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Expert Guidance on Therapeutic Strategies for Multiple Myeloma

Charise Gleason, MSN, NP-BC, AOCNP
Sagar Lonial, MD
Kathryn Maples, PharmD, BCOP
Released: May 1, 2020

Management Considerations for Patients With Newly Diagnosed Active MM

Imaging for Diagnosis and Monitoring

Charise Gleason, MSN, NP-BC, AOCNP:
Although selecting appropriate therapy is essential for patients with newly diagnosed MM, there are many other important considerations for each patient who comes into clinic. As mentioned previously, we perform extensive imaging at diagnosis; typically, this includes MRI of their whole spine or even a PET/CT scan to ensure that we have not missed any active disease. The presence of ≥ 1 sites of osteolytic bone destruction (≥ 5 mm) on CT or PET/CT is indicative of active MM. The use of low-dose whole-body CT or MRI is also recommended for monitoring patients for response to therapy and to watch for disease progression.

As Dr. Lonial mentioned, close monitoring is important to determine the tempo of the disease, so we will follow patients’ bone health more frequently at first. Another challenge for clinicians is that many patients who are diagnosed with MM are not familiar with this disease before their diagnosis, including how it affects bone. It may take several office visits for patients to process and remember all of the information they need. A multidisciplinary team approach, along with follow-up, and ongoing patient education is very helpful in communicating this information to patients and their families.

How Do (Should) We Use MRD in the Clinic Today?

Sagar Lonial, MD:
As with bone imaging, in our clinic, we also perform MRD testing on Day 100 and at 1 year. At present, such testing for MRD is done primarily through multiparameter/multicolor flow cytometry or next-generation sequencing (ie, PCR). Flow cytometry is the most commonly used MRD assessment platform in the United States, whereas molecular testing is the platform of choice in Europe. PET/CT imaging is also used to assess MRD, based on assessing tracer uptake. The next-generation sequencing assay clonoSEQ has been cleared by the FDA for MRD testing in MM (and acute lymphoblastic leukemia).

An important point is that although we are currently performing MRD testing, there is not yet enough data or long enough follow-up from trials to use this information to make treatment decisions. For example, we do not know what it means if a standard-risk patient is MRD positive at 1 year post ASCT and plans to continue lenalidomide maintenance long term. More data are needed to make a decision to use MRD status to inform treatment decisions.

CASSIOPET: PET/CT and MRD Postconsolidation Concordance and Double Negativity

Sagar Lonial, MD:
In our clinic, we will use PET/CT imaging along with MRD testing for transplant-eligible patients at Day 100 after the transplant, then again at 1 year. I agree that baseline scans provide important data. Moreau and colleagues[18] recently presented results from CASSIOPET, a CASSIOPEIA substudy, to analyze the impact of PET/CT for monitoring of newly diagnosed patients.

CASSIOPET included 268 patients enrolled in the CASSIOPEIA trial that we discussed above. PET/CT images were interpreted by a blinded independent team of nuclear medicine physician experts. At baseline, most of the patients were PET positive (80%) and had focal lesions (67% of patients). Bone marrow diffuse uptake was positive in 48.0% of patients, 17.5% of patients had paramedullary disease, and only 7.8% of patients had extramedullary disease.

Not surprising, the CASSIOPET study demonstrated that patients who received Dara in combination with VTd had better responses, deeper responses, and improvements in PFS vs those who received VTd alone. Regarding the correlation of PET/CT with outcome, the investigators analyzed the impact of both baseline PET/CT negativity and information from PET/CT obtained post consolidation. PET/CT negativity either at baseline or post consolidation was associated with more favorable PFS prognosis.

Of interest, there seemed to be a low concordance between PET/CT and MRD. In fact, of 157 patients who were PET/CT negative after consolidation, 55 patients remained MRD positive. Furthermore, more patients receiving Dara-VTd achieved PET/CT and MRD double negativity post consolidation compared with VTd alone (66.7% vs 47.5%, respectively).

Finally, the investigators found that the presence of focal lesions, the presence of paramedullary disease, and the presence of extramedullary disease on PET/CT scans were all associated with less favorable PFS in a univariate analysis. However, the presence of paramedullary disease at baseline was the only independent factor associated with less favorable PFS in a multivariate analysis.

As we learn more about the intersection of MRD assessment and PET/CT imaging and see more long-term data from ongoing trials exploring how to use this information to make treatment decisions, our approach may change.

Management of Bone Disease: Supportive Care

Charise Gleason, MSN, NP-BC, AOCNP:
For patients, as part of our discussion around bone imaging and monitoring, we also discuss bone health and monitoring vitamin D levels as patients with MM can have osteopenia.

For many years, bisphosphonate therapy has been the standard of care for supporting bone health in patients with MM. Pamidronate and zoledronic acid are the main agents used, but monitoring is critical as both carry risks of renal toxicity and osteonecrosis of the jaw.

