Jonathan L. Kaufman, MD

While we have significant improvement in outcomes of patients including deep responses and improvement in overall survival, we still have unmet needs. We still need to improve outcomes for our high-risk patients. On our highest-risk patients who have both deletion 17 and 1q abnormalities or deletion 17p and 14-16, we really need improved therapies and improved therapy approaches to these very high-risk patients. This is when we think about doing clinical trials; could we use aggressive immune therapy earlier in their course? Things like bispecific T-cell engagers and bispecific antibodies; could CAR [chimeric antigen receptor] T cells be used in this space? These are the questions we're asking. The other really important place where we have an unmet need is in the multiple refractory myeloma patient. While we have significantly improved outcomes with patients living many years, we still need new therapies for when they have multiple relapse. In [multiple] myeloma, we've been lucky enough to have approvals of several new drugs over the past several years. We really need to find those therapies that can be associated with deep and long remissions while maintaining patient quality-of-life.

In the future for myeloma therapy, with all the drugs that we have available now and the drugs that are coming that are currently in development, we can really think about changing the paradigm of myeloma and consider deep and long-lasting responses for the vast majority of patients. I believe that there are current studies being designed for that in the future.

The advice I would have for community oncologists in the context of the multiple regimens available in myeloma and the multiple new treatments that are available, is not necessarily to solely rely on NCCN [National Comprehensive Cancer Network] guidelines. The NCCN guidelines gives a list of options. It’s important for every community oncologist to have their go-to myeloma specialists, whether they communicate with them personally or they follow their advice in the papers written and the talks given, and really stick with one trusted myeloma colleague. Every myeloma physician I talk to across the country has a group of referring physicians that they connect with on a regular basis. We are all happy to help the community oncologists, because that's ultimately helping the myeloma patients.

A 75-year-old man presents with worsening fatigue on exertion, pallor, and hip pain

PE: tired appearing male, poor hand-grip strength, mild tenderness on palpation of the left hip

Hb 9.8 g/dL, corrected calcium 11.9mg/dL, LDH 295U/L, creatinine 1.4mg/dL, albumin 3.7g/dL, CrCl 50mL/min

Peripheral blood smear showed rouleaux formation

Beta-2 microgloblulin 5.1 mcg/mL, M-protein 2.2 g/dL

Lambda free light chains: 0.6 mg/dL, kappa free light chains: 14.3 mg/dL, ratio: 29 (k/l)

UPEP: M-spike of 400 mg of lambda light chains in 24 hours

PET/CT revealed lytic bone lesions in the left hip

Bone marrow biopsy shows 58% plasma cells IgG k

Diagnosis: ISS and R-ISS, standard risk, stage II MM

Patient is ineligible for ASCT due to comorbidities

Initiated treatment with daratumumab + bortezomib + melphalan + prednisone

Videos

Jonathan L. Kaufman, MD, discusses current challenges and unmet needs in the treatment landscape and provides insight into potential improvements in the future of multiple myeloma. 

Unmet Needs and the Future of Multiple Myeloma 

When we have a patient with relapsed disease, we factor in several items when considering when to treat. Just because a patient has converted from complete remission to no longer complete remission where we see a small paraprotein, we don't necessarily need to treat that biochemical relapse. We don't want to wait for the patient to have a fracture or significant symptomatic anemia or CRAB [calcium elevation, renal dysfunction, anemia, bone disease] criteria to initiate treatment. Once we see the paraproteins start to rise, we follow the patient very closely and try to institute treatment prior to significant symptomatic disease. Then similar to how we did it upfront, we have several factors when we make the decisions about what to treat. What's the patient's current performance status? What's the risk of the disease? What are the comorbidities? We have 1 additional factor; now we know how the patient tolerated and how the patient responded to prior treatment. Prior tolerance and response is also very important in helping us figure out how to make decisions about what the next treatment is.

We currently have multiple therapies for second-line therapy or for patients with relapsed disease. I would say most importantly, the standard of care for a patient with relapsed disease is 1 to 3 prior lines of therapy; that is going to be a triplet. Whether that triplet is monoclonal antibody plus proteasome inhibitor and dexamethasone, monoclonal antibody plus IMiD [immunomodulatory drug] plus dexamethasone, or proteasome inhibitor plus IMiD and dexamethasone; we have multiple regimens using those backbone therapies. As I described earlier, what the patient had previously, current performance status, and comorbidities will help define which of these multiple 3-drug combinations we'd consider using for patients with relapsed disease.

Expert in the management of multiple myeloma Jonathan Kaufman, MD, reviews factors to consider when selecting a treatment regimen for patients with relapsed disease. 

