How advances in MM are changing the treatment paradigm
In the past decade, major changes have occurred in the response criteria and treatment for relapsing multiple myeloma (MM). As the treatment of MM has advanced, so too has the molecular characterization of disease, which has expanded the definition of high-risk features beyond those used in the revised International Staging System (see box below).1
There has been a revolution in therapies for relapsed MM, says Joseph Mikhael, MD, Chief Medical Officer of the International Myeloma Foundation. “The first wave of this movement was in a series of phase 3 trials that explored multiple triplet combinations to provide deeper and more durable responses than had been seen before in relapsed myeloma,” he says. “Those trials resulted in multiple options for therapies combining agents from the three main classes of proteasome inhibitors, immunomodulatory agents and monoclonal antibodies. This is a critically important development, as high-risk MM is associated with worse progression-free and overall survival outcomes.”
More options to consider after first relapse
While it is generally agreed that more intensive therapy is warranted for patients with high-risk disease, appropriate positioning of different therapeutic options—in both the first-line and early relapse settings—remains unclear.2-4 “Among many different standard of care options, we currently lack randomized control trial data on best choice second-line therapy in relapsed/refractory multiple myeloma, including standard and especially high-risk patients,” says 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.
“Our understanding of outcomes in these patients comes mainly from subgroup analyses of major trials in patients who harbor high-risk features,” Dr. Baljevic says. Significant therapeutic advances include the following:
Anti-CD38 monoclonal antibodies (mAbs). “Introduction of anti-CD38 mAbs in the MM armamentarium represents one of the major advances that led to improvement of long-term outcomes for both newly diagnosed and relapsing MM,” says Dr. Baljevic. “Generally speaking, early incorporation of anti-CD38 mAb therapy, particularly for high-risk MM patients, is a preferred choice. While clinical trials do not have comparative head-to-head data for clear understanding if one drug may be better than the other, they all conclusively demonstrated the benefit of anti-CD38 mAb-containing triplets versus corresponding doublet therapies,” Dr. Baljevic says. Indeed, numerous clinical trials back this assertion.5-11 “Quadruplet treatments also are promising in newly diagnosed frontline settings as well as after first relapse.”
Early on, it is advisable to try to avoid repeat exposures to agents that patients may already be refractory to considering the variety of available drugs within the same or different classes, Dr. Baljevic notes. “It is essential to establish careful understanding of prior drug exposures versus refractoriness status for all treatment classes, as careful decision-making and choice of subsequent therapies needs to be tailored based on these characteristics, particularly with respect to anti-CD38 mAb therapy,” he says.
CAR T-cell and bispecific antibody therapies.
Dr. Baljevic notes that some physicians (and patients) may prefer to “upgrade” to newer generations of therapies or, increasingly, explore new options with novel mechanisms of action. “The explosion of CAR T-cell and bispecific antibody therapies in relapsing multiple myeloma and their continued studying in earlier lines will undoubtedly shape our field for years to come,” he says.
Two different CAR T-cell therapies have been approved in myeloma, both of which target the B-cell maturation antigen (BCMA) on the surface of the myeloma cell.12,13 “These therapies tripled the response rate of traditional late-stage myeloma therapies, with response rates in the 75% to 98% range,” says Dr. Mikhael. “These deep and durable responses also have the advantage of CAR T-cell therapy being a ‘one and done’ approach, as we do not routinely give maintenance therapy after T cells are reinfused.”
In addition, there are three bispecific antibodies approved for relapsed MM, two that target BCMA and one that targets the novel GPRC5D antigen on the myeloma cell.13,14 “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,” he says. Although they do require ongoing therapy, they have the advantage of not requiring T-cell collection from patients as with CAR T-cell therapy.
Focus on patient goals and inclusivity
When selecting therapy at first relapse, Dr. Baljevic says it is important to consider not only disease features and treatment history, but also patients’ unique needs. “Patient preferences and goals of care, as well as logistics of drug administration (route and frequency of administration) and treatment costs play a significant role in the ultimate decision-making process,” he says. “Patients who are part of underserved communities or demographics can be at a particular disadvantage when it comes to treatment access and subsequent long-term outcomes.”
