Managing Patients Who Have Oligosecretory or Non-secretory Disease

Yi (Lisa) Hwa

Today I thought we’d discuss the management of multiple myeloma patients who have oligo- or non-secretory disease. About 3-5% of the patients meeting diagnostic criteria for multiple myeloma do not have a quantifiable M protein present in their serum or urine. This is generally referred to as non-secretory multiple myeloma. Patients with oligosecretory MM commonly have serum M protein < 1 g/dL, urine M protein < 200 mg/24 hours or serum free light chain < 10 mg/dL. Monitoring those patients for treatment response, disease relapse, or disease progression can be challenging because their disease doesn’t follow standard laboratory features.

We now see more and more patients who had measurable M proteins at diagnosis, but later became oligo- or non-secretory at disease relapse or progression, especially after being treated with several prior-line therapies. Amie, have you seen any patients in your practice who have transitioned from secretory to oligo- or non-secretory disease? Can you share an example of how you manage those patients?

Amie Fonder

Absolutely. I'm starting to see a lot more cases where patients started with secretory disease and have transitioned with relapses--even as early as their first relapse of multiple myeloma--into oligo- or non-secretory disease. So now I'm starting to keep this on my radar earlier in the patient's disease course.

I have a recent case that I’d like to share. This patient, a 68-year-old male with IgG kappa multiple myeloma, came in for a follow-up. Per staging criteria, this patient had ISS stage I and mSMART high-risk disease due to an S-phase or labeling index over 2%, which just means that the patient's myeloma cells were rapidly dividing. He had a coexisting IgG lambda MGUS (or monoclonal gammopathy of uncertain significance).

At diagnosis, the patient had an IgG kappa M spike of 1.4 g/dL. His IgG level was 1,598 mg/dL. The kappa free light chain was 96.6 mg/dL, and the free light chain ratio was 9.78. His bone marrow biopsy at diagnosis showed 50% clonal plasma cells with an S phase of 2.49%. FISH studies showed hyperdiploid with a trisomy 11 and a monosomy 13 mutation as well as the MYC mutation.

PET-CT was chosen as the imaging modality at diagnosis, and he had multiple hypermetabolic bone lesions. This was around February of 2021. He received lenalidomide, bortezomib, and dexamethasone as his induction therapy, followed by an autologous stem cell transplant on September 16, 2021.

A day 100 bone marrow biopsy following stem cell transplant demonstrated less than 5% biclonal plasma cells: Note that it’s biclonal. He had IgG kappa myeloma with IgG lambda monoclonal gammopathy, which explains the biclonal plasma cells at the day 100 marrow. The patient was placed on lenalidomide maintenance therapy given the genetics in the FISH studies.

Lisa, do you want to say a little bit about the mSMART? That's something that perhaps not everyone is familiar with.

Yi (Lisa) Hwa

Of course. mSMART stands for Mayo Stratification for Myeloma and Risk-Adapted Therapy. The experts at Mayo Clinic provide clinical opinions and recommendations based on the best available evidence to manage plasma cell disorders, including multiple myeloma, AL amyloidosis, Waldenström macroglobulinemia, and POEMS syndrome, which stands for Bolyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes. mSMART is an excellent treatment guidelines resource for clinicians.

Amie Fonder

Is there a cost for using mSMART?

Yi (Lisa) Hwa

It’s available online for free. Dr. Rajkumar and a group of physicians work hard to keep it updated with new clinical evidence. It’s a great resource.

Amie Fonder

That's really good to know. Thanks for expanding on that a little bit.

So, back to the patient I was discussing. He came to see me in May of 2023, a little less than 2 years following his stem cell transplant. He patient presented with a 5-week history of new dull back pain in the mid to low thoracic spine.

The pain was increasing with sitting and decreasing with movement and ambulation. It wasn't waking him from sleep, so it wasn’t necessarily typical of what we usually see with myeloma bone pain. However, he'd had imaging done locally already, a CT as well as an MRI of the spine, and this MRI showed some abnormal bone marrow enhancement in the spine.