Treatment Options for Relapsed Multiple Myeloma

The Griffin trial was a phase 2 randomized trial that compared transplant eligible patients 70 years old and younger with RVd [bortezomib, lenalidomide, and Dexamethasone] as the standard arm and the combination of Dara [daratumumab] RVd as the experimental arm. The RVd was given for 4 cycles, followed by stem cell collection and single auto transplant, then 2 more cycles and lenalidomide maintenance. The study was conducted for 2 years; after the 2 years the investigator and the patient could continue to choose ongoing maintenance therapy. That was the standard arm; the experimental arm daratumumab was included as part of induction, consolidation, as well as part of maintenance therapy for up to 2 years after transplant or 24 doses or months after transplant. Then at the end of that 24 month period for those patients who had been getting daratumumab, the daratumumab would stop and they could continue lenalidomide maintenance. The primary endpoint of this study was sCR [serum creatinine] rate after consolidation, and there was a clear improvement in stringent, complete response rate after induction, transplant and consolidation with the Dara RVd arm versus RVd with 42% versus 32%. This met the primary endpoint as designed by the study, hence the study was considered a positive study. At the initial time point, there was no difference in overall and progression free survival. The reality is, we wouldn't expect that at this early time point. We did see an improvement in MRD [minimal-residual disease testing] negativity. At ASH 2020, I presented a 12-month update where we saw an improvement in sCR over time with the Dara lenalidomide maintenance over lenalidomide alone, and a significant improvement in MRD negativity rates both at the 6 month up post-transplant and the 12 month follow-up post-transplant. This was also with a maintaining MRD negativity at a significantly higher level across all subsets, including high-risk patients in the Dara RVd versus RVd. One comment about the high-risk patients: it was a very small number and the data would not be considered definitive, but we now have additional evidence that adding daratumumab to a comprehensive RVd transplant and Len [lenalidomide] maintenance can be associated with increased MRD negativity in high-risk patients.

The MAIA trial was a phase 3 trial in newly diagnosed myeloma patients who are not transplant candidates with the standard arm being the combination of lenalidomide and Dexamethasone, with treatment to progression. It is important to remember that the Dexamethasone for those patients under 75 years old was 20 mg once per week. The experimental arm was the same Len Dex [lenalidomide and dexamethasone] with the standard dose and schedule of daratumumab. Again, in this study all 3 drugs were treatment to progression. We found in this study there was a significant improvement in response rate, particularly deep responses, and an improvement in progression-free survival. From a safety perspective, we did see more neutropenia with the 3 drug combination, Dara, Len, Dex [daratumumab, lenalidomide, dexamethasone] versus Len Dex. We did see an increase in the number of upper respiratory infections, but we did not see an increase in the number of major and serious life-threatening infections. When we saw that the data of the combination of Dara, Len, Dex versus Len Dex come out, this really impacted treatment decisions across the United States as that Len/Dex was a very common regimen given for non-transplant candidates. Now with the MAIA data, there's an increased use of daratumumab and Len/Dex. Now, there has been no study of Dara, Len, Dex or DRd [daratumumab, lenalidomide, Dexamethasone] versus bortezo [bortezomib]/Len/Dex or RVd, or an RVd-lite. I think both of those regimens remain very effective. However, there's been no study that directly compared those 2 regimens. While there's no direct comparison in the context of a clinical trial of DRd versus standard regimens, the real-world analysis in the PEGASUS study showed favorable progression-free survival looking at dara-Rd versus a real-world experience of standard regimens such as RVd.

My experience with daratumumab-containing induction therapies is consistent with what we saw on the clinical trials; we've seen a higher and deeper responses at a cost of some toxicity. The toxicity is consistent with what we saw in the context of the clinical trials. Increased cytopenias, particularly neutropenia, often in the first several cycles when the daratumumab intensity is highest and the myeloma disease burden is highest. We have seen an increase in upper respiratory tract infections, but have not seen an increase in serious and life-threatening infections. Very importantly, with the approval of subcutaneous daratumumab, once the patient's beyond 6 months of therapy in the nontransplant setting, now the patient's only coming into the infusion center once per month. That visit to the infusion center using the subcutaneous daratumumab is short.