For that reason, Dr. Baljevic says it is also important to discuss clinical trials as an option. “Consideration of clinical trials is always appropriate, especially for high-risk patients, in every phase of disease, from newly diagnosed to highly relapsed/refractory MM,” he notes. “It remains our goal to ensure clinical trials are as representative as possible of different demographic populations, so that data generated can be as broadly applicable as possible. Patients belonging to underserved populations are particularly vulnerable and deserve equal access to care.”
A bright future
As research continues, stem cell transplantation will likely be less important in the future due to better drug combinations and newer immunotherapies being used in earlier lines of therapy—a development that was inconceivable a few years ago. “In my 25 years of myeloma care and research, I do not think there has been a more exciting time than the present for patients,” says Dr. Mikhael. “In all areas of myeloma care, we have outstanding research ongoing to help patients live better and live longer—and eventually, live life without myeloma as we seek a cure.”
—by Morgan Meissner
FACTORS THAT DEFINE
HIGH-RISK DISEASE
“High-risk MM can be defined in several different ways, most commonly by the presence of high-risk cytogenetic features,” 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. High-risk MM is defined by the presence of one or more of the following:
- High-risk cytogenetic features, such as t(4;14), t(14;16), t(14;20), gain 1q, del(17p), or p53 mutation.2,3 Patients who have two or more high-risk cytogenetics are classified as having ultra-high-risk disease.
- Disease characteristics, including extramedullary disease, circulating plasma cells (or secondary plasma cell leukemia at relapse) and early relapse, defined as occurring within 24 months from the start of induction therapy.1-4
- Refractoriness to prior therapies. “Prognostic markers that influence outcomes in patients with MM relapse also include patient performance status, as well as refractoriness to major anti-MM drug classes (proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies) at the time of relapse,” Dr. Baljevic says. “Triple-class or particularly penta-class refractory patients are well described for having poor long-term overall outcomes compared with those patients who are less refractory.”
- Patient-specific characteristics. “General considerations, such as frailty, underlying significant comorbid conditions (e.g., renal impairment) as well as residual toxicities from prior therapies, can all impact how well patients with relapsed or refractory disease can tolerate subsequent therapies,” Dr. Baljevic notes.
References
1. Hagen P, et al. High-risk disease in newly diagnosed multiple myeloma: beyond the R-ISS and IMWG definitions. Blood Cancer J. May 30 2022;12(5):83.
2. Costa LJ, et al. Defining and managing high-risk multiple myeloma: current concepts. J National Compr Canc Network. Dec 2020;18(12):1730-1737.
3. Marcon C, et al. Expert consensus on the definition and management of high risk multiple myeloma. Front Oncol. 2022;12:1096852.
4. National Comprehensive Cancer Network. NCCN guidelines: multiple myeloma, version 4.2023. Updated August 25, 2023.
5. Dimopoulos M, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma: results from a randomised, multicentre, open-label, phase 3 study. Lancet. Jul 18 2020;396(10245):186-197.
6. Moreau P, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. Jun 19 2021;397(10292):2361-2371.
7. Attal M, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. Dec 7 2019;394(10214):2096-2107.
8. Dimopoulos MA, et al. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma: an open-label, randomised, phase 3 trial. Lancet Oncol. Jun 2021;22(6):801-812.
9. Landgren O, et al. Subgroup analysis based on cytogenetic risk in patients with relapsed or refractory multiple myeloma in the CANDOR study. Br J Haematol. Sep 2022;198(6):988-993.
10. Spicka I, et al. Isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma patients with high-risk cytogenetics: IKEMA subgroup analysis. Eur J Haematol. Nov 2022;109(5):504-512.
11. Martin T, 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.
12. Sheykhhasan M, et al. CAR T therapies in multiple myeloma: unleashing the future. Cancer Gene Ther. 2024;31:667-686.
13. Cohen A. CAR T cells and bispecific antibodies: new options in multiple myeloma. Targeted Oncology. March 8, 2024.
14. Swan D, et al. Bispecific antibodies in multiple myeloma: Opportunities to enhance efficacy and improve safety. Cancer. 2023 Mar;15(6):1819.
Adjunctive
therapies
to manage complications
and side effects
Managing multiple myeloma (MM) encompasses not only the use of myeloma-directed therapies but also the incorporation of adjunctive treatments. Many organ systems are affected by MM, and the effects of the disease on the body can create a variety of bothersome symptoms and potentially dangerous complications. Additionally, as patients with MM are exposed to a growing number of lines of treatment—and for longer durations with maintenance therapy regimens—management increasingly requires physicians to address various side effects.
