Optimizing Anti-CD38–Based Treatment for Smoldering and Newly Diagnosed Multiple Myeloma: Pharmacist Perspectives

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Optimizing Outcomes with Anti‑CD38–Based Treatment for Smoldering and Newly Diagnosed Multiple Myeloma: Best Practices for Oncology Pharmacists

History of Smoldering Myeloma
The history of smoldering myeloma dates back to the mid '70s and early '80s, where two physicians from Mayo Clinic, Dr. Kyle and Elveback went back and reviewed 334 cases of what they called multiple myeloma. They identified six patients that actually never progressed to have a symptomatic disease. They realized maybe we should not be calling all of these patients having active myeloma when there are six patients that actually did not have any symptoms. They termed this expression smoldering multiple myeloma. That was more recently adopted in 2003 by the International Myeloma Working Group.

Historic Models for Risk Stratification of SMM
There have been a number of risk models for the stratification of patients with smoldering myeloma, and those date back to the PETHEMA risk stratification model, to the most recently, the 2020 IMWG model, which takes the Mayo 2018 model, often called the 20/2/20 criteria and they add the cytogenetics or molecular findings to that model.

IMWG‑2020 Refined Model of 2/20/20 SMM Risk Stratification.
Essentially, the 2/20/20 are numbers. A serum protein over 2 g/dL, an involved to uninvolved light chain ratio of above 20, and at least 20% of plasma cells in the bone marrow. The refined model added these additional risk factors, to show that patients with that may have one of these risk factors can be divided into low risk, low intermediate risk, intermediate risk or high risk.

Ongoing SMM Debate: To Treat or Not to Treat
The biggest ongoing debate in the field is, for patients with smoldering myeloma, do we observe them or do we treat them?

SMM: Randomized Trials Without Clear Survival Benefit
There have been a number of randomized trials without clear survival benefit, leading to this controversy. We have looked at early melphalan. We have looked at bone‑modifying agents. We have even looked at siltuximab and all of these trials, although small numbers, none of them have observed an overall survival benefit in one arm or the other.

QuiRedex: Rd and R Maintenance vs Observation in High‑Risk SMM
The QuiRedex trial, which looked at observation versus intervention with lenalidomide plus dexamethasone.

QuiRedex: Survival
There appears to be quite a difference in the lenalidomide and dexamethasone group when compared with observation, not only in PFS but also in overall survival.

There are important considerations to think about, and this is why it is important to really analyze these trials. The main consideration is this study was conducted before the widespread use of advanced imaging like PET, CT, or MRI scans, and so many patients that were on the observation group may have had active myeloma or myeloma that was not found because they were not doing these scans.

ECOG‑ACRIN‑E3A06: lenalidomide vs Observation in SMM
The second study was the ECOG‑ACRIN study, which is a study group in the United States led by Sagar Lonial, Emory Cancer Institute, and it was published and presented at ASCO about seven years ago. It looked at lenalidomide by itself versus observation in smoldering myeloma.

The progression‑free survival curves; there was also a difference with the hazard ratio of 0.28. However, this trial allowed enrollment for up to five years from the diagnosis, the advanced imaging, the PET‑CT scans, were not mandatory, over half of the patients were missing this cytogenetic FISH data, and they used older stratification criteria to stratify patients into this high‑risk.

AQUILA: Daratumumab vs Active Monitoring for High‑ Risk SMM
The third trial is the more recent AQUILA trial, which randomized patients in an international fashion to either daratumumab or active surveillance for high‑risk smoldering myeloma. Daratumumab was given every week for two cycles, every other week until cycle six, and then every four weeks for 36 months, about three years, versus active monitoring.

Primary endpoint here was progression to active myeloma using the SLiM‑CRAB criteria.

AQUILA: Baseline Disease Characteristics and Disease Progression
The investigators re‑stratified by use of the more current 2018 major risk stratification, and found that only about 37 to 40% of patients actually had high‑risk smoldering myeloma by the newer standards. They found the hazard ratio still favored the daratumumab arm.

AQUILA: PFS and PD or Deaths by IRC
The progression‑free survival by independent review committee found a progression‑free survival in favor of the daratumumab arm.

