References

1. Rajkumar SV, Kumar S. Multiple myeloma current treatment algorithms. Blood Cancer J. Sep 28 2020;10(9):94. doi:10.1038/s41408-020-00359-2

2. American Cancer Society. Tests to find multiple myeloma. Updated February 28, 2018. Available at cancer.org.

3. National Comprehensive Cancer Network. NCCN guidelines: multiple myeloma, version 2.2024. Updated December 2023. Available at nccn.org.

4. Martin T, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: updated results from IKEMA, a randomized Phase 3 study. Blood Cancer J. May 9 2023;13(1):72.

5. Schmidt TM, Fonseca R, Usmani SZ. Chromosome 1q21 abnormalities in multiple myeloma. Blood Cancer J.
Apr 29 2021;11(4):83.

6. Martin T, Richardson PG, Facon T, et al. Primary outcomes by 1q21+ status for isatuximab-treated patients with relapsed/refractory multiple myeloma: subgroup analyses from ICARIA-MM and IKEMA. Haematologica. Oct 1 2022;107(10):2485-2491.

Minimum residual disease (MRD) is increasingly being used as a crucial endpoint in clinical trials—and is emerging as a promising tool with prognostic value across the entire disease course.

Treatment for multiple myeloma (MM) has been revolutionized in recent years with the advancement of immunologic and cellular therapies that have produced unprecedented response rates. As a result, survival rates have increased dramatically over the past two decades, with predicted 5-year survival approaching 70% or greater.¹

However, even among those achieving deep responses with modern therapies, most patients still relapse due to the persistence of myeloma cells residing in the bone marrow. Minimal residual disease (MRD) has therefore emerged as a measure of the number of malignant cells remaining in a person’s body following myeloma treatment.

“We have made significant strides in achieving deep and durable responses in MM, and MRD assessment tools and their utility allows us to measure minute amounts of disease that may remain after powerful treatments are delivered,” explains Muhamed Baljevic, MD, an Associate Professor of Medicine and Director of Plasma Cell Disorders Research and Vanderbilt Amyloidosis Multidisciplinary Programs (VAMP) at Vanderbilt University Medical Center in Nashville. “MRD assessment tools carry a significant value to both clinicians and patients because they represent one of the most informative parameters to discriminate treatment responses and prognosis.”

The evolution of MRD assessment

MRD-negative status is defined as the absence of myeloma cells in the bone marrow after treatment—and the technology to evaluate this has evolved dramatically. “Over the years, our ability to assess MRD has gradually improved, from immunophenotypic approaches with great diversity of flow cytometry-based protocols, including next-generation flow assessments such as EuroFlow, to molecular approaches with allele-specific oligonucleotide quantitative polymerase chain reaction and next-generation sequencing methods,” says Dr. Baljevic.

The sensitivity of next-generation flow (NGF) and next-generation sequencing (NGS) methods are similar, with limits of detection on the order of 10- to 100-fold lower than traditional methods. Clinical turnaround time is typically faster for NGF—about 1 day, on average—than with NGS, though NGF requires fresh samples with limited (<24 hours) processing time.^2,3

“Most recently, mass spectrometry methodologies, which further refine our ability to detect minute amounts of disease, have also been used, even for screening purposes in high-risk general populations as well,” Dr. Baljevic says.

High-risk MM clinical trials confirm validity

Recently, trial data have supported the value of MRD status assessment.^4-6 For patients with high-risk MM—who are historically very difficult to treat—Dr. Baljevic notes that data from the phase 2 GMMG-CONCEPT trial are particularly exciting. In this study, 81% of high-risk newly diagnosed patients treated with isatuximab + KRd (carfilzomib, lenalidomide, and dexamethasone) achieved MRD negativity, with MRD negativity sustained for at least a year in 62.6% of patients.⁶