“It’s important to educate patients and set realistic expectations,” says Carol Ann Huff, MD, Medical Director for the Johns Hopkins Kimmel Cancer Center. “Then offer support and adjustment as needed.” Here are some of the most common symptoms, complications and side effects, as well as how to address them.
Bone damage
This complication of MM is caused by the destruction and crowding out of healthy bone marrow cells by myeloma cells. As a result, bone pain is among the most common presenting symptoms of myeloma, and more than 80% of patients will develop bone complications over the course of disease.1 These include bone fracture, as well as hypercalcemia and spinal cord compression.
In addition, certain anticancer therapies, such as steroids, can lead to weakening of the bones and may contribute to progression of bone disease.2 Patients also may have comorbid conditions that place them at risk for poor bone health, including osteoporosis, metastatic malignancies, immobility and side effects from long-term steroid and other drug use. Plus, certain factors can contribute to osteoporosis, such as renal disease and hormonal changes.
Management of bone disease typically includes the use of bisphosphonates (e.g., zoledronic acid and pamidronate) and RANK-L inhibitors (e.g., denosumab). While these drugs can help slow and even reverse the progression of bone disease, they can lead to osteonecrosis, most notably osteonecrosis of the jaw (ONJ), a rare but serious side effect that may occur with prolonged use of bisphosphonates.2
Risk for ONJ can be mitigated by reducing the frequency of treatment and by avoiding invasive jaw procedures such as dental extractions and implants during treatment. All other dental procedures, including regular cleanings, fillings, root canals and crowns, should be performed as needed. Patients should be instructed to inform their dentist that they are receiving bisphosphonates or RANK-L inhibitors and encouraged to seek a second opinion from a dental specialist before receiving invasive dental procedures.
Pain medications such as narcotics may also be used to help manage bone pain. However, because MM can compromise the health of the kidneys, avoidance of nonsteroidal anti-inflammatory drugs is generally recommended.3 In cases of severe bone disease, surgery may be needed to address fractures and other complications.
Neuropathy
Certain treatments can lead to nerve damage and peripheral neuropathy, which causes numbness, tingling or pain in the extremities. “Neuropathy can be problematic as there are not available therapies to treat this, only medications that may lessen the intensity of neuropathy symptoms,” says Dr. Huff. “Early intervention and prevention, where possible, are the best approaches.”
Neuropathy has been identified as a potential side effect of the immunomodulatory drug (IMiD) thalidomide as well as the proteasome inhibitors bortezomib and ixazomib.3 The risk for peripheral neuropathy with bortezomib can be reduced by using subcutaneous forms and weekly dosing. If peripheral neuropathy occurs, Dr. Huff suggests early intervention with dose reductions if possible. She also recommends careful questioning to identify early symptoms that may warrant dose adjustment or intervention.
“Some have found supplements helpful to lessen neuropathy, although clinical trials are lacking,” she notes. These include coenzyme Q10, B vitamins and alpha lipoic acid. “Neuropathy that is painful is also sometimes helped with gabapentin, pregabalin or duloxetine.”
Blood effects
A variety of blood effects can be observed as a result of both MM and treatment, including anemia, thrombocytopenia and neutropenia, as well as thromboembolic disease. These effects can lead to other—potentially serious—complications as well, including bleeding, infection and fatigue. In addition, neutropenia and other blood effects are seen in patients treated with anti-CD38 monoclonal antibody-based regimens, IMiDs (lenalidomide and pomalidomide), proteasome inhibitors (bortezomib) and the nuclear export inhibitor selinexor.- When patients are receiving IMiDs such as thalidomide, lenalidomide or pomalidomide, additional medications, including low molecular weight heparin, warfarin or one of the newer direct anticoagulants, are often added to reduce the risk of blood clots.3,4
Blood effects may be managed with dietary supplements (e.g., iron for anemia) as well as colony-stimulating factors. Preventive measures, including vaccinations, antibiotics, antivirals and—depending on the treatment regimen—antifungals and intravenous antibodies, may be administered to reduce the risk of infection due to neutropenia.
