Considerations in Managing Patients Newly Diagnosed With Multiple Myeloma

Angela Vickroy

Right now the standard of care for young, fit, newly diagnosed multiple myeloma patients eligible for stem cell transplant (SCT) is triplet therapy consisting of VRd, CyBorD, KRd, and IRd. Can we improve on triplet therapy for our young, fit patients?

Amy Pierre

I think we can. We also have the recently approved combination of daratumumab, bortezomib, thalidomide, and dexamethasone based on the CASSIOPEIA study,¹ although we don't use a lot of combined bortezomib and thalidomide in the United States compared to Europe. But it did show a lot of deep responses, including high rates of minimal residual disease (MRD) negativity. Stringent complete response rates were maintained in a lot of different subgroups, including those with a poor performance status or poor renal or poor hepatic function. There was an increased benefit for patients who had ISS stage 3 disease. But high-risk patients had less stringent complete response rates compared to standard risk patients. There was also more cytopenias with the addition of daratumumab, but infection rates were really similar in both groups. Overall, this tells me that this quad regimen induces deep responses but does not necessarily overcome high-risk cytogenetics.

We also have the GRIFFIN trial² looking at daratumumab with bortezomib, lenalidomide, dexamethasone; the dara/carfilzomib, lenalidomide, and dexamethasone trials; and also trials examining dara/IRd. And this year, dara/CyBorD is now a part of the NCCN Clinical Practice Guidelines.

All these studies really show high response rates and deep response rates. The study with daratumumab KRd showed that the patients who had many high-risk cytogenetic features had a 100% response rate at the end of cycle 2. And for those who received a SCT, over 90% of those patients had complete responses or stringent complete responses, and there were really high rates of MRD negativity. So we have a lot of promising therapies for newly diagnosed patients who are eligible for SCT. I think the wave of the future is going to be adding daratumumab to a lot of these triplet regimens.

What are your typical go-to regimens for our standard-risk multiple myeloma patients?

Angela Vickroy

We recently switched to bortezomib/lenalidomide/dexamethasone for all patients with standard-risk disease. Prior to this, we were using carfilzomib with lenalidomide and dexamethasone in these patients. However, the ENDURANCE trial³ showed that there was no benefit for standard-risk patients with bortezomib versus carfilzomib.

In patients with high-risk disease, we’re still using carfilzomib/lenalidomide and dexamethasone, as long as their cardiac status does not exclude them. We also use CyBorD for those patients with renal insufficiency excluding them from lenalidomide.

Currently there is no standard of care for our newly diagnosed, high-risk multiple myeloma patients. What does the current literature demonstrate about maximizing therapy for these patients?

Amy Pierre

This is a challenging patient population to treat. We know that they’re considered high risk because they relapse sooner, so we really need to obtain good disease control with our initial therapies. I think the GMMG-CONCEPT trial⁴ looking at isatuximab with carfilzomib, lenalidomide, and dexamethasone in high-risk patients has a lot of promising data. Those patients had deletion 17p, translocation 4;14, 14;16, extra copies of 1q, or higher stage disease—with more than half having deletion 17p. Despite these high-risk features, there was a 100% overall response rate. And almost half of those patients had complete responses. This is incredible! How often can you tell a high-risk patient, “I can give you a regimen and there's a 100% chance that your high-risk myeloma will respond to it”?

There were some studies also looking at adding elotuzumab to VRd for high-risk patients, and we actually found out that didn't really add benefit. There was no evidence of higher rates of deep response, but there was actually more hematologic toxicity with the addition of elotuzumab to VRd. We need more data to understand whether adding elotuzumab to VRd can improve response rates at later time points, or improve progression-free survival or overall survival. But this study changed our practice of care, as we discontinued elotuzumab for our high-risk patients who were on elotuzumab/VRd in that fashion.

Angela Vickroy

What about SCT in the newly diagnosed setting?

Amy Pierre

Yes, SCT is important in this setting, particularly for high-risk patients. The FORTE trial⁵ looked at KRd with transplant followed by KRd consolidation versus just giving 12 cycles of KRd. It showed that both regimens were equally effective in inducing high-quality responses, but also that high-risk patients receiving a SCT had a reduced risk of early relapse. So I think for our high-risk patients, we should think about continuing SCT as part of their induction. This trial supports the theory that not only does SCT deepen responses, but it also improves duration of response.

