Anti-CD38 monoclonal antibodies in early relapse

Anti-CD38 monoclonal antibodies (mAbs) have emerged as integral components of early relapse treatment approaches.³ “One of the things we started to realize was that anti-CD38 drugs, like daratumumab and isatuximab, really function optimally as part of an upfront strategy and/or as part of an early-relapse strategy,” explains Dr. Richter.

Guidelines from the National Comprehensive Cancer Network (NCCN) list daratumumab-based combination therapy as an option for primary treatment of both transplant-eligible and -ineligible patients.³ As a result, Dr. Richter notes that an increasing number of patients are entering first relapse anti-CD38-exposed. “As long as they’re not refractory to it, and most people are not refractory to an anti-CD38 going into early relapse, we recommend incorporating an anti-CD38 as part of your early relapse strategy,” he says.

Choosing an anti-CD38-based regimen

“One of the things we started to realize was, pound for pound, anti-CD38s plus carfilzomib are more efficacious regimens than anti-CD38s plus pomalidomide,” notes Dr. Richter. Within the NCCN guidelines, carfilzomib in combination with either daratumumab or isatuximab (and dexamethasone) is considered a preferred early-relapse regimen, particularly for those with bortezomib- or lenalidomide-refractory disease.³

“So for the patients we worry about the most—the high risk, the functionally high risk (early relapse), those with extramedullary disease—we tend to give an anti-CD38 plus carfilzomib,” says Dr. Huff. “And although we can never compare trial to trial, if you look at the early relapse data, the best data to date are the IKEMA data.”

The IKEMA trial: unprecedented progression-free survival

The IKEMA phase 3 clinical trial evaluated the efficacy and safety of isatuximab in combination with carfilzomib and dexamethasone (Isa-Kd) in patients with 1 to 3 prior lines of therapy. Updated results from the IKEMA trial were published in May 2023, which demonstrated a median progression-free survival (PFS) of 35.7 months after a median 44 months of follow-up, as evaluated by an Independent Response Committee.⁴ Further analysis following the FDA recommendations on censoring rules showed a median PFS of 41.7 months.

“That is an absolutely incredible number,” emphasizes Dr. Richter. “And it’s available everywhere—community, academic, you name it—and it doesn’t require any special technology.” Dr. Richter adds that for many patients, particularly those with significant cardiac disease, use of carfilzomib may be more complicated or contraindicated. In these cases, an anti-CD38-based regimen plus pomalidomide may be preferred.

Selecting an anti-CD38 mAb

Both Dr. Richter and Dr. Huff note that isatuximab and daratumumab are highly active and efficacious therapies that are well-tolerated in early relapse of MM. Dr. Richter says that for patients who responded well to daratumumab as primary treatment, there is a strong likelihood that the drug will work again. However, if patients have received another line of therapy since daratumumab, he notes he may elect to treat with isatuximab instead.

“For people who have progressed on daratumumab in an early setting, if they’ve had a chance to repopulate their CD38 expression (typically 4 to 6 months), I consider using isatuximab in the relapse setting,” says Dr. Richter.

Dr. Huff and Dr. Richter also note that there is emerging evidence to suggest that patients with a gain of chromosome 1q—typically considered a poor prognostic marker in MM—may respond to isatuximab treatment.⁵

In a subgroup analysis of the IKEMA and ICARIA-MM trials—the latter of which investigated the use of isatuximab in combination with pomalidomide and dexamethasone (Isa-Pd)—PFS was improved in isatuximab-treated patients with 1q gain mutations (1q21+) compared with patients who received Pd or Kd alone.⁶ Based on these results, one may consider isatuximab over daratumumab in combination with carfilzomib or pomalidomide in this situation.

Two key considerations for optimal treatment

First, Dr. Huff emphasizes that treatment within the early relapse setting of MM should be a collaborative process with both patients and family members. “Decision-making is shared,” Dr. Huff emphasizes. All discussions should incorporate insights from both the healthcare team and patient as well as family members involved in care.

And the second: “Try to use three-drug combinations as long as possible, substituting at least one new agent—two if high-risk early relapse,” she added. “Employ the regimen with the greatest probability for longest duration of remission while taking all other factors into consideration.”

—by Morgan Meissner

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 3.2023. Updated December 8, 2022.

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.

Treatment of multiple myeloma (MM) is based not only on the use of cancer-directed therapies but also on 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 healthcare professionals to address various treatment-related side effects.

“It’s important to educate patients and set realistic expectations,” says Carol Ann Huff, MD, Associate Professor of Oncology andMedical Director for the Johns Hopkins Kimmel Cancer Center. “Then offer support and adjustment as needed.” Here are some of the most common disease symptoms, complications and drug 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, including renal disease, hormonal changes, depression and diabetes as well as vitamin D and other vitamin/mineral deficiencies.

Management of bone disease in MM is typically based on the use of bisphosphonates such as zoledronic acid and pamidronate, as well as RANK-L inhibitors such as 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 can be seen 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 related complications.