“This is one of the first studies to include only high-risk patients without limiting enrollment on the basis of age or transplant eligibility,” adds Dr. Baljevic. High-risk status was defined by International Staging System (ISS) stage II/III disease plus a high-risk cytogenetic feature—that is, del117p, t(4;14), t(14;16) or more than three 1q21 copies.⁶

“Patients with high-risk disease generally have a harder time achieving most optimal and durable responses, which largely translates to shorter long-term overall survivals,” Dr. Baljevic says. “GMMG-CONCEPT is another in a line of fantastic trials that highlight the importance of the most effective multidrug treatment options in induction, followed by autologous stem cell transplantation for eligible patients, and prolonged consolidation, with multidrug maintenance approaches,” he says. “This can lead to unprecedented rates of sustained MRD negativity, including in patients with high-risk newly diagnosed multiple myeloma.”

Another recent development: Trials with quadruplet therapies have shown impressive results in newly diagnosed MM, notes Dr. Baljevic. For example, he says the GMMG-HD7 trial⁴ showed “incredible depth of response to induction therapy,” even before autologous stem cell transplant, with isatuximab + VRd (bortezomib, lenalidomide and dexamethasone) vs. VRd alone showing 50% vs. 36% MRD negative results by NGF EuroFlow.

In addition, the PERSEUS trial,⁵ which tested daratumumab + VRd (D-VRd) vs. VRd alone, used MRD as assessed by the clonoSEQ NGS assay during the maintenance phase of treatment. In this trial, 64% of patients receiving maintenance in the D-VRd group discontinued daratumumab after achieving sustained MRD negativity.

MRD negativity: the wave of the future for individualized care

Minimal residual disease (MRD) status is increasingly being used to assess response in clinical trials, with MRD negativity correlating with better patient outcomes. In real-world settings, achievement of MRD negativity has been found to significantly correlate with longer progression-free (PFS) and overall survival (OS), and has been found to ameliorate poor prognosis associated with high-risk genetic factors.²

“MRD assessment tools in MM represent the way of the future, with prognostic roles over the entire course of the disease,” says Dr. Baljevic. In fact, a large and growing body of evidence supports the prognostic role of MRD across the entire course of myeloma care.³ “MRD performance holds throughout different clinical contexts and treatment schemes, being predictive irrespective of the disease setting—newly diagnosed for transplant eligible and ineligible patients or relapsed/refractory—at various sensitivity thresholds and cytogenetic risks,” Dr. Baljevic says.

That means MRD could soon become a key assessment, which may provide physicians and patients more understanding of the depth of treatment response and, ultimately, help support the individualization of care. “Median survival of MM patients in contemporary times stretches well beyond 10 years, and MRD tools as early surrogate markers of long-term outcomes such as overall survival, will help us define the optimal management of all MM patients at all stages of the disease process,” Dr. Baljevic says. “Rather than single-time-point assessments, sustained MRD negativity over a longer period of time is likely the more important goal in disease management.”

—by Morgan Meissner

References

1. National Cancer Institute. Cancer stat facts: myeloma. Accessed February 28, 2024. Available at seer.cancer.gov.

2. Wang J, Li J, Zhang R, Li J, Chen L, Jin Y. Real-world prognostic significance of attaining minimal residual disease negativity in newly diagnosed multiple myeloma. Discov Oncol. Feb 17 2024;15(1):38.

3. Medina-Herrera A, Sarasquete ME, Jiménez C, Puig N, García-Sanz R. Minimal residual disease in multiple myeloma: past, present, and future. Cancers (Basel). Jul 20 2023;15(14). [epub]

4. Goldschmidt H, Mai EK, Bertsch U, et al. Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone as induction therapy for newly diagnosed, transplantation-eligible patients with multiple myeloma (GMMG-HD7): part 1 of an open-label, multicentre, randomised, active-controlled, phase 3 trial. Lancet Haematol. Nov 2022;9(11):e810-e821.

5. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. Jan 25 2024;390(4):301-313.