The data from December of 2021--so prior to when he came back to see me--showed the kappa was at 2.09 mg/dL. In November of 2022, the kappa was at 2.65 mg/dL, so there was minimal change. And then in May of 2023, the kappa was at 4.84 mg/dL, still not a change that we would necessarily think is alarming in terms of disease progression. Typically, disease progression per International Myeloma Working Group criteria would require an increase of a minimum of 10 mg/dL in the involved free light chain in order to think of it as disease progression.

Yi (Lisa) Hwa

Just so I’m sure I’m following, this patient developed new pain with abnormal marrow activity on MRI. But his laboratory results were not alarming and didn’t indicate disease relapse or progression. There was a slight up-trending of the kappa free light chain, but it was still within 90% of the level at diagnosis and the free light chain ratio remained normal.

Amie Fonder

That’s exactly right, Lisa. If this was your patient coming in with a minimal upward trend in his monoclonal protein studies, but with new pain and some evidence on outside imaging, what would you consider the optimal next steps?

Yi (Lisa) Hwa

I’ve seen some similar cases when patients had stable monoclonal protein labs but developed new or worsening bone pain. I think that the patient should be further evaluated with imaging studies. I probably would do a PET-CT and pursue a bone marrow biopsy. Did your patient proceed with such testing for further evaluation?

Amie Fonder

Yes, and I agree with you on how to proceed. My next step was to evaluate with both a PET-CT and a bone marrow biopsy. Had this patient come to me without outside imaging, I think I probably would've done a PET-CT or potentially a CT skeletal survey to evaluate for new lesions. Of course, the benefit of getting the PET scan is that you can see areas that are highly metabolically active vs. a CT skeletal, which might not pick up the nuanced changes between fat attenuation and new osteolytic involvement in a lesion that had previously been present.

This patient's PET scan showed multifocal FDG avid intraosseous plasmacytomas, with areas of activity associated with a lytic lesion in the right femur, L3 vertebral body, and the sacrum, as well as in one of his ribs. These multiple areas of enhancement are consistent with disease progression.

The bone marrow also showed less than 5% lambda light chain restricted plasma cells, and recall that the patient's clone is an IgG kappa, but he also had this IgG lambda monoclonal gammopathy at diagnosis. The S phase of these lambda light chain restricted cells was 0.6%, which is considered a low or unconcerning finding.

Yi (Lisa) Hwa

I'm glad you brought up the consideration of choosing a CT skeletal survey or PET-CT. I agree with you to choose PET in this patient case. PET scans use a radioactive tracer that allows early detection of the myeloma cells that accumulate in bones and other tissues even before resulting bone lytic lesions.

In my practice I use CT skeletal surveys sometimes at diagnosis and mostly for routine follow-up to detect any new or enlarging osteolytic lesions.

Amie Fonder

Understandably there are some areas that don't have expeditious access to PET scans, in which case doing a CT skeletal and perhaps a spine MRI like our patient had can be helpful in seeing whether or not there is evidence of disease progression.

Lisa, in your practice, when do you tend to think about the diagnosis of an oligosecretory or non-secretory patient?

Yi (Lisa) Hwa

It's important to keep in mind that oligosecretory disease is more frequent in the relapse setting compared to newly diagnosed disease. A retrospective study of 177 patients with relapsed MM reported that 10% of these patients who had secretory disease at diagnosis developed oligo- or non-secretory disease.¹ 

NCCN Guidelines recommend surveillance imaging for all myeloma patients, using either a whole-body MRI without contrast or low-dose CT or PET-CT annually or any time a patient presents with clinical suspicions.² Surveillance imaging can detect oligo- or non-secretory disease early.

Ideally, in my practice, I choose the same type of imaging study for better comparison. However, many myeloma patients are under Medicare coverage; Medicare has some restrictions on using PET-CT for surveillance purposes. I often choose a CT skeletal survey for routine follow-up.

Let’s get back to the case. Now that we know that he has oligosecretory myeloma, how do you manage the patient in terms of subsequent follow-up imaging studies? 