AQUILA: OS Benefit
There was an overall survival benefit that was significantly different, but without proper crossover post‑treatment care, the overall survival benefit is difficult to interpret.

AQUILA: Safety
If we are giving a drug, it always has safety concerns. For daratumumab, it is pretty mild drug, except we often see infection risk. Most commonly, there was more pneumonia and higher‑grade pneumonia in patients with daratumumab.

Expert's Algorithm for Managing Smoldering Myeloma
Our algorithm for managing smoldering myeloma really focuses on patients with high‑risk smoldering myeloma, based on that current 2020 IMWG high‑risk stratification. We have an option for daratumumab for some patients. Then we have lenalidomide or observation. There is no really right or wrong answer. It is really dependent on the patient, their age, comorbidities, and mainly their patient preference.

Myeloma Therapy: Transplant Eligible Newly Diagnosed Patients
All right. I am going to introduce Dr. Julian, KJ, as I call her. She is going to talk to us about transplant‑eligible patients with newly diagnosed myeloma.

Scope of the Problem
Dr. Kelley L. Julian (Huntsman Cancer Institute, University of Utah): Thank you, James. Appreciate that.

To scope the problem for treatment of newly diagnosed patients with myeloma, this year alone, we are going to have 36,000 new cases diagnosed in the United States, with over 10,000 deaths. In 2022, there was an estimated 192,000 people living with this disease in America.

We have incrementally improved the five‑year overall survival rate in the last decade but this is largely a disease of the elderly, with the median age of diagnosis at 69 years. While prognosis has significantly improved with some of these novel agents, we are going to talk about, this disease is still largely considered incurable. Let us look at how we are going to move the needle.

Myeloma Treatment Paradigm
The stem cell transplant‑eligible patients. We are going to look at some data through the induction, consolidation and maintenance phases of treatment. Trying to prolong progression‑free survival and prevent that first relapse as long as possible.

2024 IMS/IMWG Consensus on Defining High‑Risk Myeloma
First, let us level set and talk about 2024 IMS/IMWG consensus on defining high‑risk myeloma. The main goal of this consensus criteria was to move beyond the R‑ISS and the R2‑ISS, which many clinicians felt did not accurately capture the most aggressive 20% of cases in the era of quadruplets.

By consistently applying these criteria to newly diagnosed patients, clinicians can more readily identify patients who are at risk for early relapse despite our modern treatments, and this allows for more informed discussions regarding treatment and long‑term monitoring.

Depth of Response Matters!
Let us talk about the depth of response. You are going to hear me mention and James mention, MRD, which is minimal residual disease. This refers to the persistence of residual tumor cells after treatment, and is cause of major relapse.

Someone was talking with me the other day, and they used the cleared yard analogy. What that means is compared to a traditional response monitoring, if you are someone looking out of a house window down at a yard and myeloma represents if there is any weeds in the yard, it might look like, if you are looking down out of a window that the grass is perfectly clear of weeds, but what that would be kind of representative of a traditional complete remission and what that looks like, but if you got down into the grass with a magnifying glass on your hands and knees, and you looked at every single blade of grass, if you looked at 1 million blades of grass, and you are MRD negative, you would not find a single weed there.

Newly Diagnosed MM and the Evolving Role of CD38 mAb Therapy
In the transplant‑eligible side of things. Whether a patient has standard risk or high risk, they are largely going to get a quadruplet, which is an anti‑CD38 monoclonal antibody backbone with a bortezomib, lenalidomide, and dexamethasone.

Both standard and high‑risk patients are eligible for quad. Occasionally, we may give a standard risk patient less therapy than that, but that is exceedingly more rare as we get more experience with quad regimens. We follow that by transplant. Then we will have a risk‑adapted maintenance strategy.

Rationale for Anti‑CD38 + Immune Modulators in MM
Digging into the rationale for why we use anti‑CD38 monoclonal antibodies in combination with immune modulators like lenalidomide or pomalidomide. We like to target the cluster of differentiation 38 because we know it is highly expressed on the malignant myeloma cells, and it functions as a receptor adhesion molecule and an ectoenzyme mediating immunosuppression, and it is uniquely expressed in the bone marrow microenvironment and immune cells. When we combine it with the immune modulators, there is synergy through various different mechanisms.

