Recommendations and Guidelines for Bone-related Therapy Treatment

Amie Fonder

Lisa, thank you for meeting with me today. For this discussion, let's talk about bone-directed therapy in patients with multiple myeloma. These patients have bone disease in a couple of different ways: there are skeletal-related events, or SREs, and then there is the impact that myeloma has on the bones and bone metabolism.

Yi (Lisa) Hwa

Thank you, Amie. I really appreciate that you brought up such an important topic. When I work with APP trainees, some of the most common questions they have are related to the use of bone-directed therapy in managing multiple myeloma.

Amie Fonder

It's an important topic for both trainees and experienced APPs. More than 80% of patients with myeloma have some form of bone disease and SREs are very common complications for patients with myeloma.¹ These events can include pathologic fractures and cord compression. Sometimes pathologic fractures or cord compression can require palliative radiation or orthopedic intervention.

The SREs are a significant impact of morbidity and mortality as well as the quality of life for our patients, so this is a really important topic. The presence of SREs is also a prognostic factor in that it’s associated with an increased risk of death in myeloma patients and is widely used in the design of randomized controlled trials.¹

Today I’d like to review bone-directed therapy and clinical practice. There are a lot of changes in myeloma in terms of how long patients are living and the types of therapy we have. It can be difficult to assess what type of bone-directed agent we should use, how frequently we should give it, how long we should give it, and what form of administration we should use. I'm wondering if you have a patient case that you could share with us related to bone-directed therapy.

Yi (Lisa) Hwa

I'll share two patient cases today here so we can better discuss who needs to be treated when and how to treat patients with bone-directed therapy.

The first patient case is a 66-year-old female with relapsed disease. She was diagnosed with multiple myeloma in September 2019 with standard fluorescence in situ hybridization (FISH) cytogenetic feature. She received 4 months of induction therapy with VRD, which is bortezomib, lenalidomide, and dexamethasone, followed by an autologous stem cells transplant, and achieved minimal residual disease (MRD)-positive complete remission at day 100 post-transplant evaluation.

The patient was then placed on lenalidomide for maintenance and was doing well. However, over the past several months, her monoclonal protein labs have been gradually rising to indicate early relapse of the disease. We did a restaging evaluation which showed mild anemia with hemoglobin of 11.4 g/dL. Her leukocytes, platelets, calcium, and creatinine were normal. The CT skeletal survey review showed stable scattered ill-defined lucencies throughout the skeleton, but there's no new or enlarging osteolytic lesions or pathological fractures.

The patient started her second-line therapy with daratumumab, bortezomib, and dexamethasone. When I saw her in the clinic, she’d already completed two cycles of DVd treatment. In reviewing her medication list, I saw she wasn’t on any bone-directed therapy. She was previously treated with zoledronic acid and had completed a standard two-year course of therapy; therefore it was discontinued. But now she has relapsed disease. Even though there's no evidence of new bone disease with the relapse, there is baseline bone involvement on the imaging study, so the question to keep in mind is if she needs to restart bone-directed therapy.

Amie Fonder

That’s an interesting case. There’s so much to consider. What is your second case about?

Yi (Lisa) Hwa

The second case is that of a 68-year-old male patient who had an elevated total serum protein during his annual physical exam. Besides chronic back pain from a previous sports-related injury, he had no other clinical symptoms or medical comorbidities. Further evaluation showed a normal CBC calcium and creatinine. The serum M spike was 2.5 g/dL, which was IgG kappa type. The IgG was elevated to 1890 mg/dL. The serum kappa free light chain was elevated to 6.37 mg/dL and the kappa to lambda free light chain was 5.13. The 24-hour urine protein was 485 mg/24 hours and there was only the presence of a small IgG kappa monoclonal protein on the immunofixation of the urine sample. The bone marrow showed 20% kappa-restricted plasma cells and FISH cytogenetics revealed trisomies on numbers 7, 9, and 15. This was in the standard risk category. The low-dose CT skeletal survey showed that there were no osteolytic lesions.

The patient was diagnosed with smoldering multiple myeloma. At that point, we talked to him about clinical trials, but he was not interested in pursuing that approach. He decided to opt for observation per standard care.

Amie Fonder

I think these are two really great clinical examples, Lisa. When considering if either of these patients require bone-directed therapy, it's helpful to look at what the current guidelines are. We have guidelines and recommendations from the National Comprehensive Cancer Network (NCCN),² as well as the International Myeloma Working Group (IMWG).³

Both of these organizations recommend that all patients receiving primary multiple myeloma therapy should be given a bone-targeting treatment with either a bisphosphonate or denosumab, regardless of the presence or absence of myeloma-related bone disease on imaging. They also recommend a pre-treatment dental exam due to the risk of osteonecrosis of the jaw with these types of therapies.

In the setting of relapsed/refractory patients, the recommendations are to resume bone-directed therapy at relapse or progression if it has been discontinued. That recommendation is especially true for those with bone abnormalities identified on the imaging at relapse. These are recommendations for patients with active disease.^2,3

Lisa, could you share some information about what the recommendations are for patients who have the precursor conditions like smoldering myeloma, solitary plasmacytoma, or monoclonal gammopathy of undetermined significance (MGUS)?