Neuropathy

Certain myeloma 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 (which is not frequently used in modern treatment plans), as well as the proteasome inhibitors bortezomib and ixazomib. The risk for peripheral neuropathy with bortezomib treatment can be lowered by using subcutaneous formulations and weekly dosing. Dr. Huff also suggests early intervention with dose reductions if possible if peripheral neuropathy occurs and 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 (CoQ10), 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.^2,4 When patients are receiving IMiDs such as thalidomide, lenalidomide or pomalidomide, additional medications, including aspirin, low molecular weight heparin, warfarin or one of the newer direct anticoagulants, are often added to reduce the risk of blood clots.

Blood effects may be managed with dietary supplements (e.g., iron for anemia) as well as colony-stimulating factors. Preventative 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. Dr Huff notes that diarrhea is particularly a problem among people receiving 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 loperamide and other 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 treatment-related side effects

Chimeric antigen receptor (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 novel therapies 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). Use of these drugs requires prolonged monitoring to support early detection and rapid initiation of treatment within specialized centers.

—by Morgan Meissner

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.

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.

5. Glenn DG. Behavioral risk factors: a guide for oncology nurses counseling patients. Clin J Oncol Nurs. 2020;24(5):9-18.

PATIENT: JOHN, 74, WAS DIAGNOSED WITH MM IN 2018. HIS MEDICAL HISTORY WAS NOTABLE FOR MI WITH STENTING, CAD, HYPERTENSION, PREDIABETES AND CHRONIC SUPPURATIVE OTITIS MEDIA WITH HEARING LOSS.

“For high-risk patients who relapse, using the most effective therapy early is critical”

PHYSICIAN:
Patrick Hagen, MD, Associate Professor of Medicine, Division of Hematology & Oncology, Loyola University Medical Center, Maywood, IL

History:
John presented to the hospital for persistent lower back and hip pain after a fall. Serum protein electrophoresis showed 3.49 g/dL of monoclonal protein, at which time he was referred to me for evaluation. John, who was married with adult children, had led a sedentary lifestyle after retirement as a research chemist. He and his wife had previously enjoyed babysitting their two grandchildren every week, but John no longer had the energy. Initial lab findings indicated multiple myeloma (MM) and advanced skeletal imaging confirmed John had multiple lytic lesions. His bone marrow results showed a normocellular marrow with 37% lambda restricted plasma cells and a MM FISH panel showed gain 1q as well as gain of 5/5p, 9/9q and 15/15q. At diagnosis John was noted to have a 1q gain, which is a common genetic abnormality occurring in 40% of MM cases and is associated with inferior outcomes. Both NCCN guidelines and mSMART 3.0 guidelines include gain1q as a high-risk genetic abnormality. Yet despite the frequency and high risk, management of patients with gain1q is poorly defined. John and I discussed treatment, including potential adverse effects, and he was ready to start therapy immediately.

First-line therapy included bortezomib-lenalidomide-dexamethasone (initiated as seven 28-day cycles). John achieved a very good partial response (VGPR) to induction therapy, and he was put on weekly maintenance therapy while his otitis media was being addressed in anticipation of high-dose chemotherapy and stem cell transplantation, which he would subsequently undergo. Adjunct treatments included denosumab.

Unfortunately, after 37 months, John’s MM progressed: M-protein reappeared and lambda sFLC increased, with additional lab work and bone marrow results indicating progression. He also had worsening fatigue and increased bone pain. PET-CT scan showed new low-level involvement in his ribs, pelvis and proximal femur, with greatest uptake notable in the right iliac wing.

Initiating treatment: 
John and I discussed second-line therapy. He was a good candidate for a regimen that included isatuximab. Recent data show that isatuximab, when used in combination with carfilzomib + dexamethasone or pomalidomide + dexamethasone, can significantly prolong progression-free survival in high-risk patients and, in particular, those with gain of 1q. Again, I counseled John on potential adverse effects before initiating treatment.

John started isatuximab + carfilzomib-dexamethasone (Kd). During cycle 1, his infusion time was decreased to 75 minutes at week 3 due to the absence of infusion-related reactions. Because of his chronic supporative otitis media, denosumab was discontinued due to concern for osteonecrosis. At cycle 3 follow-up, John’s labs showed partial response (see Table, column 3, below) and his fatigue and bone pained resolved.

At cycle 6 follow-up, John showed VGPR, and immunofixation electrophoresis showed IgG lambda M-protein. Bone marrow showed no clonal plasma cells, and John said he felt well. After cycle 12, John’s status remained the same (see Table, column 4, below), and he continues to feel well. John and his wife are grateful he has the energy again to enjoy their family as they look forward to the birth of their third grandchild.

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 gain of 1q. It is key to remember that 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 John, prioritizing a regimen with the highest long-term efficacy can improve outcomes and help them live as well as possible for as long as possible.