Gastrointestinal effects
A variety of MM treatments can cause gastrointestinal problems such as constipation, diarrhea, nausea and vomiting.2,3 Dr. Huff notes that diarrhea is particularly a problem with long-term lenalidomide treatment. “For lenalidomide-associated diarrhea, use of bile acid-binding resins can help,” she says. “Cholestyramine or colesevelam are often more helpful than OTC antidiarrheals.”
Dr. Huff notes that constipation can also occur with steroid use, as well as with the use of antiemetics such as ondansetron and certain pain medications. Stool softeners or laxatives can help relieve constipation, as well as a high-fiber diet, increased water intake and gentle exercise.
Sleep disturbances
Sleep problems such as insomnia are a common side effect associated with steroid use. Changes in sleeping patterns can also be indicative of nervous system effects associated with bispecific antibody therapies.2
“Sleep disturbances can be mitigated in some by changing the time of day of steroid administration, using sleeping medications, and with dose reductions of steroids where necessary,” says Dr. Huff. For example, she says, “Sometimes nighttime dosing helps as patients sleep through the first 6 to 8 hours.” She cautions that this approach will not work for all patients, though, and may not be possible depending on the requirements of treatment. At times, steroid dose reductions where medically appropriate may be needed. Melatonin or other sleep aids are of variable help.
Novel drug side effects
CAR T-cell therapies and bispecific antibodies represent new classes of drugs that have revolutionized MM treatment, particularly in later stages of disease. However, with these has come a new set of rare but potentially serious side effects, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).2,3 Use of these drugs requires prolonged monitoring to support early detection and rapid initiation of treatment within specialized centers.
—by Morgan Meissner
NONDRUG INTERVENTIONS FOR MANAGING MYELOMA SYMPTOMS
In addition to adjunctive medical treatments, it’s important to discuss nondrug therapies with patients, notes Shebli Atrash, MD, Assistant Professor of Clinical Medicine, Wake Forest Medical College, and multiple myeloma specialist at Atrium Health Levine Cancer Institute, Charlotte, NC. “Complementary and supportive therapies can significantly manage symptoms and improve the quality of life for individuals with multiple myeloma,” he says. Here, Dr. Atrash discusses some of the nondrug interventions that can help.
Q. What types of exercise do you recommend to patients and why?
A. Many myeloma therapies increase the risk of blood clots. Therefore, physical activity and exercise are advisable. Walking is the preferred physical activity because running or lifting weights could cause fractures in weak bones. Other good options include a stationary bike with low level of resistance or an elliptical machine. In general, there should be more focus on light exercises. I tell my patients, “The more you do, the better, but if you have muscle soreness the next day it means you overdid it.”
Q. Which complementary therapies might be helpful?
A. There are several options, but I’ll point out two of them. First, acupuncture appears to be promising and is currently undergoing investigation to explore its capabilities in the treatment of peripheral neuropathy, nausea and fatigue. Another thing that can help patients overall: engaging in creative activities to reduce stress. These activities—for example, journal writing, taking an art class or doing photography—can offer a sense of accomplishment and distraction from symptoms.
Q. What psychosocial interventions do you recommend?
A. The available support groups for multiple myeloma are exceptional because of the strength of support that families and friends have created. These can provide emotional support, a sense of community and a venue to share experiences and coping strategies. Patients can find them through the International Myeloma Foundation (myeloma.org), the Leukemia & Lymphoma Society (lls.org) and similar organizations.
Q. Are there any simple, everyday strategies that
patients may find helpful?
A. Yes, and one of the most important is hydration. Myeloma progression is often complicated with dehydration symptoms. Staying hydrated can help manage symptoms such as fatigue and constipation and help protect the kidneys from myeloma injury.
In addition, muscle cramps remain a problem for patients on chemotherapy. Swallowing a teaspoon of mustard or an ounce of pickle juice might help decrease muscle cramps, as reported anecdotally by patients. It has not been determined why these may help. Some research speculates it could be because they contain acetic acid, which the body uses to produce acetylcholine, an essential neurotransmitter for leg muscle contractions. Yellow mustard is the only kind of mustard documented to relieve nighttime leg cramps, although more research is needed to confirm this.
References
1. Bernstein ZS, et al. Bone disease in multiple myeloma: biologic and clinical implications. Cells. Jul 27 2022;11(15).
2. American Cancer Society. Drug therapy for multiple myeloma. Updated August 15, 2023. Available at cancer.org.
3. The Multiple Myeloma Research Foundation. Treatments for multiple myeloma. Available at themmrf.org.
4. Mikulaki D, et al. Risk factors of infection in relapsed/refractory multiple myeloma patients treated with lenalidomide and dexamethasone (RD) regimen: real-life results of a large single-center study. J Clin Med. 2022 Oct;11(19):5908.
