relapse.

Expert insight on the optimal management of transplant-ineligible newly diagnosed multiple myeloma in light of available therapies and clinical data.

Addressing Transplant-Ineligible Newly Diagnosed Multiple Myeloma

 How do we determine risk in newly diagnosed patients with myeloma? There are a number of factors that we look at. One is the cytogenetic risk factors. Does the patient have a myeloma that harbors del(17p) or 1 of the high-risk IGH translocation such as 14;16, 14;20, or 4;14? There’s an increase in the body of literature supporting increased risk with regard to gain of 1q21.1. In particular, 4 or more copies are harbored by the multiple myeloma. We also look at the International Staging System [ISS]. Patients with ISS stage III disease certainly don’t fare as well as their stage I and II counterparts. Then there’s the revised ISS, which incorporates cytogenetic risk and high LDH [lactate dehydrogenase], which we know is a marker of more aggressive proliferative disease along with the ISS. There’s a number of other factors that we look at, including the presence of circulating plasma cells in peripheral blood; 5% or more typically connotes a more aggressive version of multiple myeloma. Advanced imaging techniques, such as PET [positron emission tomography]/CT, can help us determine whether there’s the presence of extramedullary multiple myeloma at the time of diagnosis, which is also an indicator of high-risk disease.

The goal of treatment for a patient with newly diagnosed multiple myeloma is to drive the disease into as deep of a remission as possible and, by doing so, ameliorate the morbidities they’re experiencing related to their multiple myeloma at the time of initial diagnosis and to prevent additional morbidity arising as a result of their multiple myeloma over the long term. Deep remission and sustained remission achieve both of those goals, but we want to do it in a way that’s not overly toxic with regard to adverse effects.

How do we determine if a patient is eligible for autologous stem cell transplantation? Increasingly we’re using age less frequently as that determinant. There are a good number of patients 70 years of age and older, and they’re perfectly capable of getting through high-dose melphalan chemotherapy, just as well as their 50- and 60-year-old counterparts. We look at fitness frailty more than we do chronologic age. Does the patient have comorbidities that would impact the safety of going through high-dose chemotherapy? There are a number of frailty scores, including 1 that was adapted by the International Myeloma Working Group that could help predict potentially more severe adverse effects related to treatment for patients with myeloma. Those metrics can be very helpful in making a decision about whether to proceed with transplant.

Peter Voorhees, MD, provides a broad overview on risk assessment and the goals of therapy in multiple myeloma management.

Peter Voorhees, MD | Authors

Articles

Unmet Needs and Future Directions in the Management of Multiple Myeloma

Practical Considerations for the Management of Multiple Myeloma

Multiple Myeloma: Clinical Implications of the MAIA Trial

Transplant-Ineligible Newly Diagnosed MM: Results From the MAIA Trial

Addressing Transplant-Ineligible Newly Diagnosed Multiple Myeloma

Risk Assessment and Goals of Therapy in Multiple Myeloma