Induction Regimens in TE Patients With NDMM: Efficacy
Starting with the DETERMINATION trial, this was a phase III major landmark study that evaluated the role of early autologous stem cell transplant versus not, in the era of modern triplet therapy with continuous maintenance.

The most critical takeaway for this DETERMINATION trial for your clinical practice, is that while transplant did offer a massive PFS benefit 67 months versus 46 months it did not translate into an overall survival advantage when we have more effective salvage options available.

Transplant is still an option. It is a viable option for a lot of patients, but this did open the door for other options to also be kept in mind if you have a patient who maybe is not good for transplant.

Moving to the GRIFFIN and PERSEUS trials. GRIFFIN was the phase II, and PERSEUS was the phase III trials that definitively studied and established daratumumab with a combination of bortezomib, lenalidomide, and dexamethasone as the front‑line quadruplet induction for these transplant‑eligible patients. While GRIFFIN provided the proof of concept and used IV daratumumab, PERSEUS confirmed these findings in a larger population using the subcutaneous formulation.

Moving over to the isatuximab trials, you have got the GMMG‑HD7 and the IsKia. What I want to highlight is that these are the isatuximab trials that really provided the evidence we needed to move these into the front‑line setting as well.

The HD7 trial was the premier induction quadruplet for transplant‑eligible patients. Similarly to PERSEUS, which focused on the daratumumab, this trial provided the high‑level evidence we needed with isatuximab-based backbones, with the primary endpoint of MRD‑negativity, which was significant.

The IsKia trial highlighted the effectiveness of this Isa‑KRd quad in high‑risk and double‑hit myeloma patients. The MRD negativity rate with the Isa‑KRd arm were consistently high across the risk groups. This trial did demonstrate that this Isa‑KRd quad could be considered the gold standard for high‑risk, newly diagnosed transplant‑eligible myeloma patients.

MRD Is Prognostic for Both PFS and OS
Stopping to think about the importance of MRD, MRD‑negative status surpasses the prognostic value of a complete response or complete remission achievement for PFS and OS.

MRD negativity should be considered as one of the most relevant endpoints for transplant‑eligible and elderly fit patients with myeloma, because standard complete response is no longer a high enough bar, given that the MRD negative status represents a much deeper clearance of disease.

PERSEUS: PFS and MRD Negativity Rate
The PERSEUS trial showed consistent PFS benefit across all of these subgroups, including the small subset of patients in this trial that had high‑risk disease. MRD negativity was sustained over time, an odds ratio of 4.4. The clinical meaning there is that patients in the daratumumab‑VRd arm were four times more likely to achieve and maintain MRD negativity for at least one year, as compared to those patients in the VRd triplet arm.

I want to point out that safety profile was very safe. No unique signals were seen in the PERSEUS trial other than the grade 3/4 neutropenia, which was upwards of 60%. This did not lead to an increase in treatment discontinuations.

GMGG‑ CONCEPT: MRD Negativity Rate and Response
The CONCEPT trial really proved that high‑risk disease requires high‑intensity therapy. The use of the Isa‑KRd heavy quadruplet induction, followed by triplet maintenance of Isa‑KR, was studied and is currently one of the most effective strategies for closing the survival gap between those high‑risk and standard risk patients.

MIDAS: MRD‑Driven Strategy Following Isa‑KRd Induction in Transplant‑ Eligible NDMM
The MIDAS trial was really the first one to demonstrate that a response‑adapted therapy is feasible in multiple myeloma. The standard risk question was answered through arm A versus arm B. Everyone received Isa‑KRd induction followed by an MRD evaluation. Those who were MRD negative were randomized to either Isa‑KRd for another six cycles and lenalidomide maintenance, or a transplant, followed by two cycles of consolidation and lenalidomide maintenance.