Yi (Lisa) Hwa

Yes, absolutely. In patients with smoldering multiple myeloma, NCCN recommends using bone-directed therapy only if those patients who are enrolled in clinical trials that require bone-directed therapy.²

The IMWG multiple myeloma-related bone disease panel recommends bisphosphonate use in patients who have smoldering myeloma, MGUS, and solitary plasmacytoma only there's evidence of osteoporosis and those patients should be monitored and treated according to the osteoporosis guideline. For patients with a solitary lytic lesion or solitary plasmacytoma without any evidence of osteoporosis, the guideline does not recommend any bone-directed therapy.³

Amie, would you like to give a brief review of FDA-approved bone-directed therapy agents?

Amie Fonder

Sure. Like with multiple myeloma, we are continually looking at data associated with bone disease for myeloma. We have several options now for managing bone disease in patients with active myeloma. FDA-approved agents for managing bone disease in patients with multiple myeloma include bisphosphonates, such as pamidronate and zoledronic acid, as well as the more recently approved RANKL (receptor activator of nuclear factor-kappa B and its ligand)-inhibitor, denosumab.^4,5

There are other bisphosphonates available that are FDA-approved for other indications, but the IMWG recommends IV administration of bisphosphonate. The Medical Research Council (MRC) IX Trial demonstrated that intravenous administration of bisphosphonate significantly reduced SREs by 26% compared with oral bisphosphonate.⁶ That’s why the recommendation is for the two listed here, pamidronate and zoledronic acid, which are intravenously administered.

Yi (Lisa) Hwa

A common question is how to determine whether to use bisphosphonates or denosumab. In a phase 3 double-blind, randomized control study of newly diagnosed disease, patients received either 120 mg of subcutaneous denosumab every 4 weeks vs. placebo, or they randomized to the arm to receive 4 mg of IV zoledronic acid every 4 weeks vs. placebo. Both drugs were shown to have equivalent benefits in preventing skeletal-related events and there was no difference in overall survival.

But a higher incidence of hypocalcemia and less renal toxicity were reported in patients treated with denosumab. Based on the data, the NCCN Guideline recommends denosumab as the preferred choice for patients with renal impairment. Zoledronic acid is preferred to treat when a patient presents with hypercalcemia, but it is not recommended for those patients with severe renal dysfunction.

As APP clinicians, it’s important to consider cost-effectiveness when we’re choosing treatment options. If patients are eligible for both of the therapies, in my clinic I tend to prescribe zoledronic acid because it’s much less expensive than denosumab. We always need to think about financial toxicity as a contributing factor to their quality of life.

Amie Fonder

That’s a great consideration. As we’ve talked about in some of our other discussions, physical toxicity is not the only toxicity that needs to be considered. There are also the financial and time/emotional burdens that some of these treatments trigger.

Regarding physical toxicities, the primary one we often talk about with bone-modifying agents is osteonecrosis of the jaw. As the NCCN recommends, our practice here is to request that patients receive dental clearance before we start any bone-modifying agent, just to ensure that their dentist knows that we are planning to use bone-modifying agents, which then gives them the opportunity to have any invasive dental procedures done. We want to make sure that if there is any minor dental work that needs to be completed, like fillings, it can be done before we start. Or if the patient needs a more invasive dental procedure, like a pulled tooth or implant, we don't want to start the medicine until after they have the procedure. I think most of us who work in a myeloma-specific practice have seen osteonecrosis of the jaw, and I've seen cases as minor as a completely asymptomatic patient who has an issue identified on imaging and as major as a patient with a fistula between their bone and their mouth. That one required antibiotic therapy for a chronic infection of the fistula tract. It’s an important toxicity, so we need to discuss it with our patients and try to mitigate the risk as much as possible.

Of course, sometimes patients require dental procedures after the treatment has already started and, if we can do it safely, we’ll time the dental procedure in such a way that patients can take a break from the bone-modifying agents before and after the dental procedure. If there's evidence of osteonecrosis of the jaw, then we typically don't use the bone-modifying agents anymore or we work with the dentist and potentially even a bone endocrinologist to determine if there are other options for those patients.

Yi (Lisa) Hwa

With bone-directed therapy, one important consideration of using denosumab is the potential risk of rebound osteoporosis. I explain to patients that, unlike bisphosphonate, which induces osteoclast apoptosis and inhibits osteoclast activity, denosumab prevents pre-osteoclasts from becoming active osteoclasts. After discontinuation of denosumab, there's a vast increase of osteoclast cell numbers and activities which can lead to a subsequent profound increase of bone turnover resulting in rebound osteoporosis.

Studies have reported that rebound osteoclastogenesis normally happens 6 to 12 months after discontinuation of denosumab.⁷ NCCN recommends administering a maintenance dose of denosumab every 6 months or giving the patient a single dose of IV bisphosphonate after stopping treatment with denosumab.

Amie, what are the dosing and interval guidelines we should follow when using bone-directed therapy?

