In a recent Amgen-sponsored Multiple Myeloma Expert Forum in July 2021, Professor Sagar Lonial (Department of Hematology and Medical Oncology, Chief Medical Officer, Winship Cancer Institute, Emory University School of Medicine, Georgia) presented his insights into the management of multiple myeloma (MM) in older and frail patients. Here are some highlights from his talk.

How do we define ‘older’ in MM?

Professor Lonial explained that “biological age is no longer sufficient” when categorising patients with MM. He noted patients tend to be categorised into three groups:

• Younger – typically under 70 years of age
• Older – typically 70-77 years of age
• Frail – typically older than 78 years of age

However, he pointed out that the best distinguisher of older versus younger patients is “performance status, not the numerical age”.

Why approach older patients differently?

In general terms, Professor Lonial described older patients as “more sensitive to toxicity due to their lower physical reserve.” Professor Lonial felt that effective therapy in these patients should give “a high response rate, not have severe toxicity and ultimately improve survival compared to standard comparators”.

When looking at the 10-year relative survival rates,¹ Professor Lonial noted that “the group that seems to have gained the greatest benefit from all the new drugs we have available now is the younger population, whereas patients over the age of 70 have not really seen that kind of longevity improvement in overall survival (OS)”.¹  With this in mind, he described evidence demonstrating that a Complete Response (CR) was associated with longer progression-free survival (PFS) and OS in elderly patients.² Professor Lonial’s take-away was that “despite the speed with which they achieve CR may be slower, as you’re going a little bit more gently – using less dose intensity with elderly patients – but the endpoint of trying to get patients to a deep response should be the same”.

Evidence for changing the treatment regimen

The FIRST trial “was the first trial that changed the line of therapy in the context of frail older patients”, noted Professor Lonial. This phase III trial compared continuous Rd vs Rd18 vs MPT in newly diagnosed MM patients ineligible for transplant. It showed that you didn’t have to have an alkylator in the induction therapy for an older, frailer patient,³ and for Professor Lonial “was the end of melphalan and prednisone-based approaches, because what you saw was that Rd and Rd18 did as well, if not better, in terms of PFS as melphalan, prednisone or MPT.³ This was an important trial to let us put alkylators by the wayside”.

This was further supported by a number of studies showing treatment efficacy of regimens that do not contain alkylators. Professor Lonial highlighted key efficacy data from these studies to showcase the benefits achievable with novel treatments such proteosome inhibitors, immunomodulatory drugs and/or monoclonal antibodies:

• SWOG S0777 – VRd vs Rd in newly diagnosed MM without intent for immediate ASCT, highlighting efficacy in patients aged ≥65 years.^4,5
  • In an updated analysis of this study published in 2020⁵ (n= 460) with median follow-up of 84 months, median OS was 65 months for VRd and 56 months for Rd (HR 0.769; 96% CI, 0.520 – 1.138: P=0.168).
• Evaluation of VRd-lite – A Phase II study in ASCT ineligible patients over the age of 65 years evaluated of modified VRd treatment, finding that it was well-tolerated and continued to be highly effective in this population, with robust PFS and OS.⁶
  • The modified regimen includes 9 x 35-day cycles of lenalidomide 15 mg (Days 1-21), bortezomib 1.3 mg/m²/wk SC (Days 1, 8, 15, 22) and dexamethasone 20 mg orally day of and after bortezomib. This is followed by 6 cycles of consolidation with lenalidomide and bortezomib.
  • Median age at study entry was 73 years (range 65 – 91)
  • Median PFS: 35.1 months (95% CI, 30.9 – ∞)
  • Median OS: not reached at a median follow-up of 30 months
• ALCYONE and MAIA: Pooled analysis of impact of MRD-negative status on patients over the age of 65 years (or transplant ineligible due to coexisting morbidities) and treated with daratumumab + Rd (MAIA) or daratumumab + VMP (ALCYONE), highlighting the importance of MRD negativity in all patients⁷
  • The addition of daratumumab induced higher rates of MRD-negativity: DRd 28.8% vs Rd 9.2%, p<0.0001; D-VMP 28.3% vs VMP 7.0%, p<0.0001
  • MRD-negative patients had improved PFS vs MRD-positive patients, irrespective of treatment

Frailty assessment the key to determining optimal approach

Professor Lonial summarised his talk by saying we “really need to better define what optimal treatments should include independent of age alone, which includes a better definition of what frailty is.” He also reminded the audience that “even if patients don’t appear frail, their physical reserve may limit how they handle intense treatment”. While Professor Lonial expressed the belief that “monoclonal antibody-based induction treatments appear to allow us to give more treatment without as much toxicity, risk adaptation remains an issue requiring more research”.

ASCT=autologous stem cell transplant; CI=confidence interval; DRd=daratumumab, lenalidomide, dexamethasone; D-VMP=daratumumab, bortezomib, melphalan, prednisone; HR=hazard ratio; MRD=minimal residual disease; MPT=melphalan, prednisone and thalidomide; ORR=overall response rate; Rd=lenalidomide, dexamethasone; Rd18=18 cycles of Rd; VMP=bortezomib, melphalan, prednisone; VRd=bortezomib, lenalidomide, dexamethasone.

References:

1. Brenner H, et al. Blood 2008;111:2521-26.
2. Gay F, et al. Blood 2011;117:3025-3031.
3. Facon T, et al. Blood 2018; 131(3):301–310.
4. Durie, BGM, et al. Lancet 2017;389(10068):519-527.
5. Durie, BGM, et al. Blood Cancer J. 2020; 10(5):53
6. O’Donnell EK, et al. Br J Haematol 2018;182(2):222-230.
7. San Miguel JF, et al. ASH 2020; Session 653:Abstract 2317.