If we look at the STaMINA trial,⁶ which examined long-term outcomes among myeloma patients receiving a single transplant with or without consolidation therapy with VRd versus a tandem autologous SCT and then maintenance, the long-term outcomes in that trial were similar, but there was a suggested improved progression-free survival benefit for those with high-risk myeloma who received a tandem transplant. This tells us that a second transplant or RVd consolidation doesn't add much benefit for those with standard-risk myeloma. But for high-risk disease, maybe a tandem is the way to go.

What do you think about the need for a SCT for a patient with standard-risk cytogenetics who has achieved MRD negativity at the conclusion of induction therapy?

Angela Vickroy

That’s a good question. We’re still doing SCT for this population, but I don't think that there is a uniform school of thought across all practicing myeloma experts. The other question is, what do you do when someone is MRD negative and then they become MRD positive? Do we start them back on treatment? Does the patient then move to transplant if not previously transplanted? We need more data to support that patient population.

Amy Pierre

What about patients with newly diagnosed disease ineligible for a SCT? How are you approaching treatment for this population?

Angela Vickroy

In the transplant-ineligible patient population, we are using daratumumab, lenalidomide, and dexamethasone based on the MAIA clinical trial.⁷ The treatment is very well tolerated, even among the older population, and elicits a great response. We are also using bortezomib, lenalidomide, and dexamethasone in this population. A doublet, such as lenalidomide and dexamethasone, is reasonable in those who cannot tolerate triplet therapy.

Amy Pierre

We're always under the assumption that people are ineligible for SCT because they may be of advanced age and they wouldn't be able to tolerate a triplet. But in the MAIA trial, as you referenced, it is really well tolerated, even in patients older than age 75. And now there's more data looking at daratumumab with bortezomib, lenalidomide, and dexamethasone and also analyzing dara/IRd in the SCT-ineligible population. I’m sure dara/IRd would be an attractive regimen in this setting as it’s an oral therapy, and with dara potentially given as a quick subcutaneous injection.

Angela Vickroy

Yes, the newly approved subcutaneous daratumumab is a great option for our patients. What has been your experience with this new formulation?

Amy Pierre

Patients are super excited to receive daratumumab in subcutaneous formulation, because outside of that initial monitoring period with the first administration, there is an overall shorter chair time, less infusion-related reactions, and not much skin toxicity either. I've had a couple patients tell me that it slightly burned as it was being administered, but otherwise they are super happy about having it as an SC injection.

Angela Vickroy

I agree, many of my patients have switched to the subcutaneous formulation and have tolerated it well. I had one patient with a skin reaction approximately 1 hour after administration. It was reported as red and warm surrounding the injection site. But by the time that I received the call to evaluate the injection site reaction, the site was no longer red or warm. And most of the data shows that within 2 hours, the skin reaction resolves itself.

Amy Pierre

What about maintenance therapy? Should we look beyond lenalidomide for maintenance? What else is available, and what else have we studied in the maintenance setting?

Angela Vickroy

In our practice, we’re using dual maintenance chemotherapy for high-risk disease, including a proteasome inhibitor, in addition to an immunomodulatory drug Usually, lenalidomide and bortezomib, or lenalidomide and ixazomib is recommended. Ixazomib is a three-times-a-month regimen, which is very convenient for our patients. Bortezomib requires the patient to come in for treatment twice a month.

The DRAMMATIC clinical trial⁸ is also underway now, looking at daratumumab and lenalidomide versus lenalidomide in patients post-transplant. I am excited to see the results of this trial. Monoclonal antibodies are an exciting addition to our maintenance regimens, and hopefully the addition will deepen the response for patients post-transplant. The DRAMMATIC trial is also looking at MRD negativity in these patients, and is evaluating it throughout the post-transplant period, which I think is important and something patients are interested in seeing in their disease response.

Speaking of MRD negativity, why is it important for our multiple myeloma patients?