When we think about managing toxicities for patients on daratumumab, first we have to think about what we're going to do before dosing. It is very important to get a type-and-screen to make sure you know blood typing; it can be a challenge after daratumumab. It is also very important to get a hepatitis B profile because we know a hepatitis B reactivation is possible. If a patient has a history of hepatitis B, and then monitoring LFTs [liver function tests] will be important. Consideration of using antivirals for hepatitis B suppression could be considered. In the first several cycles using daratumumab, the other thing that we have to think about when is the development of cytopenias, particularly neutropenia, and monitoring that carefully. Then with daratumumab, you have to think about infusion-related reactions. With the use of subcutaneous daratumumab from the start, infusion-related reactions are about half of what we see with IV. With IV, you have any infusion-related reaction at approximately 50%, and when you use subcutaneous it's somewhere in the range of 20% to 25%.

Jonathan L. Kaufman, MD, considers updates from the GRIFFIN trial, the MAIA trial, and the PEGASUS study and comments on factors to consider for daratumumab-containing induction regimens.

Updates from Recent Clinical Trials in Multiple Myeloma

There are currently standard treatments for induction in newly diagnosed symptomatic myeloma patients. When we make our decisions about the standard treatment for newly diagnosed myeloma, the first thing that we do is determine whether the patient is or is not a transplant candidate. If the patient is not a transplant candidate, here in the United States, there are typically 2 regimens that are considered standard. One is the combination of bortezomib, lenalidomide, and Dexamethasone, otherwise known as RVd.RVd was studied in a nontransplant setting; both transplant and nontransplant candidates were used and it was compared to the combination of lenalidomide and dexamethasone. There was clearly a benefit of the 3-drug RVd over RD [lenalidomide and dexamethasone] in terms of response rate, progression-free survival and overall survival. For the nontransplant candidate, RVd will likely be modified to what we know as something like RVd light; lenalidomide is dose reduced, Dexamethasone is dose reduced and bortezomib is given once a week versus twice a week. The other common regimen used now in patients with newly diagnosed myeloma who are not transplant candidates, is the combination of daratumumab, lenalidomide and Dexamethasone, otherwise known as DRD. This was studied in the MAIA study that compare DRD versus RD for newly diagnosed nontransplant candidates. There was a clear benefit both from response rate, as well as progression-free survival in the patients for the 3 drug arm versus the 2 drug arm. We have not seen survival data yet for this regimen; I presume that we’ll see it whether it’s positive or negative over the years to come. The other thing that has changed over the past year with the advent of subcutaneous daratumumab; this is a very convenient regimen for patients. In the context of the pandemic despite having to come into the infusion center for daratumumab due to it being subcutaneous dosing, they would have to come in for a relatively short period of time. That has been a very important treatment for my nontransplant eligible patients in the context of the COVID-19 pandemic. For patients who are younger and are transplant candidates, there are now several standards of care. RVd remains the standard of care; it has shown a very high response rate and a very good regimen as induction. KRd has been studied; the combination of carfilzomib, lenalidomide, dexamethasone was compared against RVd in a study. In this group of patients where they weren’t high risk there was no difference in outcomes. We’ve seen recent data that KRd with transplant followed by either KR or our maintenance was very effective, including in high-risk patients. We’re now starting to see 4 drug therapy, the addition of daratumumab plus RVd as well as the addition of daratumumab plus KRd. In addition to daratumumab, we’ve seen 3 drug backbone regimens like KRd with Isatuximab and the second anti-CD38 antibody approved for myeloma approved in the relapse setting.

Key opinion leader in hematology Jonathan L. Kaufman, MD, discusses standard treatment options for newly diagnosed multiple myeloma in transplant and nontransplant treatment settings.

Standard Induction Therapy in Newly Diagnosed MM

The first thing that we do for the patient with newly diagnosed disease is make the determination: does the patient have symptomatic disease or not? In this case, the patient clearly had symptomatic disease; he had hypercalcemia, lytic bone disease, anemia, and mild kidney renal insufficiency. The next question we ask is: is the patient a candidate for transplant? This patient was not a candidate for transplant; it is primarily based on a combination of age and poor performance status. We have not formally evaluated the patient’s cardiac function, lung function and liver function; however, those are additional things that we would consider whether the patient is a transplant candidate or not. Then once we identify whether the patient is a transplant candidate or not, then we have a series of decisions of what treatment options are available. The other important thing for this patient is he was clearly very symptomatic from myeloma. It's important that we institute a highly effective therapy to not only get control of the myeloma, but to also improve his performance status. When we consider treatments for this patient, we want to consider treatments that not only have good long-term outcomes, but also have very high and rapid response rates.

From a comorbidity standpoint, it's important to understand a patient's underlying cardiac function, liver function and renal function in order to make the best treatment; particularly to help us determine whether the patient is a transplant candidate or not. In a patient who is 79 years old, those patients are not likely going to be transplant candidates. Let's say this patient was 71 or 72 years old; understanding those other comorbidities would really help us make decisions whether the patient was a transplant candidate or not.