Managing
the pain
and fatigue
of multiple myeloma
Adjusting to the idea that you must face down a form of chronic blood cancer for the rest of your life is hard enough, and then there’s dealing with the daily reality—namely, the pain and fatigue that dog the days of many with multiple myeloma (MM), according to a survey in the Annals of Hematology.1 Understanding why they are reported so often is complex. “It’s partially related to the disease itself,” explains Kate Campion, DNP, AGACNP, a nurse practitioner in heme malignancies specializing in MM at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital. After all, MM is a cancer of plasma cells in the bone marrow, which can impact not only the bones (giving them a moth-eaten appearance), but also organs like the kidneys. It can also lead to lytic lesions (i.e., the loss of pockets of bone), fractures, and spinal cord compression, all of which contribute to discomfort and exhaustion.
Plus, Campion points out that other factors, including anemia and side effects of the drugs used to treat the disease, can contribute to making a patient feel run down. Not to be underestimated is the psychological element—there is good evidence that both pain and fatigue are linked to global distress as well as depression in patients with MM, according to research published in Cancer Nursing.2
The encouraging news is that a multipronged care approach to easing discomfort, decreasing stress, and boosting energy can be a boon to MM patients. And while pain medication like acetaminophen (for patients on blood thinners) and gabapentin (for nerve pain) may be of help, other lifestyle and psychosocial strategies may also improve outcomes. Campion breaks down those she’s found helpful in her practice below.
Recommend hydration and good nutrition
While Campion says there’s no specific diet recommended for MM patients, adopting a well-balanced, nutrient-dense meal plan can help anyone feel better, so it makes sense to counsel patients on such an approach. Think a good mix of unprocessed foods with lots of colorful vegetables and lean protein. “Water intake is also something to look at,” says Campion. “As long as there aren’t fluid restrictions from a cardiac standpoint, staying well hydrated may help.” The American Cancer Society’s nutrition guides can be a good place to point a patient for more guidance.
Encourage exercise
While MM patients may not always feel motivated to exercise, Campion insists she’s seen benefits when patients “stay moving as much as possible.” She adds, “From the fatigue standpoint, it can help patients avoid muscle wasting and encourage the body to stay at the right point in the circadian rhythm, so it may help patients sleep well.” Plus, as a 2023 literature review in the Journal of the Advanced Practitioner in Oncology points out, study participants who are active often show better measures of fatigue, pain and mood.3
Of course, every patient is different, and the amount and type of activity for each one should be tailored to them. However, generally, Campion recommends low-impact exercise. “Cycling tends to be something that our patients can do and enjoy. Swimming is one of the best things—a full body workout and no impact on the joints. Walking is another—we encourage patients to take even just a 15- to 20-minute walk a day.”
Helping patients focus on something to look forward to—and work toward—can keep them moving as well. “I ask if there’s something specific you want to be doing that you can no longer do—like pickleball, golf or spending time with grandkids without exhaustion,” she says. Identifying something to build strength and stamina toward can help keep them motivated—and meeting those goals can improve their quality of life.
Treat anemia
Between 60% and 70% of patients have anemia at the time of diagnosis, according to the International Myeloma Foundation, which contributes to the weak and tired feeling. How Campion tackles anemia depends on the cause. If it’s present at diagnosis, treating the myeloma may correct it, but for those experiencing it as a side effect of medication or who have a concurrent issue with iron deficiency, she suggests replacing it with a supplement.
Suggest a massage
“Massages are great self-care,” insists Campion. When it comes to aches and pains, a trip to a massage therapist may be helpful; however, a practitioner should take care in the kind they recommend to cancer patients. “Generally, a relaxation massage will be okay; however, we guide our patients to avoid deep tissue massage,” says Campion. That type of treatment can be too rough for those with MM.
Talk about sleep
“A lot of times if your pain is uncontrolled, it affects sleep,” says Campion. “Taking steroids as part of treatment can impact it. But you also just have stress around the diagnosis—thinking about the treatment, what’s coming next what’s coming down the road can keep people up.” For help for the last point, Campion suggests reaching out for counseling or support groups either online or in their area to help manage feelings of isolation and provide an outlet to talk about stress, anxiety and depression.
