Key Clinical Decisions in Frontline Multiple Myeloma Management

Background Results Conclusions

Given the goal of using the most effective therapies as early as possible, what would be considered the optimal frontline treatment approach today and in the near future, assuming cost and regulatory constraints are not limiting factors?

Although the current standard of care is quadruplet therapy (anti-CD38 monoclonal antibody, lenalidomide, proteasome inhibitor, and dexamethasone), it is clear that the field is moving very quickly. The approach is not likely “one size fits all.” Looking ahead, there are interesting approaches in clinical development, including iberdomide-based induction regimens (iberdomide is a CELMoD ) and incorporation of bispecific antibody therapy as part of upfront therapy. It is also likely that CAR T-cell therapy will eventually become an important part of upfront treatment, particularly for patients with high-risk disease.

What strategies do you use when discussing ASCT with patients who are hesitant about the procedure?

I generally explain that for transplant, safely delivering melphalan is paramount and that numerous clinical trials have shown improved depth and duration of response with the procedure. I talk about viewing frontline therapy as a 3-pronged strategy that incorporates induction, transplant, and maintenance and that each prong contributes to the overall duration of disease control. I talk about the quality-of-life data from the phase III DETERMINATION trial, which showed only transient changes in quality of life in the transplant arm, so ASCT is a short-term investment with respect to a disruption to normal life and perturbation of quality of life with a long-term goal of delaying disease relapse.

Have patients ever asked about receiving a second stem cell transplant, and how do you address those requests?

Yes, patients often ask about a second transplant. I confirm that we always collect enough cells for 2 transplants, but in the current era, it is exceedingly unlikely that I would recommend a second transplant. We talk about all the new salvage therapies that have been and are being developed, which are very effective. In that setting, current options are less toxic and more effective than a salvage transplant. We also discuss how the stored stem cells are sometimes useful for stem cell boosts for patients with prolonged cytopenias post–CAR T-cell therapy.

Given the similar progression-free survival data between arms in the BENEFIT trial, do you think it is worthwhile to add bortezomib?

In the phase III BENEFIT trial , patients were randomized to receive either isatuximab plus bortezomib/lenalidomide/dexamethasone or isatuximab plus lenalidomide/dexamethasone. I think the question of whether to use quadruplet therapy for frail, older patients has not been completely answered. Unfortunately, clinical trials are not always reflective of our real-world transplant-ineligible population. Certainly, longer follow-up is needed to better assess progression-free survival, but I think a major takeaway from this study is that quadruplet therapy can induce deeper responses. One key question is whether measurable residual disease negativity in a frail, older patient is the primary goal or whether the primary goal is disease control while minimizing impact on quality of life. Another key question is how quickly one can de-intensify treatment and continue with a maintenance-type approach (eg, daratumumab plus lenalidomide). Overall, I always take an individualized approach with each patient, whether starting with a triplet and then intensifying to a quadruplet vs sticking with a triplet or starting with a quadruplet and then de-escalating therapy, and carefully consider modifications to dosing and schedule in an effort to preserve quality of life.

Your Thoughts

What differences in experiences do you see between quadruplet and triplet regimens in your practice for patients with multiple myeloma? -->