Amy Pierre

MRD negativity is basically having no evidence of minimal residual disease in the bone marrow. We know that myeloma cells in the peripheral blood are about 100-fold lower than what you would find in the bone marrow. So when you do MRD testing in the bone marrow, you're looking a little bit deeper. The NCCN Clinical Practice Guidelines supports the usage of MRD testing in myeloma and recommend obtaining MRD status before starting maintenance therapy. We know that if someone is MRD negative, there's a 50% reduced risk of progression. But we really need to define MRD negativity rates in the newly diagnosed setting, particularly in the setting of using these quad regimens, with or without SCT.

There are several ways to conduct MRD testing, including next-generation sequencing and flow cytometry-based MRD testing—both of which have their advantages and disadvantages. But MRD testing is still a work in progress, and as we talked about, we're not really sure what to do if someone is MRD positive. We need more trials to investigate the clinical significance in the long term and how to utilize MRD-adapted or MRD-driven therapy for myeloma.

If you look at subsequent analysis from the IFM 2009/DETERMINATION trial,⁹ you see that more patients achieve MRD negativity with a SCT. But for those who were indeed MRD negative, there was little difference in progression-free survival rates with or without SCT. MRD negativity can actually overcome high-risk cytogenetic features. If you had high-risk disease and you achieved MRD negativity, you actually had a better progression-free survival rate than a standard-risk myeloma patient who was MRD positive. So either way, if you are MRD negative, standard risk or high risk, you have better outcomes.

Angela Vickroy

I think that for the patients who are MRD negative, it helps their mindset, which is great. On the opposite side of that, those patients who are MRD positive, it's pretty detrimental to them. This is something that I try to really have candid conversations with my patients about.

Amy Pierre

I agree. But people who are MRD negative can also get a false sense of security. I've had MRD-negative patients who relapsed within 6 months of transplant, so what does that mean? There's a lot we still need to do with MRD negativity.

Angela Vickroy

Another issue we see among patients with multiple myeloma is that it occurs two to three times more commonly in African-Americans than in other ethnic groups, and this population has been known to experience disparities in novel therapeutics, SCT, and clinical trials. Why is this disease so common in African-Americans, and how to improve upon this?

Amy Pierre

The proposed reason African-Americans have a higher incidence of multiple myeloma is because they have a two- to threefold increased risk of developing MGUS, which is an established risk factor and precursor for developing multiple myeloma. Unfortunately, the disparities that exist are what you just mentioned: less usage of novel therapeutics including bortezomib and lenalidomide , decreased usage of and referrals for SCTs. African-Americans with multiple myeloma are also less likely to participate in clinical trials. Up to 20% of myeloma patients are African-American, yet we only see 4-6% of African-Americans generally enrolled in clinical trials. And we know that participating in a clinical trial provides you the benefit of getting novel or promising therapeutics in myeloma.

We do know that African-Americans have higher myeloma-specific survival rates, but they actually have worse overall survival rates compared to other ethnic groups. The proposed reason African-Americans have better myeloma-specific survival rates is that they tend to have biologically less aggressive disease. They tend to have higher rates of translocation 11;14 and less deletion 17p, but they have more comorbidities overall, so that could contribute to their inferior overall survival rate and actually more hospitalizations and complications related to their myeloma.

But we need to do better than just improved myeloma-specific survival rates, right? The data shows that we're improving survival rates for all ethnic groups, but at disparate rates. For every 1.3 years of life gained for white patients with myeloma, we've only gained 0.8 years for African-Americans. So we need to do better by helping them obtain care or second opinions at specialized centers with myeloma specialists or Centers of Excellence, expedite referrals for SCT, understand what unique characteristics that we see in African-Americans with myeloma, including higher comorbidities, higher rates of anemia and renal issues, higher levels of LDH, lower-risk cytogenetic features, and provide counsel on the value of clinical trial participation. And most important overall, we need to employ cultural competency: have respect for cultural diversity, a willingness to learn and listen from patients, appreciate the role of family in decision making for treatment, invest in and gain trust, build rapport with patients, and avoid stereotyping and generalizations for this patient population.