6. Leypoldt LB, Tichy D, Besemer B, et al. Isatuximab, carfilzomib, lenalidomide, and dexamethasone for the treatment of high-risk newly diagnosed multiple myeloma. J Clin Oncol. Jan 1 2024;42(1):26-37.

7. Gay F, Roeloffzen W, Dimopoulos MA, et al. Results of the phase III randomized IsKia trial: isatuximab-carfilzomib-lenalidomide-dexamethasone vs carfilzomib-lenalidomide-dexamethasone as pre-transplant induction and post-transplant consolidation in newly diagnosed multiple myeloma patients. Presented at the American Society of Hematology (ASH) Annual Meeting, December 2023.

Partnering with patients and offering support throughout their journey can boost their resilience after a relapse.

The many psychosocial challenges that patients with multiple myeloma (MM) face stem from knowing that their disease is incurable, and they almost certainly will experience relapse.¹ What’s more, according to findings from a study based on data collected from interviews with 50 relapsed and/or refractory MM patients, for many of them, relapse had a greater negative impact on their emotional well-being than their initial diagnosis, with the news of their recurring symptoms bringing on feelings of hopelessness, devastation and resignation.²

Kate Campion, DNP, AGACNP, a nurse practitioner in the hematologic malignancies department at the Sidney Kimmel Comprehensive Cancer Center, has seen this in her own practice, explaining that for the patient, “A diagnosis of cancer of any type is overwhelming—many things are happening quickly, and patients often don’t have time to process everything. With time, information and a multidisciplinary team approach, patients and their families feel supported and come to a better understanding of their disease. They get into a routine—but the routine changes at the time of relapse, which can be disconcerting.”

This can have many impacts. For example, one study estimated that approximately 25% of patients with MM are diagnosed with psychological distress and symptoms of depression.³ Among the burdens outlined by the authors: failed hopes and expectations of a cure, loss of emotional and physical stability and worries about burdening loved ones, among others. “It’s not just the health of these patients—you have to take into consideration the broad impacts that this diagnosis has on all aspects of their life: financial implications of paying for treatment, loss of income for themselves and their caregivers in time away from work to receive treatment, as well as the impact that the diagnosis has on their hopes, dreams and future plans,” says Campion.

The study authors also surveyed physicians about their patients’ distress and found that, while the majority of hematologists were aware of the emotional burdens related to relapse, many did not feel confident or that they had the time or tools to discuss these issues.³

Fortunately, there are simple steps you can take to improve their ability to not only cope but also thrive. Campion has seen the effects of helping her patients first-hand and offers these suggestions for providing psychosocial support after relapse.

1. Create a support team.

It’s crucial for physicians to help construct a healthcare team for each patient to address the impact of the condition from all angles, including the support of a clinical nurse specialist, as well as management of pain and psychological support ideally from someone specializing in oncology.

Campion emphasizes the importance of adding a social worker to the mix, who can help patients with the psychosocial aspects of their cancer, including advanced directives, and finding financial support for those who need assistance, among other things. She recommends engaging these team members in a patient’s care as soon as possible. “The earlier we can get social workers involved in addressing the needs of the individual patient, the better off they’ll be in the long run,” she says.

2. Be attuned to their emotions and provide reassurance.

For Campion, one of the most important things a healthcare provider can do for a patient processing the information that they have relapsed is to offer a path forward and be attuned to their reaction. So in addition to offering treatment options, also ask patients how they’re doing emotionally and normalize their reactions. Campion offers this example: “If I’m detecting anxiety, I state that ‘What I’m hearing is that you’re anxious. I want you to know that this is normal for patients in this situation, and you are not alone.’”

She adds, “It’s important to remind them that this is a lifelong partnership. We’re here to provide guidance, answer questions and help them and their family and caregivers. We assure them that we will always be forthcoming and honest and will ensure that we are following their wishes. This can open the door for the bigger, scarier conversations.”

For clinicians who are hesitant to broach the topic, Campion’s advice is to jump in. “Practice makes perfect. It can be uncomfortable at first, but the earlier you start those conversations, the more routine it will become,” she says.