Sagar Lonial, MD:
An alternative is denosumab, a RANKL inhibitor that is noninferior to zoledronic acid. Raje and colleagues[19] conducted a large phase III trial comparing the bone-targeting agent denosumab with zoledronic acid in patients with newly diagnosed MM. In this study, patients (N = 1718) were randomized to denosumab 120 mg SC plus IV placebo vs zoledronic acid 4 mg IV plus SC placebo. The time to skeletal-related event—primary endpoint of noninferiority to zoledronic acid—was met for denosumab, with an HR for time to first skeletal-related event of 0.98 (P = .01). However, denosumab was not superior for time to first or subsequent on-study skeletal-related events.

Looking at bone and renal adverse events, the group that received denosumab had a significantly lower incidence of treatment-emergent renal adverse events regardless of whether patients had normal or abnormal renal function. The incidence of osteonecrosis of the jaw appears to be slightly higher with denosumab than with zoledronic acid, although these numbers are small (35 vs 24 patients in a population of more than 1700). These results suggest that denosumab may have less impact on renal function than zoledronic acid, which is an important issue for patients with MM.

Kathryn Maples, PharmD, BCOP:
Typically, we begin with bisphosphonates for bone health in patients with newly diagnosed disease and then switch to denosumab, depending on how long the patient has been receiving bisphosphonate therapy. We can certainly restart bisphosphonates at first relapse but will typically switch to denosumab after the 5-year mark of bisphosphonate therapy, if the patient develops new bone disease while receiving bisphosphonate therapy, or for patients with severe renal impairment.

Lastly, kyphoplasty and vertebroplasty use bone cement to reduce vertebral fracture and pain. Some patients may benefit from spinal braces, and all patients need to be regularly monitored for bone health.

Myelosuppression and Infection

Charise Gleason, MSN, NP-BC, AOCNP:
Both MM and some treatment regimens for MM are associated with myelosuppression.[20] Myelosuppression can increase the risk of infection, decrease quality of life, and result in treatment interruption. Management is primarily through dose reductions.

Infection prophylaxis is, consequently, an important part of managing patients with MM.[21] First, patients should remain up to date on appropriate vaccinations. In addition, they should receive varicella-zoster virus prophylaxis when receiving PIs or Dara. The use of IVIG/prophylactic antibiotics is controversial and should only be employed when truly warranted. Patient education emphasizing the importance of alerting treating clinicians of potential infection can reduce unnecessary antibiotic use.

Regarding vaccination, in addition to being up to date on vaccinations before transplant, in our clinic, we can also vaccinate after transplant, typically starting after 6-12 months. This can include an annual influenza vaccine and pneumococcal vaccination every 5 years. Other vaccines used in MM following ASCT include polio, diphtheria-tetanus-pertussis, and meningitis vaccines.

MM: Supportive Care and Treatment Specific Considerations

Charise Gleason, MSN, NP-BC, AOCNP:
Pharmacists and nurses have important roles in the management of patients with MM, including monitoring for edema or other issues.

The first cycle of treatment is often the most difficult for patients, but many of them eventually feel better with treatment. A patient like the newly diagnosed case patient, who presented with a lot of pain, would feel better on treatment. On the other hand, some of our patients have few symptoms and then start these regimens and experience many adverse events. Either way, supportive care throughout treatment is critical to both quality of life and treatment outcomes.

The main adverse events we see in clinical practice are steroid-related adverse events, such as insomnia and swelling.

Kathryn Maples, PharmD, BCOP:
My initial role with newly diagnosed patients is to provide education on their new treatment regimens and then help with any other supportive care.

We already discussed the need for antiviral and vaccine prophylaxis. Another important consideration is deep vein thrombosis prophylaxis. IMiDs (lenalidomide, pomalidomide, and thalidomide) have been associated with deep vein thrombosis and prophylaxis with an anticoagulation agent is recommended with IMiD-based regimens.[22,23] The risk of deep vein thrombosis can be reduced with the use of the dexamethasone, which is included in induction therapy backbones, along with thromboprophylaxis.

Several of our patients may have other comorbidities that may affect dosing or a history of diabetes that requires monitoring blood sugar and watching for signs of peripheral neuropathy closely. Bortezomib[24] and thalidomide are neuropathic, and the risk of developing significant neuropathy is greater when patients have baseline neurologic dysfunction.

Caution should be used when considering carfilzomib-based treatment in patients with cardiac comorbidities, particularly those with previous therapy with cardiotoxic agents.[25]

With Dara, most patients will have an infusion-related reaction on the first day, so we counsel them to expect it and reassure them it is normal, manageable, and should not happen each time. These infusion reactions can be managed with premedication with antihistamines, antipyretics, and corticosteroids.

Charise Gleason, MSN, NP-BC, AOCNP:
Patients can also have appetite disturbances, so working with them to manage this issue can include talking to them about supplements or foods to avoid.

Some patients will need transfusion support, and much of that monitoring is conducted by our nursing staff. We give patients an electrolyte replacement if their potassium is dropping. Also, as an academic center, we have the opportunity to bring in nutrition support and social workers. The patients really benefit from a multidisciplinary team approach.

Provided by the Annenberg Center for Health Sciences at Eisenhower

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