Her other recommendation: going over good sleep hygiene with the patient. “This includes limiting screen time before bed and trying to have a set bedtime routine to get your brain and body ready to sleep,” she says.
Greenlight taking it easy
It may seem obvious to suggest rest to patients, but it’s easy to overlook—and having a care provider encourage it may be just the catalyst a patient needs to make it a priority. “I think that’s so important. Your body is going through a lot, especially while on active treatment,” Campion says. While encouraging exercise is important, she tells her patients: “If your body is tired and telling you to take a nap, it’s time to pause!”
Emphasize stress relief
Stress is not a friend to anyone grappling with pain or fatigue. Keeping it in check can be very helpful, says Campion, “Especially early on in the first cycle or two of treatment,” when there are many unknowns, and patients “are glued to the results of their treatment.” Acupuncture, yoga and meditation are all on her list of recommendations. She also encourages patients to tell their doctors exactly what thoughts and questions may be keeping them up at night. She tells them: “Don’t sit on it, stressing about the what-ifs! Send us a message through the charting system, and we’ll respond.”
Consider pain-relief interventions
Some patients who are experiencing pain and fatigue from MM may benefit from the addition of certain therapies to their care plan. For example, radiation therapy.4 Explains Campion, for people with large and painful lesions, “Radiation therapy decreases the activity at the lesion, and the myeloma is essentially dead at that spot.” It can also be helpful in targeting masses because “it decreases the size [of the mass] so it’s not pressing on the nerve.”
Vertebroplasty (in which bone cement is injected into problem vertebrae) and kyphoplasty (a similar procedure using inflatable balloons) have also proven to be effective pain relief in treating fractures, and a 2023 study found these therapies to be equally effective in their outcomes on pain relief and quality of life improvements.5
Keep a calendar
Campion’s last suggestion for managing pain and fatigue: Helping a patient identify if their medication is a contributing factor. She does that by having her patients record how they’re feeling on a calendar. “We like to use calendars because some patients use a calendar to keep track of medications already. It’s nice to use that also for recording side effects and how it’s related to the cycle—if the effects are drug-related, I would expect symptoms to build at the beginning of the drug cycle.” This can help her adjust doses or make decisions about what strategies to recommend from there.
—by Beth Shapouri
References
1. Nielsen LK, et al. Health-related quality of life in patients with multiple myeloma participating in a multidisciplinary rehabilitation program. Ann Hematol. 2021;100(9):2311-2323.
2. Wilson Rogers LP, et al. Are pain and fatigue in multiple myeloma related to psychosocial factors?: a systematic review. Cancer Nurs. 2020;43(3):E121-E131.
3. Hillengass M, et al. J. Physical activity in multiple myeloma: a review of the current literature. J Adv Pract Oncol. 2023;14(2):153-158.
4. Tsang RW, et al. Radiation therapy for solitary plasmacytoma and multiple myeloma: guidelines from the international lymphoma radiation oncology group. Int J Radiat Oncol Biol Phys. 2018;101:794-808.
5. Garnier J, et al. Kyphoplasty versus vertebroplasty in osteoporotic thoracolumbar spine fractures. Short-term retrospective review of a multicentre cohort of 127 consecutive patients. Orthop Traumatol Surg. 2012;6:S112-S119.
Case Study
PATIENT: WAYNE, 69, WAS DIAGNOSED WITH MM IN 2012. HIS MEDICAL HISTORY WAS NOTABLE FOR CORONARY ARTERY DISEASE WITH A HISTORY OF 3 STENTS, HEART FAILURE WITH PRESERVED EJECTION FRACTION, ATRIAL FIBRILLATION, HYPERTENSION AND TYPE 2 DIABETES.
“We had to consider
his high-risk features before starting second-line therapy”
PHYSICIAN:
Patrick Hagen, MD
Associate Professor of Medicine, Division of Hematology & Oncology, Loyola University Medical Center, Maywood, IL
History:
In 2012, Wayne presented to the hospital complaining of progressive lower back pain with radiation to the front of his abdomen for the previous 2 months. He was prescribed physical therapy and OTC pain medication without improvement. Eventually his symptoms worsened to the point that he needed a walker.