Amie Fonder

That's a great question. I'm glad that you highlighted your clinical practice for surveillance imaging because the surveillance imaging in someone with oligosecretory or non-secretory myeloma is a little bit different. Since we don't have serum or urine monoclonal protein studies that are fluctuating with the processes that are happening in the bones or within the bone marrow, it's important for these patients to have more frequent bone imaging.

For my patient population, I typically order another PET-CT about 2 months after changing their systemic therapy to determine if the treatment is working. If the treatment is working, then typically I’ll check approximately every 3 to 4 months just for disease monitoring purposes, depending on how aggressive the patient's myeloma has been in the past and how well they're responding to the current therapy.

Of course, if there's new pain we would potentially get a PET scan sooner. The PET scans are helpful because they show the activity within the bone lesions, not just new damage to the skeleton. If this patient had come in and there was just one bone lesion that was FDG-avid on the PET scan and no other evidence of bone progression or what we call CRAB features (Hypercalcemia, Renal failure, Anemia, and Bone disease) of the myeloma, then we might consider radiating that lesion instead of changing the entire systemic therapy.

In that case we might refer the patient to radiation oncology. After the patient receives a palliative dose of radiation, we’ll continue with the same systemic therapy while still monitoring those PET-CT scans at that interval. I just want to note that the irradiated lesion might remain FDG-avid for up to 6 months after the radiation. Until this time, we would use imaging to rule out new lesions in the setting of that maintained systemic therapy.

PET-MRI is also a modality at some institutions. There are times to use this, particularly if we're worried about a patient potentially having cord compression or if we want to look for marrow-enhancing lesions. That’s when it’s an optimal time to use a PET-MRI. That being said, in my experience, patients with pain have a hard time tolerating a PET-MRI because they have to lie still for so long.

It's important to know that these modalities exist and then be able to have the conversation with a patient about what modality of imaging may be best, both for monitoring their disease and being tolerable enough for good-quality images to be obtained.

You mentioned that Medicare has some limitations on PET scans. What strategy do you use for patients who are on Medicare or have insurance that might balk at paying for surveillance imaging with a PET-CT, specifically for those patients with oligosecretory or non-secretory myeloma where it's really important to get a PET-CT?

Yi (Lisa) Hwa

When I order a PET-CT, I document the indications to evaluate relapse or progression of oligo- or non-secretory multiple myeloma, and then choose the correct diagnosis for billing. Documentation is important to help patients get reimbursed.

Amie, what other considerations do you have when you're managing a patient with oligo- or non-secretory multiple myeloma?

Amie Fonder

One other consideration is the helpfulness of pathology analysis on the lesion in question. If that area is amenable to biopsy, confirming the presence of monotypic plasma cells can be appropriate. We want to make sure that we are treating the patient for the right disease.

And since patients with cancer are at higher risk for developing other cancers, it can be helpful to obtain a tissue sample and make sure that it is truly a myeloma relapse or a plasmacytoma that's developed so you can rule out any surprise alternative diagnoses. I've biopsied many, many oligo- and non-secretory lesions over the years, and in general they tend to be myeloma lesions. But if you're not sure or if the lab and the patient’s clinical picture don't make sense, getting a tissue sample is a very reasonable option.

Yi (Lisa) Hwa

That’s an excellent point. I saw a patient who had stable blood tests and a PET-CT showed a new lesion. We did a biopsy and it turned out to be metastatic breast cancer.

I would like to add another comment about clinical trials. Some clinical trials may allow enrollment of patients with oligo- or non-secretory MM if they have measurable disease on imaging studies, for example a new or active lesion of 2 cm or greater in diameter. Never automatically exclude patients with oligo- or non-secretory disease from all clinical trials as they may still be eligible for some studies.

Amie Fonder

I'm glad you brought that up. We still need to consider clinical trials, although, as you said, many of them exclude oligo- or non-secretory disease. But sometimes there’s a trial that allows it, so it's important not to rule that out as a potential therapeutic intervention for a patient. 

Thanks for chatting with me, Lisa.

Yi (Lisa) Hwa

Yes, thank you too. This was a great discussion.