3. Guard against isolation and depression.

Because isolation can have a negative impact on a patient’s frame of mind, Campion suggests asking patients questions such as, “Who do you have in your life to talk to? What is important to you? Where do you find strength and support?” and, when needed, “Have you been connected with a counselor?” She also recommends directing them to support groups to help them build relationships with other patients.

One thing she pays special attention to: “When I hear that they’re not seeing people as much, that’s a red flag that they may be withdrawing from relationships,” says Campion, adding that such behavior “can raise a concern for depression, which is something many of our patients experience.”

Complicating matters is that when COVID numbers climb, patients may choose to limit social interaction for health reasons. In those cases, she says, “I try to encourage them to find alternative ways to get together if they don’t feel like going out—maybe invite somebody over for a cup of coffee, or just maintain the relationship by answering the phone when people call.”

4. Help them devise a practical plan.

For patients who have relapsed and are concerned about burdening family and caregivers, Campion’s advice is to make a plan. Items to consider: deciding who among their family and friends to pull into their care, having a game plan for getting to and from appointments and, if they are working, speaking to their HR department about what to do if they need to employ the Family Medical Leave Act (which allows for missing work intermittently).

She also suggests ensuring that patients implement advance directives for end-of-life care early in the course of their disease if they have not already done so. While a healthcare provider may be hesitant to make this recommendation, she says it can actually help patients feel more in control knowing that they’ve laid out their wishes. It also answers some of the unknowns when patients think about the worst-case scenario, which can add to their overall stress, and help alleviate worries about burdening others with “big decisions.” Says Campion, “I feel like that’s one of the best gifts we can give to our families.”

5. Provide education throughout their journey.

Campion has found one of the best ways to address a patient’s anxiety after a relapse is with education—but with the right sources. “When patients go home and read everything they can, it tends to be very overwhelming and just adds to the confusion,” she says. “So I like to try to help direct them to a couple of places that have good information.” One of her favorites is the International Myeloma Foundation (myeloma.org), where patients can find information on treatments, new medications and clinical trials, and connect with other patients.

She also takes some extra time to go over the specifics. “I’m frequently re-educating them on the course of the disease so they understand what labs we’re following so there are no surprises,” she explains. She also makes sure to talk through what a future relapse may look like so they’re less likely to be caught off-guard.

6. Encourage healthy outlets.

Research suggests that stress relief is important not only for emotional resiliency, but also for enhancing immunity, including in people with chronic disease.⁴ That’s why Campion encourages patients to continue doing things they enjoy that bring them peace, such as meditation, religious activities and yoga. In general, she also advises her patients to leave the house for a walk “to be outside in the sunshine and change your view for a couple of minutes.” She says walking can not only help shift a patient’s frame of mind, it can also encourage those with low energy levels to stay active, which in turn may help alleviate their fatigue.

—by Beth Shapouri

References

1. Ahmed A, et al. Relapsed and refractory multiple myeloma. StatPearls [Internet]. Updated June 8, 2023.

2. Hulin C, et al. Living with the burden of relapse in multiple myeloma from the patient and physician perspective. Leuk Res. 2017 Aug;59:75-84.

3. Noonan K, et al. A focus on relapsed multiple myeloma. J Adv Pract Oncol. 2022 Jul;13(suppl 4):15-21.

4. Morey JN, et al. Current directions in stress and human immune function. Curr Opin Psychol. 2015 Oct 1;5:13-17.

PATIENT: CATHERINE, 46, WAS DIAGNOSED WITH MULTIPLE MYELOMA IN 2019. SHE ALSO HAD A HISTORY OF HYPERTENSION, OBESITY AND GERD.