MIDAS: MRD Negativity
In these early responders, arm A and arm B comparison on the post‑induction side were virtually the same. This was a non‑statistically significant p‑value, and suggests that for patients who achieve early deep molecular clearance with Isa KRd induction, adding a transplant does not significantly deepen the response further.

MIDAS: Changes in MRD Status
In summary, MRD is a valid tool for making real‑time clinical decisions in this disease. Upfront transplant may be optional for patients who achieve a deep molecular response. However, potent consolidation can also effectively substitute for more intensive surgical‑like approaches, such as tandem transplants in slow responders.

AURIGA: Daratumumab/Lenalidomide vs Lenalidomide as Posttransplant Maintenance Therapy for NDMM.
Lastly, the AURIGA trial demonstrated that adding subcutaneous daratumumab to standard lenalidomide maintenance was significant in the 12‑month mark. The MRD negativity conversion rate was 50% versus 18%, and showed prolonged progression‑free survival compared to lenalidomide alone for myeloma patients who were remaining MRD positive post transplant.

Summary of Transplant‑Eligible NDMM
In summary, for transplant‑eligible newly diagnosed patients, we have a uniform definition of high‑risk myeloma, which is now in place and moving the needle for treating these patients aggressively.

Quad induction is clearly important and drives higher rates and depth of response pre‑consolidation.

The role of high‑dose therapy continues to be important. Risk‑adapted maintenance remains an important approach, and the data on early depth of response predicting long‑term outcomes does need continued PFS confirmation. With that, I will hand it back over to James.

Myeloma Therapy: Transplant Not Planned
Dr. Davis: Thank you. Now my job is to talk about the role of induction treatment or frontline treatment for patients who may be frail or older.

Myeloma Therapy for Transplant‑Ineligible Patients
Typically, we are not transplanting patients who are frail or above the age of 70. We are trying to get away from this age, this absolute age.

Frontline treatment currently involves induction of a three or four‑drug regimen and then the consolidation phase, we are not doing autologous stem cell transplant as much for these patients; we are moving to more prolonged induction strategies. You continue the induction from stopping at four cycles and going to transplant. You continue that induction for six to eight to sometimes 9 or 12 cycles. Then, eventually, you move on to a maintenance phase, which is typically giving a one or two‑drug maintenance, something like lenalidomide, maybe lenalidomide plus bortezomib or lenalidomide plus daratumumab, as Kelley described previously.

Clinical Considerations for Treatment Decisions in Transplant‑Ineligible Patients With MM
There are some considerations on how to pick and how to evaluate patients that are elderly or frail. Like I said previously, we are essentially just getting away from this age cutoff, we are incorporating frailty assessments that include performance status, comorbidity index scores, personal preferences, things like that.

The MAIA trial is the landmark trial that showed the combination of daratumumab, lenalidomide and dexamethasone, or DRd, essentially beat the doublet of lenalidomide plus dexamethasone in this older transplant‑ineligible population. Not only did the median progression‑free survival trump the two‑drug regimen, but also, there was an overall survival benefit at seven and a half years of follow‑up.

The SWOG 0 triple 7 trial, compared the older regimen of VRd versus Rd in this transplant‑ineligible or deferred transplant population, and showed benefits in regards to progression‑free and overall survival.

Transplant‑Ineligible Quadruplet Trials
This really sets the stage for our three big quadruplet therapy trials. These three trials are the BENEFIT trial, which was a cooperative group trial we will cover, the IMROZ trial, and the CEPHEUS trial.

BENEFIT: Isatuximab + VRd in Transplant‑Ineligible NDMM
The BENEFIT trial looked at the quadruplet of isatuximab plus bortezomib, lenalidomide, and dexamethasone, and it compared that to still isatuximab‑containing regimen, but also lenalidomide and dexamethasone. They gave that for 12 cycles, and then they dropped the bortezomib after cycle 18. They dropped the dexamethasone as well. Then, from cycle 19 onwards, they gave just the isatuximab and the lenalidomide.

BENEFIT: MRD Negativity Rate and PFS in ITT Population
What they found was the MRD negativity rates favored four drugs over three. There were higher rates of MRD negativity at both 12 and 18 months for the four‑drug regimens. There was about a 5.2% difference in progression‑free survival favoring the quadruplet versus the triplet. The primary outcome for this study was looking at MRD. MRD here was the goal and that is what they were able to achieve.