When we think about decision making, we do use at age as well as performance status, particularly ECOG [Eastern Cooperative Oncology Group] performance status. When we make decisions, age is probably the least important decision. When we talk about patients in their late 70s/early 80s, those patients are never going to be transplant candidates. We treat them in regimens that are not used in preparation for transplant. More importantly, in making decisions for older patients, is their performance status. In a patient in their early or mid-70s or late 60s where they may or may not be a transplant candidate, it’s really important that understanding what their performance status is. When we think about performance status, I really think about not only the performance status of how their myeloma is making them sick, but what were they like 6 months before the diagnosis of myeloma? When we think about that, especially for our patients between 65 to 80 years old, if their performance status was excellent and their performance status is only limited because of myeloma, I often will treat those patients as transplant candidates; that they will be transplant candidates once we get the myeloma under control. This contrasts with the patient who gets diagnosed, whose has a poor performance status; not because of active myeloma, but because of other comorbidities.

When we think about newly diagnosed disease and making decisions, we have to think about the individual patient; what's the current symptom burden of the patient? What are the kidney functions of the patient? Does the patient have baseline neuropathy that would help make decisions? What's the risk status of the patient? We put all of these questions into the decision-making. The disease characteristics, ie, risk, patient characteristics, ie, comorbidities, and then how the disease is affecting the body. Those are the clinical features; just like in this case where the clinical features are prominent with anemia, hypercalcemia, and painful bone disease.

An expert hematologist discusses factors to consider when determining a treatment approach in newly diagnosed multiple myeloma including symptom burden, comorbidities, age, and ECOG performance status.

Treatment Considerations for Newly Diagnosed MM

Today I'll be presenting a patient with newly diagnosed [multiple] myeloma who is not a transplant candidate. He is a 75-year-old man who presented with worsening fatigue on exertion, pallor, and hip pain. He has a past medical history of osteoarthritis. When we saw him, he appeared to be tired, had poor hand grip strength, and mild tenderness to palpation of his left hip. His ECOG performance status was 2; he had to spend some part of the day resting because of these new symptoms.

Upon laboratory evaluation, he was found to be anemic with a hemoglobin of 9.8 g/dL. His calcium was elevated with a corrected calcium 11.9 mg/dL. LDH [lactate dehydrogenase] was elevated at 295 U/L. Creatinine was modestly elevated at 1.4 mg/dL. Albumin was preserved at 3.7 g/dL and creatinine clearance was measured at approximately 50 ml/minute. His peripheral smear showed Rouleaux formation. Beta 2 microglobulin was modestly elevated at 5.1 mcg/mL, and his M protein was 2.2 g/dL. His free lambda light chain was 0.6 mg/dL and his free Kappa light chain was 14.3 mg/dL, for an elevated kappa lambda ratio of 29. FISH [fluorescence in situ hybridization] testing revealed hyperdiploidy. Urine protein electrophoresis revealed 400 mg of a Kappa light chain in a 24-hour urine.

His PET [positron emission tomography] scan revealed lytic bone lesions, including FDG avidity in his left hip. Bone marrow biopsy revealed 50% to 60% plasma cells that were IgG Kappa; he [received a diagnosis of] myeloma. His ISS [International Staging System] stage was ISS stage 2, and his revised ISS stage was ISS stage 2. He'd be considered a standard risk myeloma. He was considered not a candidate for transplant; based on his age, which was the least important of the 3 comorbidities, which were moderate, but mostly performance status. This patient was initiated on therapy with the combination of daratumumab, lenalidomide and Dexamethasone.

The patient's prognosis at diagnosis is dependent on his stage and risk status as well as fitness. We likely put him based on his performance status and symptoms in the frail category. He doesn't have high-risk myeloma by revised ISS stage or by FISH, however he does have ISS and revised ISS stage 2 myeloma and an elevated LDH; he is frail. His prognosis is relatively poor, but not as bad as a biologically high-risk patient.

Jonathan L. Kaufman, MD reviews the case of a 75-year-old man with multiple myeloma by discussing the patient’s presentation, clinical workup, and initial prognosis. 

Jonathan L. Kaufman, MD | Authors

Articles

Unmet Needs and the Future of Multiple Myeloma

Treatment Options for Relapsed Multiple Myeloma

Updates from Recent Clinical Trials in Multiple Myeloma

Standard Induction Therapy in Newly Diagnosed MM

Treatment Considerations for Newly Diagnosed MM

Case Overview: A 75-Year-Old Man with Multiple Myeloma