“Choose the regimen with the highest efficacy at each line of therapy”

PHYSICIAN:
Carol Ann Huff, MD
Associate Professor of Oncology and Medical Director, Johns Hopkins Kimmel Cancer Center

History:
Catherine presented to the hospital with a pathologic fracture of her left femur. She underwent surgical repair, and her test results confirmed a diagnosis of multiple myeloma rISS Stage II, IgA lambda MM and MM FISH panel revealing t(4;14), -13). Catherine had a family and worked full time, so she was eager to start therapy.

Her first-line therapy included bortezomib, lenalidomide and dexamethasone (VRd). After we reviewed adverse effects, she started VRd for 6 cycles with subsequent ASCT. She achieved stringent complete response prior to ASCT. We were unable to do MRD testing with NGS because the baseline sample was non-informative, but we could perform flow cytometry and found her to be MRD negative at 1 x 10-5, which she maintained post-ASCT.

Catherine then went on maintenance therapy with lenalidomide and bortezomib. She continued working until the fall of 2023, about 5 years post-ASCT, when her labs showed evidence of recurrent MM based on her IgA and lambda light chain levels; she was asymptomatic. Repeat bone marrow biopsy showed 20% lambda light chain restricted plasma cells. A PET-CT bone scan revealed a new FDG avid lesion in her right femoral neck without evidence of lytic changes.

Initiating therapy:
We discussed next steps and agreed that the most important considerations were efficacy and durability. I told Catherine she was a good candidate for isatuximab. Recent data from the IKEMA trial showed that isatuximab, used in combination with carfilzomib + dexamethasone (Kd), can significantly prolong progression-free survival (PFS) in patients with high-risk genetic abnormalities. Before starting the regimen, Catherine had a baseline cardiovascular assessment, and I advised that she monitor her blood pressure, as carfilzomib may lead to blood pressure elevation in some patients, and stressed the importance of day and timing of treatment.

Catherine achieved partial response after cycle 1 and continued to work full time. After cycle 3, she achieved a very good partial response. She is tolerating the regimen well and is currently in cycle 8, having now achieved a stringent complete remission. We are hopeful that she, like those in the IKEMA trial, will achieve a median PFS >40 months. Catherine and I also discussed the many exciting new therapies as possibilities for subsequent lines of treatment. However, I reiterated that choosing the most active, most durable regimen at each line of therapy is the best strategy for achieving long-term disease-free and overall survival. She is pleased with how well she is doing and looks forward to continued remission.

Considerations:
It is important to choose the regimen with the highest efficacy at each line of therapy. High-risk patients (e.g., presence of high-risk chromosomal changes, impaired kidney function, refractory to multiple drug classes) continue to have suboptimal outcomes. Isatuximab + Kd is an efficacious second-line therapy, especially if a patient has never received it before and/or is not relapsing off of anti-CD38 therapy. In the IKEMA trial, treatment with isatuximab + Kd after early relapse resulted in median progression-free survival for approximately 42 months in high-risk patients. For people like Catherine, prioritizing a regimen with the highest long-term efficacy can help them live as well as possible for as long as possible.

KOL on Demand

Deeper and more durable responses

Q: How are the latest therapeutics improving the prognosis for relapsing MM? 

A: I do not think there has been a more exciting time than the present for patients with multiple myeloma (MM). There has been a revolution in therapies for relapsed MM. The first wave of this movement was in a series of phase III trials that explored multiple triplet combinations to provide deeper and more durable responses than had been seen before in relapsed myeloma. This has now resulted in multiple options for therapies combining agents from the three main classes of proteasome inhibitors, immunomodulatory agents and monoclonal antibodies. In addition, a fourth class of agents, XPO1 inhibitors, has been developed and now incorporated into early relapse triplet combinations.