Key Takeaways

• Frontline multiple myeloma treatment is evolving toward the use of quadruplet therapy regimens.
• Treatment strategies should be individualized based on patient fitness, preferences, and goals of care. Multiple myeloma management continues to evolve as new therapies expand treatment options and improve patient outcomes. Healthcare professionals are increasingly faced with complex decisions that include when to initiate treatment, how to tailor frontline therapy based on disease characteristics and patient preferences, and how to counsel patients about the role of autologous stem cell transplant (ASCT) . In this commentary, Sarah A. Holstein, MD, PhD, shares perspectives on these key clinical questions and discusses practical approaches to patient management in the current treatment landscape. How do you quickly identify patients who should start treatment before completing a full workup vs after completing a full workup? If there is evidence of acute renal insufficiency (generally very high levels of light chains), the first step is to initiate pulse dexamethasone (40 mg daily for 4 consecutive days). If the patient is hospitalized, is undergoing workup, and has acute renal failure, hydration, steroids, and bortezomib should be initiated as soon as possible once the labs show evidence of multiple myeloma (ie, abnormal free light chain ratios and/or monoclonal immunoglobulins as detected by serum protein electrophoresis/serum immunofixation electrophoresis and/or urine protein electrophoresis/urine immunofixation electrophoresis). Bone marrow biopsy and whole-body imaging should be scheduled as soon as possible, but it is not necessary to wait for the results to begin treatment. If, however, there is not an indication for urgent treatment (ie, no acute renal failure or hypercalcemia), it is preferred to complete the entire workup (labs, bone marrow biopsy, whole-body imaging) and then start definitive induction therapy. If disease burden is high and induction therapy is delayed, I would also advise an initial course of pulse dexamethasone for debulking while awaiting initiation of therapy. Nevertheless, if a patient is presenting with something like spinal cord compression, then steroids plus urgent referral to radiation oncology are in order. Given the goal of using the most effective therapies as early as possible, what would be considered the optimal frontline treatment approach today and in the near future, assuming cost and regulatory constraints are not limiting factors? Although the current standard of care is quadruplet therapy (anti-CD38 monoclonal antibody, lenalidomide, proteasome inhibitor, and dexamethasone), it is clear that the field is moving very quickly. The approach is not likely “one size fits all.” Looking ahead, there are interesting approaches in clinical development, including iberdomide-based induction regimens (iberdomide is a CELMoD ) and incorporation of bispecific antibody therapy as part of upfront therapy. It is also likely that CAR T-cell therapy will eventually become an important part of upfront treatment, particularly for patients with high-risk disease. What strategies do you use when discussing ASCT with patients who are hesitant about the procedure? I generally explain that for transplant, safely delivering melphalan is paramount and that numerous clinical trials have shown improved depth and duration of response with the procedure. I talk about viewing frontline therapy as a 3-pronged strategy that incorporates induction, transplant, and maintenance and that each prong contributes to the overall duration of disease control. I talk about the quality-of-life data from the phase III DETERMINATION trial, which showed only transient changes in quality of life in the transplant arm, so ASCT is a short-term investment with respect to a disruption to normal life and perturbation of quality of life with a long-term goal of delaying disease relapse. Have patients ever asked about receiving a second stem cell transplant, and how do you address those requests? Yes, patients often ask about a second transplant. I confirm that we always collect enough cells for 2 transplants, but in the current era, it is exceedingly unlikely that I would recommend a second transplant. We talk about all the new salvage therapies that have been and are being developed, which are very effective. In that setting, current options are less toxic and more effective than a salvage transplant. We also discuss how the stored stem cells are sometimes useful for stem cell boosts for patients with prolonged cytopenias post–CAR T-cell therapy. Given the similar progression-free survival data between arms in the BENEFIT trial, do you think it is worthwhile to add bortezomib? In the phase III BENEFIT trial , patients were randomized to receive either isatuximab plus bortezomib/lenalidomide/dexamethasone or isatuximab plus lenalidomide/dexamethasone. I think the question of whether to use quadruplet therapy for frail, older patients has not been completely answered. Unfortunately, clinical trials are not always reflective of our real-world transplant-ineligible population. Certainly, longer follow-up is needed to better assess progression-free survival, but I think a major takeaway from this study is that quadruplet therapy can induce deeper responses. One key question is whether measurable residual disease negativity in a frail, older patient is the primary goal or whether the primary goal is disease control while minimizing impact on quality of life. Another key question is how quickly one can de-intensify treatment and continue with a maintenance-type approach (eg, daratumumab plus lenalidomide). Overall, I always take an individualized approach with each patient, whether starting with a triplet and then intensifying to a quadruplet vs sticking with a triplet or starting with a quadruplet and then de-escalating therapy, and carefully consider modifications to dosing and schedule in an effort to preserve quality of life. Your Thoughts What differences in experiences do you see between quadruplet and triplet regimens in your practice for patients with multiple myeloma? -->