IMROZ: Isatuximab + VRd in Transplant‑Ineligible NDMM
The IMROZ trial was another isatuximab trial. Instead of isolating the effect of bortezomib, they isolated the effect of isatuximab.

You have the older triplet VRd, which, after a number of cycles, just continued more of a maintenance of lenalidomide index. They compare that to VRd plus isatuximab, eventually dropping the bortezomib due to the risk of neuropathy.

IMROZ: PFS and MRD Negativity Rate
60 months progression‑free survival was almost 20% different, favoring the quadruplet arm. MRD negativity at ten to the negative fifth was also favoring the four‑drug regimen over the older standard of the three‑drug regimen. Four drugs beats three in both of the isatuximab trials.

CEPHEUS: Daratumumab + VRd in NDMM Without Planned Transplantation
What about the daratumumab trial? The CEPHEUS trial. This trial is isolating the effect of daratumumab. We are looking at daratumumab plus VRd continued for eight cycles and then on to daratumumab Rd maintenance, versus the older triplet of VRd, then dropping the bortezomib due to the risk of neuropathy at cycle nine and continuing lenalidomide and dexamethasone‑based maintenance. They are looking at MRD negativity, progression‑free survival.

CEPHEUS: PFS and MRD Negativity Rate
We can see, again, four drugs beat three. Almost a 20% difference and 54‑month progression‑free survival in favor of the daratumumab VRd arm, MRD negativity also favored four drugs over three.

All of these trials, there was slightly more adverse effects in the four-drug arms. Typically, these are infections. Upper respiratory infections are common with these anti‑CD38 monoclonal antibodies. Those are things to watch out for in these patients.

Safety of Quadruplet Therapy in Transplant‑Ineligible Patients
IMROZ 30 versus 19%. Pneumonia infections, 92 versus 86% in the CEPHEUS trial.

The BENEFIT trial is a good one to look at because it did isolate the effect of the bortezomib. In the non‑bortezomib arm, the Isa‑Rd arm, there was far less peripheral neuropathy in these patients. Grade 2+ peripheral neuropathy is something to watch out for if you have frail patients and older patients, because peripheral neuropathy happened in almost 30% of these patients, versus 10% of patients and those who did not receive bortezomib. That is something that we have a low threshold to either dose reduce or eliminate that drug if we are giving older, more frail patients bortezomib, or if they have baseline diabetes, or if they have baseline peripheral neuropathy. Those are things to consider as well.

Down With Dex!
I will be remiss if I did not mention the current trending movement Down with Dex, led by one of my colleagues and friends, Rahul Banerjee, at Fred Hutch in Seattle. He and some other brilliant minds published some studies looking at the efficacy of dexamethasone and whether keeping the dose as high as 40 mg a week, versus lowering the doses and even eliminating dexamethasone at or before cycle six changes efficacy in patients that are receiving these regimens. They found that, surprisingly, eliminating dexamethasone after patients achieve response does not limit efficacy going forward. In my practice and my center, we get rid of dexamethasone as soon as we can to help avoid some of these side effects these patients are experiencing.

Important Lesson in Transplant‑Ineligible Patients
Some important takeaways for these transplant‑ineligible patients, we are able to give quads to most patients unless they have uncontrolled diabetes or baseline peripheral neuropathy. Most patients are able to tolerate these quads.

It is important to assess not only age but frailty.

We do not really know the optimal length of how long the quad is to be given for and when to best look at maintenance. We are going to find out some more about that in the coming years.

Then some really pharmacy provider pearls at my center, and it is shown, most of these trials gave bortezomib twice a week. We, at my center, always do weekly bortezomib because it has shown equivalent efficacy and less side effects. We typically start the lenalidomide not at 25 mg like a lot of these trials did, but at a lower 10 to 15 mg dose, and then we can always go up if patients do well.

For patients over 65 or 70, we often start at dexamethasone 20 mg and rapidly taper as we see a response or if they have side effects.