Wayne was sent for an MRI, which revealed a T10 compression fracture with associated soft tissue abnormality and renal lesion suspicious for malignancy. He was then transferred to our medical center to have surgery for his fracture. His pathology report revealed a plasmacytoma.
Wayne, married with one son, retired 4 years ago. He and his wife enjoyed gardening, and every few weeks they drove an hour to visit their son and two grandchildren. However, Wayne’s recent symptoms, including increasing fatigue and exacerbation of chronic back pain, had prevented him from doing what he enjoyed.
When Wayne came to see me, his initial serum studies showed immunofixation electrophoresis with a monoclonal IgG-kappa M-protein with a suppressed albumin and normal B2-microglobulin. Bone marrow biopsy showed >30% plasma cell monoclonality and a negative MM FISH panel. A skeletal survey was unremarkable, other than the already known T10 lesion. Based on these results, Wayne’s diagnosis was IgG-kappa MM R-ISS stage II. We discussed treatment, including potential adverse effects. He started on bortezomib and dexamethasone, completing 7 cycles of therapy, which he tolerated well. Bone marrow biopsy after cycle 6 did not show significant reduction in tumor burden, so lenalidomide was added, which he tolerated well, other than fatigue. Subsquently, he achieved a very good partial response (VGPR) to induction therapy. After receiving 11 cycles of chemotherapy and autologous stem cell transplantation (ASCT), he was put on maintenance therapy with lenalidomide. Adjunct treatments included denosumab.
Wayne remained in remission for nearly 10 years. Unfortunately, 2 years ago he relapsed following increasing fatigue, exacerbation of chronic back pain and recurrent infections. Serum studies showed M-protein had reappeared and kappa and lambda free light chains had increased, among other signs of progression. Bone marrow biopsy showed 67% plasma cells and MM FISH panel was positive for del17p, a high-risk chromosomal abnormality.
Initiating treatment:
Wayne and I discussed second-line therapy, including adverse effects. He was a good candidate for a regimen that included isatuximab, as recent data have shown significantly prolonged progression-free survival in high-risk patients. We started Wayne on isatuximab-carfilzomib-dexamethasone (KRd), which he tolerated well.
After eight cycles, he showed VGPR and bone marrow showed no clonal plasma cells. He also had clinical improvement with increased energy, minimal back pain and no more infections. He had a repeat bone marrow biopsy showing he was in complete response with no detectable malignant plasma cells in the bone marrow, but MRD testing was positive, indicating minimal residual disease activity. He received a second ASCT and was put on maintenance therapy with isatuximab. At his 1-month follow-up, Wayne said he felt better and was back to his normal activities, for which he and his wife were grateful. He is now 18 months post-transplant and remains on isatuximab maintenance and in complete response.
Considerations:
While there has been significant advancement in treatments for MM, unmet needs remain. High-risk patients continue to have suboptimal outcomes, including patients who are older, have high-risk chromosomal changes, have impaired kidney function and those who are refractory to multiple drug classes.
In a subgroup analysis of the IKEMA trial, treatment with isatuximab + Kd after early relapse of MM resulted in median progression-free survival for approximately 42 months in a patient population enriched with high-risk genomics including del17p. After relapse, it’s critical to use the most efficacious treatment early rather than reserving it for third-line or later therapy in order to achieve the deepest and longest remissions. For high-risk patients like Wayne, prioritizing a regimen with the highest long-term efficacy can improve outcomes and help them live as well as possible. In addition, the combination of isatuximab + Kd is well tolerated and rarely leads to adverse events requiring dose reductions or discontinuation of therapy, which for a patient like Wayne (and most MM patients over the age of 70) is critical due to his many comorbidities.
KOL on Demand
Q&A
Insight on managing
multiple myeloma
Helping patients cope
Q: Are there aspects of living with multiple myeloma that HCPs may not fully appreciate or address?
A: Living with multiple myeloma, a complex and often unpredictable cancer, introduces a variety of challenges that may extend beyond the immediate scope of medical treatment. Healthcare professionals (HCPs) might sometimes overlook the full impact of the disease, particularly the psychological, social and long-term management aspects that significantly influence patient well-being. Patients with multiple myeloma often endure chronic pain and fatigue, which can severely limit daily functioning and diminish quality of life. Moreover, the emotional and psychological toll of managing a chronic, life-threatening illness can lead to significant stress and mental health issues, potentially affecting patient adherence to treatment protocols and overall treatment outcomes.