Amie Fonder

There is a little less consistency now than there was 5 to 10 years ago in terms of the frequency of administration. Before the advent of denosumab, most patients received either zoledronic acid or pamidronate, in 12 monthly doses, followed by 12 quarterly doses.

However, there has been prospective data demonstrating that dosing quarterly at diagnosis is not inferior to monthly, with no difference in prevention of skeletal-related events.⁸ There's a bit of a provider preference in terms of how to start it. In our practice, many providers will start monthly dosing, particularly in patients with a high disease burden or a lot of skeletal disease with their diagnosis, and then go to a quarterly schedule either when they transition to a stem cell transplant or they achieve a good response to induction therapy.

There are considerations for patients with active osteoporosis in addition to their myeloma, and with SREs you could choose to follow the monthly dosing for a longer period of time. Zoledronic acid is dosed at 4 mg IV and can be dose adjusted for mild renal insufficiency. Patients with moderate to severe renal impairment should receive an alternate agent as we discussed before.

With pamidronate, there are dosing options of 30, 60, or 90 mg. Often for renal insufficiency, it's preferred to dose reduce a little bit, but 90 mg would be the highest dose we would use. Regarding the different doses of pamidronate, a study published in 2010 looked at 30 mg vs. 90 mg and identified no statistically significant difference in the clinical trials in SREs, overall survival, or progression-free survival.⁹ 

There are a lot of options we can consider with patients to determine what is best suited for them, including their preferences.

Yi (Lisa) Hwa

Another comment question is how long we should treat patients with myeloma with bone-directed therapy. When deciding on treatment duration, we should consider individualized assessments for a patient’s fracture risk based on their gender, age, ethnicity, BMI, history of fracture, and any presence of osteopenia or osteoporosis. We also need to consider how well the patient tolerates bone-directed therapy. The efficacy of bone-directed therapy is also associated with the depth of myeloma response, therefore considering hematological response is also important.

You mentioned the MRC Myeloma IX trial. In a retrospective analysis of over 1,100 transplant-eligible patients recruited to that trial, zoledronic acid was shown to have superior benefits in preventing SREs only in the subset of the patients who achieved a very good partial response (VGPR) or less at day 100 post-transplant evaluation. For those patients who already achieved complete remission (CR), giving zoledronic acid didn’t add any benefit. In the evaluation of survival outcome, zoledronic acid was associated with a significant benefit in overall survival only in the patients who achieved partial response and there are no overall survival benefits in patients who achieved CR or VGPR.⁶

The current recommendations by NCCN and IMWG are to continue bone-targeting treatment for up to 2 years and treating patients beyond 2 years should be based on clinical judgment. Therapy should be continued for patients with active disease and restarted at the time of disease relapse or progression. IMWG also recommends continuing bone-directed therapy beyond 2 years for those patients who have not achieved hematologic CR or VGPR.

Amie Fonder

Lifestyle interventions should also be considered for managing patients with bone disease and multiple myeloma. It’s important for these patients to take in adequate calcium, whether by food or through supplements, and vitamin D supplementation. The need for vitamin D supplementation varies depending on where you are in the country. Our clinics are in the Midwest, so a lot of our general population tends to be deficient in vitamin D.

We typically run a vitamin D level when patients are diagnosed, which can be monitored throughout the course of their illness. We want to make sure patients are getting a balanced diet, adequate hydration, quitting smoking if they're active smokers, reducing alcohol intake, and exercising. Some of our patients with weak bones or SREs like fractures might need to modify exercises to ensure they're not putting themselves at risk for pathologic fractures.

Exercise, particularly weight-bearing exercise, is proven to help improve bone strength.

Lisa, we've discussed the recommendations. Now let’s circle back to the cases of the 66-year-old female with relapsed myeloma and the 68-year-old male with newly diagnosed smoldering myeloma.

Yi (Lisa) Hwa

Good idea. To recap the first case, the 66-year-old female with relapsed disease was on lenalidomide maintenance, following VRD induction and autologous stem cell transplant.

She has completed 2 years of zoledronic acid when her myeloma was in treatment response. Although her CT skeletal survey did not show any progressed myeloma bone disease at relapse, NCCN and IMWG guidelines recommend that any patients at relapse should resume bone-directed therapy. So, we put her back on quarterly zoledronic acid.

The second case was of a 68-year-old male patient with smoldering myeloma who was not interested in clinical trials. We decided on standard care with a regular every-3-month observation.

Per NCCN and IMWG guidelines, there's no need for bone-directed therapy for smoldering myeloma unless there's evidence of osteoporosis, in which case the patient should be treated using the osteoporosis guideline. Because osteoporosis can happen to male patients too, we recommend getting a baseline bone density test for screening. That patient did not have any evidence of osteoporosis, therefore, we did not start any bone-directed therapy for him.

Amie Fonder

This was really helpful, Lisa. Thank you for your insights and the literature- and evidence-based information, as well as for sharing your clinical practices. I really appreciate the time.

Yi (Lisa) Hwa

Well, thank you, Amie. This has been a wonderful experience and I think these conversations really help us learn a lot from each other. I also appreciate your clinical expertise, and I'm looking forward for future opportunities for further discussions.