The second major wave of relapsed therapies has been focused on later relapse and has been in the realm of immunotherapy with both CAR T-cell therapy and bispecific antibodies. Indeed, two different CAR T-cell therapies have been approved in myeloma, both of which target the BCMA (B-cell maturation antigen) on the surface of the myeloma cell. These therapies literally tripled the response rate of traditional late-stage myeloma therapies, with response rates in the 75% to 98% range. These deep and durable responses also have the advantage of CAR T-cell therapy being a “one and done” approach whereby we do not routinely give maintenance therapy after T cells are reinfused. There have also been three bispecific antibodies approved for relapsed myeloma—two that target BCMA and one that targets the novel GPRC5D antigen on the myeloma cell. These therapies have a response rate of approximately 63% to 75%, at least doubling the rate of prior therapies (with the exception of CAR T). Although they do require ongoing therapy, they do not need T-cell collection from the patient as with CAR T-cell therapy. Both CAR T-cell therapy and bispecific antibodies do come with the risks of CRS (cytokine release syndrome), neurologic toxicities and infections, but we are working toward minimizing their risks while optimizing their benefit.

—Joseph Mikhael, MD, MEd, FRCPC, FACP, Chief Medical Officer, International Myeloma Foundation; Professor, Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), City of Hope Cancer Center; Adjunct Professor, College of Health Solutions, Arizona State University

Complementary therapies

Q: What are nondrug therapies that can help manage MM?

A: One of the key phrases that guides me as I care for patients with myeloma is “we do not treat myeloma, we treat people.” We want to explore all options of therapy, both pharmacological and nonpharmacological. MM, both the disease and its treatment, comes with many symptoms that can significantly impair quality of life, including fatigue, pain, neuropathy, weight loss, insomnia and many others.

Several nondrug interventions have been explored. Fatigue can be addressed by staying active, optimizing sleep, considering aromatherapy, practicing mindfulness and doing deep breathing techniques. Similarly, methods to reduce myeloma pain may include gentle exercise, yoga, meditation, acupuncture, companionship, counseling and art/music therapy.

Neuropathy can be rather severe both from the disease itself and from therapy. Some nondrug strategies include dietary supplements (e.g., B vitamins and alpha lipoic acid), lotions/creams, essential oils, meditation and warm baths. For more information on nondrug therapies, patients can visit the International Myeloma Foundation website (myeloma.org).

—Joseph Mikhael, MD

Redefining exercise

Q: How can patients with MM exercise safely considering their risk of fracture? 

A: Myeloma is different from other cancers when it comes to physical activity. For patients with MM, the thought of exercising may be daunting due to the risk of fracture. Therefore, I like to reframe the discussion, especially for patients who are frail. I tell them it’s about decreasing sedentary time and trying to stay active. The goal is to encourage patients to preserve their independence and ability to do daily activities because it correlates with better outcomes.

A good way to broach the subject is to ask patients what they feel confident doing. Have them focus on increasing time doing activities they enjoy—for example, if they like gardening, encourage them to spend an extra hour working on their plants. When it comes to encouraging movement, I try to align with people’s lives, what they’re familiar with and what they enjoy.

Also, research shows that fitness trackers can motivate patients with MM. I like this approach because it encourages them to take more steps and helps them track their progress.

—Elizabeth O’Donnell, MD, Director of Early Detection and Prevention, Dana-Farber Cancer Institute

Promising research

Q: What are some promising advances on the horizon that could improve outcomes for relapsing MM?

A: Treatment options for MM are rapidly expanding. Working on the research side, we can see that many new treatments are very effective, and we cannot wait for those to make it to the approval finish line. For example, CAR T is expanding to include more targets other than BCMA. Other CAR T therapies are being built with more than one target or more than one arm for stronger connection with the same target. Similarly, bispecific antibodies are exploring novel targets as well.

In addition, newer CAR T therapies will be tested from an allogenic source to omit the preparation time and allow for mass production similar to that of bispecific antibodies, which have the advantage of immediate availability without manufacturing delay. Finally, many new targets are emerging every year, including small molecule drugs that are explicitly targeting plasma cells or plasma cell survival pathways such as CD73 inhibitor, perk inhibitor and IRF4 modulations.

—Shebli Atrash, MD, Assistant Professor, Clinical Medicine, Wake Forest University School of Medicine