All right. I am going to turn it back over to KJ. She is going to take us home with pharmacist supportive care and the importance of supportive care as it relates to pharmacists taking care of these patients.

Supportive Care
Dr. Julian: Thank you so much, James.

Supportive Care in Frontline Therapy
Looking at supportive care for frontline therapy specifically, first I would be remiss if we did not talk about how we have really improved safety and patient satisfaction through the use of subcutaneous anti‑CD38 monoclonal antibodies. When we think about our monoclonals, we think of daratumumab and isatuximab, as we have mentioned. The biggest side effect that we see largely up front is an infusion or injection site reaction. Transitioning these patients from IV therapy to subcutaneous injection really improves quality because of the time saved and the side effect profile.

The COLUMBA trial was really the landmark trial that got subcutaneous daratumumab approved. That is on the market. It is widely used throughout myeloma space. Isatuximab has three trials that got their subcutaneous OBI or on‑body injector system to market.

Important to stop and mention that, no matter what, whether you are giving an agent IV or subcutaneous formulation, every patient needs premedications because the risk is still there for an infusion or injection reaction. So, thinking about your dexamethasone steroid and your acetaminophen, diphenhydramine, things like that. Occasionally, you give some other medications in their based on institutional standards, but in general, the premeds have to stay the same to mitigate the risk of a reaction.

For the IRAKLIA, IZALCO, and ISASOCUT, these studies are looking at different combinations of isatuximab subcutaneous injection versus the IV. The overall response rates are extremely high.

Very low rate of infusion reactions. Almost non‑existent for the isatuximab trials and the infusion reactions for daratumumab were in the high 30s, low 40s percentage range. You are easily cutting that by half or a third or even more than that when you are looking at these subcutaneous injections.

The key takeaway is that these are maintained efficacy, way better safety, and both patient and provider satisfaction was greatly improved across all these trials. Keeping in mind, super important to remember that they all still need premedications. That does not change, but using subcutaneous formulations has really moved the needle for our patients.

Infection Prophylaxis Measures
As far as infection prophylaxis measures, it is important to remember that the monoclonal antibodies and the proteasome inhibitors that we use really put patients at high risk for viral reactivation of HSV and VZV. These patients should remain on acyclovir or an equivalent drug for the duration of therapy, and even for a few months after, to mitigate that risk.

If a patient is neutropenic, we are looking at bacterial prophylaxis with levofloxacin. Neutropenia of an ANC less than 1,000, you would consider growth factor support, which we use liberally at my institution. I know others do as well.

When they are neutropenic, you need to consider prophylaxis with fluconazole to prevent invasive fungal infections. We are following standard antiviral recommendations. If a patient was exposed to influenza or COVID‑19, and recommending vaccination per institutional recommendations.

Then I would be remiss if I did not call out hypogammaglobulinemia, as marked by an IgG less than 400. We do not see this as often in the induction space, but this is something that the pharmacist plays a huge role in identifying. We can give those patients IVIG to keep them on therapy and safe.

Thrombosis: Management DVT and PE Risk
Thrombosis. This is a huge risk in the myeloma patient population, especially in the first six months of therapy. The pharmacist can play a huge role in managing DVT and PE risk by adjusting medications and schedules and working through the different scoring systems, which can be found if you search the guidelines, and assess the risk. Many patients qualify for DOAC. If you are thinking they are at higher risk, especially if they are going to be on IMiDs. Some centers do feel comfortable with aspirin, but either way, the pharmacist can really take point in some of those conversations and balancing the risk versus benefit.

We do not normally see super high rates of thrombocytopenia in the induction setting, but it can happen. Balancing your medications with the platelets are important to think about there.

The symptoms that come around peripheral neuropathy are largely numbness, tingling, prickling sensations, even sensitivity to the touch. We can prevent this and it is reversible in most cases. Early reporting of these symptoms and intervention are critical to make sure that this is reversible for our patients because we want to treat them for as long as possible.

Whether we do neuroprotective supplements, we prescribe an oral or topical pain medication, ensure their environment is safe so they are not a fall risk, or even dose adjust or dose hold.