To address these multifaceted challenges, it is crucial for HCPs to adopt a holistic care approach. This approach should include regular and thorough assessments of physical symptoms like pain and fatigue, as well as the provision of comprehensive support services. Referrals to pain management specialists and palliative care should be made when necessary to help manage symptoms effectively. Furthermore, emotional and psychological support through counseling services and support groups should be readily available to help patients cope with the mental health challenges posed by the disease.
Educational initiatives are also essential. By thoroughly informing patients about the nature of multiple myeloma and involving them in treatment decisions, HCPs can empower patients, enhancing their engagement and compliance with treatment plans. Employing a multidisciplinary team approach—integrating the expertise of oncologists, nurses, social workers, and psychologists—is vital. Such teams can work collaboratively to address the comprehensive needs of multiple myeloma patients, ensuring that all aspects of the disease are managed, from the physical to the psychosocial. This integrative strategy not only improves the care experience, but also optimizes clinical outcomes, paving the way for a more patient-centered approach to chronic cancer management.
—Francisco J. Esteva, MD, PhD, Chief, Division of Hematology and Medical Oncology at Lenox Hill Hospital, New York City
MRD assessment
Q: What is the role of MRD in the treatment of multiple myeloma?
A: Minimal residual disease (MRD) status is increasingly being used to assess treatment response, with MRD negativity correlating with better patient outcomes. MRD assessment tools in multiple myeloma represent the wave of the future, with prognostic roles over the entire course of the disease. MRD performance holds throughout different clinical contexts and treatment scenarios, 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. Ultimately, using MRD tools as early surrogate markers of long-term outcomes such as overall survival will help us define the optimal management of all multiple myeloma patients at all stages of the disease process. Rather than single-time-point assessments, sustained MRD negativity over a longer period of time is likely the more important goal in disease management.
—Muhamed Baljevic, MD, Director of Plasma Cell Disorders Research and Vanderbilt Amyloidosis Multidisciplinary Programs, Vanderbilt University Medical Center, Nashville
Early detection
Q: What is smoldering multiple myeloma, and how do you monitor these patients?
A: Smoldering multiple myeloma represents a critical, precancerous stage in the development of multiple myeloma, positioned between monoclonal gammopathy of undetermined significance (MGUS) and symptomatic multiple myeloma. Unlike MGUS, which has a lower risk of progression, smoldering multiple myeloma is characterized by a greater burden of malignant plasma cells, but does not manifest organ damage or overt symptoms typically associated with active multiple myeloma. Therefore, while immediate treatment may not be necessary, vigilant patient monitoring is essential due to the elevated risk of progression to active disease, which stands at approximately 10% per year for the first 5 years following diagnosis.
Monitoring patients with smoldering multiple myeloma is a complex, multifaceted process aimed at early detection of disease progression to initiate timely treatment and mitigate potential complications. This surveillance includes regular clinical assessments and diagnostic evaluations. Blood tests are routinely conducted to measure levels of monoclonal proteins, which are indicative of the plasma cell population dynamics. Additionally, bone marrow biopsies are performed periodically to assess cellular changes and progression risk more directly.
Imaging studies, such as MRI or CT scans, play a crucial role in detecting early signs of bone damage or other structural abnormalities that could suggest a transition toward symptomatic myeloma. The frequency and intensity of monitoring are tailored based on individual risk assessments, which incorporate specific biomarkers and disease characteristics. Patients deemed at high risk of progression might undergo more frequent testing and closer clinical observation. This proactive monitoring strategy is vital in managing patients with smoldering multiple myeloma, as it allows healthcare professionals to swiftly address any changes in the disease state, thereby optimizing patient outcomes and preparing for potential treatment initiation at the earliest signs of active myeloma.
—Francisco J. Esteva, MD, PhD
Clinical Minute:
Special thanks to our medical reviewers:
Carol Ann Huff, MD, Associate Professor of Oncology and Medical Director, Johns Hopkins Kimmel Cancer Center
Muhamed Baljevic, MD, Associate Professor of Medicine, Director of Plasma Cell Disorders Research and Vanderbilt Amyloidosis Multidisciplinary Programs (VAMP) at Vanderbilt University Medical Center in Nashville
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